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

Abstract

The invention provides novel fluorinated cyclic derivatives of sulfonamides and sulfones, and compositions and methods of preparation and use thereof, that are useful in treating various diseases and disorders related to TRPML activities such as neurodegenerative diseases, lysosome storage diseases, muscular dystrophy, age-related common neurodegenerative diseases, oxidative stress or reactive oxygen species (ROS) related diseases, aging, etc.

Description

FLUORINATED CYCLIC DERIVATIVES OF SULFONAMIDES AND SULFONES,AND COMPOSITIONS AND METHODS THEREOFPriority Claims and Related Patent Applications

[0001] This application claims the benefit of priority from U.S. Provisional Application Serial Nos. 63 / 460,744, filed on April 20, 2023, and 63 / 546,566, filed on October 31, 2023, the entire content of each of which is incorporated herein by reference in its entirety.Technical Field of the Invention

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

[0003] The lysosome, the cell’s recycling center, can mediate the degradation of a variety of biomaterials (proteins, lipids, and membranes) into smaller molecules or building blocks, which will be subsequently transported out of lysosomes for re-utilization or energy (see, e.g., de Duve 2005 Nat Cell Biol 7(9): 847-9; Parkinson-Lawrence, el al. 2010 Physiology (Bethesda) 25(2): 102-15). Problems in either the degradation step (due to lack of hydrolytic enzymes) or the transport step may lead to lysosome storage (of accumulated materials) and more than 50 human diseases collectively called lysosome storage diseases (LSDs). Lysosome storage can in turn affect lysosomal degradation and membrane transport / trafficking, making a positive feedback loop and a vicious cycle. Because lysosome storage is also seen in common neurodegenerative diseases such as Alzheimer’s and Parkinson’s, understanding the mechanisms underlying the positive feedback loop may provide therapeutic approaches not only for LSDs, but also forcommon sporadic neurodegenerative diseases. A lysosome-localized Ca2+channel, TRPML1 , has been recently identified as a key regulator of most membrane trafficking processes in the lysosome. Human mutations of TRPML1 cause lysosomal trafficking defects, lysosome storage, and neurodegenerative and retinal diseases.

[0004] TRPML1 (also abbreviated as ML1), a member of the TRP-type Ca2+channel superfamily, is the principle Ca2+channel in the lysosome (see, e.g., Cheng, etal. 2010 FEBS Lett 584(10): 2013-21). Loss-of-function mutations in the human TRPML1 gene cause Type IV Mucolipidosis (ML4), a lysosome storage neurodegenerative disease. TRPML1 (abbreviated as ML1- / -) skin fibroblasts from ML4 patients are characterized by the accumulation of enlarged endosomal / lysosomal compartments (vacuoles) in which lipids and other biomaterials build up, suggestive of trafficking defects. Analyses of trafficking kinetics suggest that the primary defects are in the late endocytic pathways. First, ML1 is likely required for the formation of transport vesicles from the late endosome and lysosome (LEL) to the Trans-Golgi Network (TGN) (LEL- to-TGN retrograde trafficking). Second, fusion of lysosomes with the plasma membrane (referred to as lysosomal exocytosis), a process that is important in cellular waste elimination, membrane repair, and phagocytosis, is defective in ML4 cells. Defects in either of these trafficking steps could lead to lysosome storage. Because the release of Ca2+from lysosomes (lysosomal Ca2+release) is essential for both trafficking steps, it is hypothesized that ML1 is indeed the Ca2release channel that regulates lysosomal trafficking.

[0005] PI(3,5)P2, a low-abundance phosphoinositide, is the primary activator of ML1 and a positive regulator of lysosomal trafficking. Both TRPML1 -lacking and PI(3,5)P2-deficient cells exhibit defects in LEL-to-Golgi retrograde trafficking and autophagosome-lysosome fusion, suggesting that the TRPML1-PI(3,5)P2system represents a common signaling pathway essential for late endocytic trafficking.

[0006] Due to the function of lysosome in lysosomal trafficking, lysosomes are required for quality-control regulation of mitochondria, the “power house” of the cell and the major source of endogenous ROS (reactive oxygen species). Damaged mitochondria causes oxidative stress, which is a common feature of most LSDs, neurodegenerative diseases, and aging (Xu, et al.2015 Anna Rev Physiol 77, 57-80). Recent studies suggest that mitochondria are localized in close physical proximity to lysosomes (Elbaz-Alon, et al. 2014 Dev Cell 30, 95-102; Li, et al. 2015 Cell Mol Neurobiol 35, 615-621). Hence, the lysosomal membrane is potentially anaccessible and direct target of ROS signaling. Given that ROS reportedly regulates ion channels (Bogeski, et al. 2014 Antioxid Redox Signal 21, 859-862), it is possible that lysosomal conductances, particularly through lysosomal Ca21channels such as TRPML 1, may mediate ROS -regulation of lysosomal function. Indeed, electrophysiological studies revealed that whole- endolysosome TRPML1 currents were directly activated by ROS.

[0007] A regulatory imbalance can result in elevated ROS levels and oxidative stress, which are believed to underlie a variety of 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). Given the role of TRPML1 in mediating ROS-induced autophagy, a TRPML1 agonist might be able to clear the excessive ROS, thereby ameliorating the ROS related diseases and aging, especially photo aging in the skin.

[0008] Transcription factor EB (TFEB) regulates autophagy and lysosome biogenesis. Overexpression of TFEB has been reported to induce cellular clearance in a number of lysosome storage diseases, including Pombe Disease, Cystinosis, multiple sulfatase deficiency, as well as neurodegenerative diseases, including Parkinson’s disease and Huntinton’s disease (Settembre, etal., 2013 Nat Rev Mol Cell Biol 14(5), 283-96). Therefore, activation of TRPML1 by TRPML1 agonists may also lead to cellular clearance in all the aforementioned diseases, providing therapeutic targets for these devastating diseases.

[0009] Previously a potent synthetic agonist for TRPML1 has been reported (Shen, et al. 2012 Nat Commun 3, 731). This SF-51 -related compound (Mucolipin Synthetic Agonist 1 or ML- SA1) could induce significant [Ca2+]cytincreases in HEK293 cells stably or transiently expressing ML1-4A. In electrophysiological assays, ML-SA1 robustly activated whole-cell IMLI-4Δand whole-endolysosome ML1 . ML-SA1 also activated whole-cell / TRPML2and / TRPML3, but not six other related channels. ML-SA1 (10 pM) activation of whole-endolysosome IML1 was comparable to the effect of the endogenous TRPML agonist PI(3,5)P2(IpM), and these agonists were synergistic with each other. ML-SA1 activated an endogenous whole-endolysosome TRPML-like current (ZML-L) in all mammalian cell types that were investigated, including Chinese Hamster Ovary (CHO), Cos-1, HEK293, skeletal muscle, pancreatic β and macrophage cells. ML-SA1 activated whole-endolysosome IML- Lin wild-type (WT; ML I ), but not ML4 (ML1- / -) human fibroblasts, suggesting that although ML-SA1 targets all three TRPMLs, the expression levels of TRPML2 and TRPML3 are very low, and TRPML 1 is the predominantlysosomal TRPML channel in this cell type. These results suggest that ML-SA1 is a reasonably specific and potent agonist that can be useful for modulating the functions of TRPMLs.

[0010] High concentration of ML-SA1 (~10 pM) is needed to effectively activate TRPMLs. Since that concentration is usually difficult to achieve in vivo, ML-SA1 cannot be used to treat the above TRPML-related diseases. Recently, a number of more potent TRPML1 agonists have been developed. (See, e.g., WO2022076383A1). However, most of these potent agonists are highly hydrophobic molecules that are either metabolically labile and / or have or very limited brain penetrance, which in turn leads to poor oral bioavailability and limited exposure in diseased organs, especially in the brain.

[0011] There is an urgent need for orally bioavailable, highly brain-penetrant, and potent TRPML activators, in particular, compounds that are useful in treating disorders related to TRPML activities such as neurodegenerative diseases, lysosome storage diseases, muscular dystrophy, ROS or oxidative stress related diseases, metabolic diseases, metastatic cancer, and aging.Summary of the Invention

[0012] The invention is based in part on novel fluorinated cyclic derivatives of sulfonamides and sulfones, pharmaceutical compositions thereof and methods of their preparation and use in treating or reducing various diseases or disorders. In particular, compounds, compositions and methods of the invention are useful in treating diseases or disorders mediated by or associated with TRPMLs.

[0013] In one aspect, the invention generally relates to a compound having the structure of formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 9-membered carbocycle, or heterocycle substituted with 1-8 F’s;Ring B is a substituted or unsubstituted phenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, or thiophene, or a substituted or unsubstituted bi- or multi-cyclic carbocyclic or heterocyclic ring system;P is CH, N or CR2;Q is CH, N or CR2;U is C or N;V is C or N;W is CH, N, C(=O), C(=S) or CRW1RW2, wherein each of RW1and RW2is independently H or C1-6alkyl;X is C or N;Y is C, CRYor N, wherein RYis H, F or C1-6alkyl;R1is selected from the group consisting of F, CHF2, -CF3, -CH2CF3, CF2CH3, CF2CH2F, CF2CHF2, -CF(CH3)2, -OCF3and -OCH(CH3)2; each R2is independently selected from the group consisting of halogen, unsubstituted or substituted C1-6alkyl and C1-6alkoxy, OH, CN, NRR , N(R)C(=O)RR , C(=O)R and C(=O)NRR’; each R3is independently selected from the group consisting of halogen, CN, CF3, C1-5alkyl, C3-7cycloalkyl and heterocyclic; each of R and R is independently H, or C1-6alkyl or cycloalkyl, optionally, R and R , together with the nitrogen or carbon atom to which they are attached, form a 3 - to 6-membered ring, each optionally substituted with 0-3 substituents independently selected from the group consisting of C1-3alkyl, halogen, OH, O C1-3alkyl and CN; m is 0, 1, 2, 3 or 4;n is 1 , 2, 3, 4, 5, 6, 7 or 8; and i is 0, 1 or 2.

[0014] In another aspect, the invention generally relates to a pharmaceutical composition comprising a compound disclosed herein.

[0015] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition that comprises a compound disclosed herein.

[0016] In yet another aspect, the invention generally relates to a method for treating or reducing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0017] In yet another aspect, the invention generally relates to a method for treating or reducing the effect of aging comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0018] In yet another aspect, the invention generally relates to a method for treating or reducing oxidative stress or ROS related diseases or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a TRPML1 agonist or a composition comprising of a TRPML1 agonist disclosed herein.

[0019] In yet another aspect, the invention generally relates to a method for treating or reducing oxidative stress or ROS related diseases or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0020] In yet another aspect, the invention generally relates to use of a compound disclosed herein, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.Definitions

[0021] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. General principles of organic chemistry, as well as specific functional moieties and reactivity, are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 2006.

[0022] The following terms, unless indicated otherwise according to the context wherein the terms are found, are intended to have the following meanings.

[0023] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 16 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

[0024] Any compositions or methods disclosed herein can be combined with one or more of any of the other compositions and methods provided herein.

[0025] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0026] Definitions of specific functional groups and chemical terms are described in more detail below. When a range of values is listed, it is intended to encompass each value and sub- range within the range. For example, “C1-6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6alkyl. Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -C(=O)-O- is equivalent to -O-C(=O)-.

[0027] Structures of compounds of the invention are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds that are not inherently unstable and / or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions (e.g., aqueous, neutral, and several known physiological conditions).

[0028] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural reference, unless the context clearly dictates otherwise.

[0029] As used herein, “at least” a specific value is understood to be that value and all values greater than that value.

[0030] 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 recited 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 includethe recited elements and exclude other elements of any essential significance to the compositions and methods. For example, “consisting essentially of’ refers to administration of the pharmacologically active agents expressly recited and excludes pharmacologically active agents not expressly recited. The term consisting essentially of does not exclude pharmacologically inactive or inert agents, e.g., pharmaceutically acceptable excipients, carriers or diluents. The term “consisting of’, when used to define compositions and methods, shall mean excluding trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.

[0031] As used herein, the terms “disease” and “disorder” are used interchangeably and refer to any condition that damages or interferes with the normal function of a cell, tissue, or organ.

[0032] As used herein, the term “hydrate” means a compound which further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0033] As used herein, the term "pharmaceutically acceptable” refers to being suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable form" of a disclosed compound includes, but is not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, polymorphs, isomers, prodrugs, and isotopically labeled derivatives thereof. In one embodiment, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable salts, esters, prodrugs and isotopically labeled derivatives thereof. In some embodiments, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable isomers and stereoisomers, prodrugs and isotopically labeled derivatives thereof.

[0034] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids andbases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bi sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-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, valerate salts, and the like. In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoracetic 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, salicylic acid, and the like.

[0035] The salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, such as by reacting the free base or free acid of a parent compound with a suitable base or acid, respectively. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. 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, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, tri ethyl amine, tripropylamine,and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt can be chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0036] In certain embodiments, the pharmaceutically acceptable form is a "solvate" (e.g., a hydrate). As used herein, the term "solvate" refers to compounds that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate can be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 1 to about 100, or 1 to about 10, or 1 to about 2, about 3 or about 4, solvent or water molecules. It will be understood that the term "compound" as used herein encompasses the compound and solvates of the compound, as well as mixtures thereof.

[0037] In certain embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term "prodrug" (or “pro-drug”) refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug can be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood). In certain cases, a prodrug has improved physical and / or delivery properties over the parent compound. Prodrugs can increase the bioavailability of the compound when administered to a subject (e.g., by permitting enhanced absorption into the blood following oral administration) or which enhance delivery to a biological compartment of interest (e.g., the brain or lymphatic system) relative to the parent compound. Exemplary prodrugs include derivatives of a disclosed compound with enhanced aqueous solubility or active transport through the gut membrane, relative to the parent compound.

[0038] The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7- 9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium 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 in full by reference herein. Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pHcompared to the parent compound, or it can enhance absorption from the digestive tract, or it can enhance drug stability for long-term storage.

[0039] Prodrugs commonly known in the art include well-known acid derivatives, such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, amides prepared by reaction of the parent acid compound with an amine, basic groups reacted to form an acylated base derivative, etc. Of course, other prodrug derivatives may be combined with other features disclosed herein to enhance bioavailability. As such, those of skill in the art will appreciate that certain of the presently disclosed compounds having free amino, arnido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of the presently disclosed compounds. The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include 4- hydroxyproline, hydroxylysine, demosine, isodemosine, 3 -methylhistidine, norvalin, beta- alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds having a carbonate, carbamate, amide or alkyl ester moiety covalently bonded to any of the above substituents disclosed herein.

[0040] Particularly favored prodrugs and prodrug salts are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or central nervous system) relative to the parent species. Examples of prodrugs include derivatives where a group that enhances aqueous solubility or active transport through the gut membrane is appended to the structure of formulae described herein. (See, e.g., Alexander, et al. 1988 J Med Chem 31, 318-322; Bundgaard, et al. 1985 Elsevier: Amsterdam 1-92; Bundgaard, et al. 1987 J Med Chem 30, 451-454; Bundgaard, H. A Textbook of Drug Design and Development; Harwood Academic Publ.: Switzerland, 1991, 113-191; Digenis, et al. Handbook of Experimental Pharmacology 1975, 28, 86-112; Friis, et al. Textbook of Drug Design and Development; 2 ed.; Overseas Publ.: Amsterdam, 1996, 351-385; Pitman 1981 Medicinal Research Reviews 1, 189-214.)

[0041] As used herein, the term “pharmaceutically acceptable” excipient, carrier, or diluent refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve 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 carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; 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; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymer as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0042] As used herein, the term “polymorph” means solid crystalline forms of a compound or complex thereof which may be characterized by physical means such as, for instance, X-ray powder diffraction patterns or infrared spectroscopy. Different polymorphs of the same compound can 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 in formulation and product manufacturing), hygroscopicity, solubility, and dissolution rates (which can affect bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical characteristics (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). Differentphysical properties of polymorphs can affect their processing. For example, one polymorph might be more likely to form solvates or might be more difficult to filter or wash free of impurities than another due to, for example, the shape or size distribution of particles of it. As used herein, the term “solvate” means a compound which further includes a stoichiometric or non-stoichiometric amount of solvent such as water, acetone, ethanol, methanol, di chloromethane, 2-propanol, or the like, bound by non-covalent intermolecular forces.As used herein, the term “stable compounds” refers to compounds which possess stability sufficient to allow manufacture and which maintain 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 production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or disorder responsive to therapeutic agents).

[0043] As used herein, the term “stereoisomer” refers to both enantiomers and diastereomers. As used herein, the term “substantially free of other stereoisomers” means less than 25% of other stereoisomers, preferably less than 10% of other stereoisomers, more preferably less than 5% of other stereoisomers and most preferably less than 2% of other stereoisomers, or less than "X"% of other stereoisomers (wherein X is a number between 0 and 100, inclusive) are present. Methods of obtaining or synthesizing diastereomers are well known in the art and may be applied as practicable to final compounds or to starting material or intermediates. Other embodiments are those wherein the compound is an isolated compound. The term “at least X% enantiomerically enriched” as used herein means that at least X% of the compound is a single enantiomeric form, wherein X is a number between 0 and 100, inclusive.

[0044] As used herein, the terms “treatment” or “treating” a disease or disorder refers to a method of reducing, delaying or ameliorating such a condition before or after it has occurred. Treatment may be directed at one or more effects or symptoms of a disease and / or the underlying pathology. The treatment can be any reduction and can be, but is not limited to, the complete ablation of the disease or the symptoms of the disease. Treating or treatment thus refers to any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving or stabilizing a patient's physical or mental well-being. The treatment or ameliorationof symptoms can be based on objective or subjective parameters, for example, the results of a physical examination, neuropsychiatric exams, and / or a psychiatric evaluation. As compared with an equivalent untreated control, such reduction or degree of amelioration may be at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% as measured by any standard technique.

[0045] As used herein, the terms "alk" or "alkyl" refer to straight, branched or cyclic hydrocarbon groups having 1 to 12 carbon atoms containing no unsaturation. Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer in the given range; e.g., "1 to 10 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, “alkyl” can be a C1-6alkyl group. In some embodiments, “alkyl” can be a C1-3alkyl group.

[0046] As used herein, the term "alkenyl" refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having at least one double bond. Where an alkenyl group is bonded to a nitrogen atom, it is preferred that such group not be bonded directly through a carbon bearing a double bond.

[0047] As used herein, the term “alkoxy” refers to an -O-alkyl radical.

[0048] As used herein, the term "alkynyl" refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having at least one triple bond. Where an alkynyl group is bonded to a nitrogen atom, it is preferred that such group not be bonded directly through a carbon bearing a triple bond.

[0049] As used herein, the term "alkylene" refers to a divalent straight chain bridge of 1 to 5 carbon atoms connected by single bonds (e.g., -(CH2)X-, wherein x is 1 to 5), which may be substituted with 1 to 3 lower alkyl groups.

[0050] As used herein, the term "alkenylene" refers to a straight chain bridge of 2 to 5 carbon atoms having one or two double bonds that is connected 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-.

[0051] As used herein, the term "alkynylene" refers to a straight chain bridge of 2 to 5 carbon atoms that has a triple bond therein, is connected by single bonds, and may be substituted with 1to 3 lower alkyl groups. Exemplary alkynylene groups are -C=C-, -CH2-C=C-, -CH(CH3)C=C- and -C=C-CH(C2H5)CH2-.

[0052] As used herein, the term “arylalkyl” refers to a moiety in which an alkyl hydrogen atom is replaced by an aryl group.

[0053] As used herein, the terms “cycloalkyl” and "cycloalkenyl" as employed herein includes saturated and partially unsaturated cyclic, respectively, hydrocarbon groups having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbon.

[0054] As used herein, the terms “aromatic”, “ar” or “aryl” refer to a radical with 6 to 14 ring atoms (e.g., Ce-i4 aromatic or Ce-i4 aryl) that has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, naphthyl, and anthracene). An aryl group may be, for example, 6 membered monocyclic, 10 membered bicyclic or 14 membered tricyclic ring systems, each with 6 to 14 carbon atoms.

[0055] As used herein, the term “halo” or "halogen" refers to any radical of fluorine, chlorine, bromine or iodine.

[0056] As used herein, the terms “carbocycle”, “carbocyclic” and “carbocyclyl” each refers to a monocyclic or polycyclic radical that contains only carbon as ring atoms, and can be saturated or partially unsaturated. Fully saturated carbocyclic is termed cycloalkyl. Partially unsaturated cycloalkyl groups can be termed "cycloalkenyl" if the carbocycle contains at least one double bond, or "cycloalkynyl" if the carbocycle contains at least one triple bond. Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted carbocyclic groups. The term "carbocyclic" also includes bridged and spiro-fused cyclic structures containing no hetero ring atoms. The term also includes monocyclic or fused-ring polycyclic (z.e., rings which share adjacent pairs of ring atoms) groups. Polycyclic groups include bicycles, tricycles, tetracycles, and the like. Unless stated otherwise in the specification, a carbocyclic group can be optionally substituted by one or more substituents.

[0057] As used herein, the term "heteroaiyl" or, alternatively, "heteroaromatic" refers to a refers to a radical of a 5-18 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic, tetracyclic and the like) aromatic ring system (e.g., having 6, 10 or 147t electrons shared in a cyclic array) having ring carbon atoms and 1-6 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous and sulfur ("5-18 membered heteroaryl"). Heteroaryl polycyclic ring systems can include one ormore heteroatoms in one or both rings. Whenever it appears herein, a numerical range such as "5 to 18" refers to each integer in the given range; e.g., "5 to 18 ring atoms" means that the heteroaryl group can consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. In some instances, a heteroaryl can have 5 to 14 ring atoms. In some embodiments, the heteroaryl has, for example, bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl" by removal of one hydrogen atom from the atom with the free valence are named by adding "-ene" to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylene. The term “heteroaryl”, for example, may refer to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, and, in addition, having a completely conjugated pi-electron system, wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples, without limitation, of heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, quinazoline, isoquinoline, purine and carbazole.

[0058] As used herein, the terms "heterocycle", "heterocyclic" or "heterocyclyl" refer to fully saturated or partially unsaturated cyclic groups, for example, 3 to 7 membered monocyclic, 7 to 12 membered bicyclic, or 10 to 15 membered tricyclic ring systems, which have at least one heteroatom in at least one ring, wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and / or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system.

[0059] As used herein, the term “oxo” refers to an oxygen atom, which forms a carbonyl when attached to carbon, an N-oxide when attached to nitrogen, and a sulfoxide or sulfone when attached to sulfur.

[0060] As used herein, the term “substituents” refers to a group “substituted” on any functional group delineated herein, e.g., alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, or heteroaryl group at any atom of that group. Suitable substituents include, without limitation halogen, CN, NO2, OR15, SR15, S(O)2OR15, NR15R16, C1-C2perfluoroalkyl, C1-C2perfluoroalkoxy, 1 ,2-methylenedioxy, C(O)OR13, C(O)NR15R16, OC(O)NR15R16, NR15C(O)NR15R16, C(NR16)NR15R16, NR15C(NR16)NR15R16, S(O)2NR15R16, R17, C(O)R17, NR15C(O)R17, S(O)R17, S(O)2R17, R16, OXO, C(O)R16, C(O)(CH2)mOH, (CH2)nOR15, (CH2)mC(O)NR15R16, NR15S(O)2R17, where m is independently 0-6 inclusive. Each R13is independently hydrogen, C1-C4alkyl or C3-C6cycloalkyl. Each R16is independently hydrogen, alkenyl, alkynyl, C3-C6cycloalkyl, aryl, heterocyclyl, heteroaryl, C1-C4alkyl or C1-C4alkyl substituted with C3-C6cycloalkyl, aryl, heterocyclyl or heteroaryl. Each R17is independently C3-C6cycloalkyl, aryl, heterocyclyl, heteroaryl, C1-C4alkyl or C1-C4alkyl substituted with C3-C6cycloalkyl, aryl, heterocyclyl or heteroaryl. Each C3-C6cycloalkyl, aryl, heterocyclyl, heteroaryl and C1-C4alkyl in each R15, R16and R17can optionally be substituted with halogen, CN, C1-C4alkyl, OH, C1-C4alkoxy, NH2, C1-C4alkylamino, C1-C4dialkylamino, C1- C2perfluoroalkyl, C1- C2perfluoroalkoxy, or 1,2-methylenedioxy.

[0061] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0062] The compounds of this invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention. The compounds of this invention may also be represented in multiple tautomeric forms, in such instances, the invention expressly includes all tautomeric forms of the compounds described herein. All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.Detailed Description of the Invention

[0063] The invention provides novel fluorinated cyclic derivatives of sulfonamides and sulfones, including salts, solvates, hydrates and polymorphs thereof, as TRPML modulators. The invention also provides pharmaceutical compositions comprising a compound of this invention and the use of such compositions in treating a range of diseases and conditions associated with TRPML or related to TRPML activities, such as neurodegenerative diseases, lysosome storagediseases, muscular dystrophy, ROS or oxidative stress related diseases, and damages caused in skin or photoaging.

[0064] In one aspect, the invention generally relates to a compound having the structure of formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 9-membered (e.g., 4-, 5-, 6-, 7-, 8- or 9-membered) carbocycle or heterocycle substituted with 1-8 F’s;Ring B is a substituted or un substituted phenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, or thiophene, or a substituted or unsubstituted bi- or multi-cyclic carbocyclic or heterocyclic ring system;P is CH, N or CR2;Q is CH, N or CR2;U is C or N;V is C or N;W is CH, N, C(=O), C(=S) or CRW1RW2, wherein each of RW1and RW2is independently H or C1-6alkyl;X is C or N;Y is C, CRYor N, wherein RYis H, F or C1-6alkyl;R1is selected from the group consisting of F, CHF2, -CF3, -CH2CF3, CF2CH3, CF2CH2F, CF2CHF2, -CF(CH3)2, -OCF3and -OCH(CH3)2; each R2is independently selected from the group consisting of halogen, unsubstituted or substituted C1-6alkyl and C1-6alkoxy, OH, CN, NRR , N(R)C(=O)RR , C(=O)R and C(=O)NRR’; each R3is independently selected from the group consisting of halogen, CN, CF3, C1-5alkyl, C3-7cycloalkyl and heterocyclic;each of R and R is independently H, or C1-6alkyl or cycloalkyl, optionally, R and R , together with the nitrogen or carbon atom to which they are attached, form a 3 - to 6-membered ring, each optionally substituted with 0-3 substituents independently selected from the group consisting of C1-3alkyl, halogen, OH, OC1-3alkyl and CN; m is 0, 1, 2, 3 or 4; n is 1, 2, 3, 4, 5, 6, 7 or 8; and z is 0, 1 or 2.

[0065] In certain embodiments, Ring B is an unsubstituted phenyl or substituted phenyl.

[0066] In certain embodiments, z is 0 and Ring B is unsubstituted phenyl:

[0067] In certain embodiments, z is 0 and Ring B is a substituted phenyl:wherein R3is a halogen atom (e.g., F).

[0068] In certain embodiments, Ring B is an unsubstituted pyridinyl:

[0069] In certain embodiments, Ring B is a substituted or unsubstituted thiophene.

[0070] In certain embodiments, z is 0 and Ring B is a substituted or unsubstituted thiophene. In certain embodiments, Ring B is an unsubstituted thiophene:

[0071] In certain embodiments, Ring B is a substituted or unsubstituted pyrrole. In certain embodiments, Ring B is an unsubstituted pyrrole:19SUBSTITUTE SHEET (RULE 26)

[0072] In certain embodiments, Ring B is bicyclo[l.l. l]pentane:

[0073] In certain embodiments, Ring B is 2-oxabicyclo[2.2.2]octane.

[0074] In certain embodiments, Ring B is:

[0075] In certain embodiments of (I), X is N.

[0076] In certain embodiments of (I), X is N, P is CH, Q is CH, U is C and V is C:

[0077] In certain embodiments of (Ia), W is N:

[0078] In certain embodiments of (Ia), W is CH:SUBSTITUTE SHEET (RULE 26)

[0079] In certain embodiments of (I), X is C.

[0080] In certain embodiments of (I), X is C, P is CH, Q is CH, U is N, V is C and W is N:

[0081] In certain embodiments of (I)-(Ia), Y is N.

[0082] In certain embodiments of (I)-(Id), Y is C.

[0083] In certain embodiments of (I)-(Id), Y is CH.

[0084] In certain embodiments of (I)-(Id), Ring A is a 4-membered carbocyclic or heterocycle substituted with one or more F’s.

[0085] In certain embodiments of (I)-(Id), Ring A is a 5-membered carbocyclic or heterocycle substituted with one or more F’s.

[0086] In certain embodiments of (I)-(Id), Ring A is a 6-membered mono- or bicyclic carbocyclic or heterocycle substituted with one or more F’s.

[0087] In certain embodiments of (I)-(Id), Ring A is a 7-membered mono- or bicyclic carbocyclic or heterocycle substituted with one or more F’s.

[0088] In certain embodiments of (I)-(Id), Ring A is an 8-membered bicyclic carbocyclic or heterocycle substituted with one or more F’s.

[0089] In certain embodiments of (I)-(Id), Ring A is a 9-membered bicyclic carbocyclic or heterocycle substituted with one or more F’s.21SUBSTITUTE SHEET (RULE 26)

[0090] In certain embodiments of (I)-(Ia), Ring A is a heterobicycle substituted with one or more F’s.

[0091] In certain embodiments of (I)-(Ia), Ring A is substituted with two or more F’s (e.g., 2, 3, 4, 5, 6, 7 or 8 F’s).

[0092] In certain embodiments of (I)-(Ia), Ring A has a structural formula selected from:22SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)

[0093] In certain embodiments of (I)-(Ia), Ring A has a structural formula selected from:SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)

[0094] In certain embodiments of (I)-(Id), Ring A has a structural formula selected from:

[0095] In certain embodiments of (I)-(Ia), Ring A is:wherein each R4is independently D, OH, CN, or C1-2alkyl optionally substituted with 0-3 (e.g., 0, 1, 2 or 3) F’s, or two R4’s along with the carbon atom they are bound to form a 3- or 4- membered carbocyclic or heterocyclic ring, or two R4’s along with the carbon atoms they are bound to atom for a 3- to 7-membered (e.g., 3-, 4-, 5-, 6- or 7-membered) carbocyclic or heterocyclic ring; n is 1, 2, 3, 4, 5 or 6; and j is 0, 1, 2, 3 or 4.

[0096] In certain embodiments, j is 0. In certain embodiments, j is 1. In certain embodiments, j is 2. In certain embodiments, j is 3. In certain embodiments, j is 4.

[0097] In certain embodiments of (I)-(Ia), R1is CHF2.26SUBSTITUTE SHEET (RULE 26)

[0098] In certain embodiments of (I)-(Id), R1is CF2CH3.

[0099] In certain embodiments of (I)-(Id), R1is CF2CHF.

[0100] In certain embodiments of (I)-(Ia), R1is CF2CH2F2.

[0101] In certain embodiments of (I)-(Ia), R1is F.

[0102] Non-limiting examples of27SUBSTITUTE SHEET (RULE 26)

[0103] In certain embodiments, the compound has the structural formula:(M

[0104] In certain embodiments, the compound has the structural formula:

[0105] In certain embodiments, the compound has the structural formula:

[0106] In certain embodiments, the compound has the structural formula:28SUBSTITUTE SHEET (RULE 26)

[0107] In certain embodiments, the compound has the structural formula:

[0108] In certain embodiments, the compound has the structural formula:

[0109] In certain embodiments, the compound has the structural formula:

[0110] In certain embodiments, the compound has the structural formula:29SUBSTITUTE SHEET (RULE 26)

[0111] In certain embodiments, the compound has the structural formula:wherein each R4is independently C1-2alkyl optionally substituted with 0-3 (e.g., 0, 1, 2 or 3) F’s, or two R4’s along with the carbon atom they are bound to form a 3- or 4-membered carbocyclic or heterocyclic, or two R4’s along with the carbon atoms they are bound to atom for a 3 - to 6- membered (e.g., 3-, 4-, 5- or 6-membered) carbocyclic or heterocyclic ring; n is 1, 2, 3, 4, 5 or 6; and j is 0, 1, 2, 3 or 4.

[0112] In certain embodiments, the compound has the structural formula:wherein each R4is independently C1-2alkyl optionally substituted with 0-3 (e.g., 0, 1, 2 or 3) F’s, or two R4’s along with the carbon atom they are bound to form a 3- or 4-membered carbocyclic or heterocyclic, or two R4’s along with the carbon atoms they are bound to atom for a 3 - to 6- membered (e.g., 3-, 4-, 5- or 6-membered) carbocyclic or heterocyclic ring; n is 1, 2, 3, 4, 5 or 6; and j is 0, 1, 2, 3 or 4.30SUBSTITUTE SHEET (RULE 26)

[0113] In certain embodiments of (Im)-(In), each R4is independently D, OH, CN, or C1-2alkyl optionally substituted with 0-3 F’s.

[0114] In certain embodiments of (Im)-(In), two R4’s along with the carbon atom they are bound to form a 3-membered carbocyclic ring.

[0115] In certain embodiments of (Im)-(In), two R4’s along with the carbon atom they are bound to form a 4-membered carbocyclic or heterocyclic ring.

[0116] In certain embodiments of (Im)-(In), two R4’s along with the carbon atoms they are bound to atom for a 3- to 7-membered carbocyclic or heterocyclic ring.

[0117] In certain embodiments of (Ie) -(In), j is 0.

[0118] In certain embodiments of (Ie)-(In), j is 1 or 2.

[0119] In certain embodiments of (Ie)-(In), j is 3 or 4.

[0120] In certain embodiments of (Ie)-(In), j is 1 and R4is bound to a carbon atom adjacent to the N atom. In certain embodiments, R4is CF3.

[0121] In certain embodiments of (Ie)-(In), j is 2 and both R4’s are bound to a carbon atom adjacent to the N atom of Ring A. In certain embodiments, one or both of the two R4’s is a C1-3alkyl, optionally substituted with 1-5 F’s.

[0122] In certain embodiments of (Ie)-(In), j is 2 and the two R4’s, along with the carbon atom they are bound to, form a cyclopropyl group.

[0123] In certain embodiments of (Ie)-(In), j is 2 and the two R4’s along with the carbon atoms they are bound to atom for a 5- to 7-membered carbocyclic or heterocyclic ring.

[0124] In certain embodiments of (I)-(In), n is an integer selected from 1, 2, 3, 4, 5 or 6.

[0125] In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6.

[0126] In certain embodiments of (Ie)-(In), R1is CF2CH3.

[0127] In certain embodiments of (Ie)-(In), R1is CF2CH2F.

[0128] In certain embodiments of (Ie)-(In), R1is CF2CHF2.

[0129] In certain embodiments of (Ie)-(In), R1is CHF2.

[0130] In certain embodiments of (Ie)-(In), R1is F.

[0131] In certain embodiments of (I)-(In), m is 0.

[0132] In certain embodiments of (I)-(In), m is 1.31SUBSTITUTE SHEET (RULE 26)

[0133] In certain embodiments of (I)-(In), m is 2.

[0134] In certain embodiments of (I)-(In), m is 1 and R2has a positioning represented by:

[0135] In certain embodiments, R2has a positioning of:

[0136] In certain embodiments, R2is a halogen.

[0137] In certain embodiments, R2is Cl.

[0138] In certain embodiments, R2is amino, OH, Ci alkyl or alkoxy, optionally substituted with 0-3 (e.g., 0, 1, 2 or 3) F’s.

[0139] Exemplary compounds of the invention include those listed in Table 1 below.Table 1. Exemplary Compounds32SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)37SUBSTITUTE SHEET (RULE 26)38SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)

[0140] In certain embodiments, a compound disclosed herein has one or more deuterium atoms in place of one or more hydrogen atoms.

[0141] In certain embodiments, a compound disclosed herein has one deuterium atom in place of one hydrogen atom.

[0142] In another aspect, the invention generally relates to a pharmaceutical composition comprising a compound disclosed herein.

[0143] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition that comprises a compound disclosed herein.

[0144] In certain embodiments, the unit dosage is a tablet.

[0145] In certain embodiments, the unit dosage is a capsule.

[0146] In yet another aspect, the invention generally relates to a method for treating or reducing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0147] In certain embodiments, the methods disclosed herein are suitable for treating diseases or disorders that are mediated by the TRPMLs. In certain embodiments, the methods44SUBSTITUTE SHEET (RULE 26)disclosed herein are suitable for treating disease or disorders that are mediated by loss-of- function in TRPML1, e.g., type IV Mucolipidosis (ML4) and Niemann-Pick type C (NPC).

[0148] In certain embodiments, the disease or disorder is a lysosome storage disease, or a related disease or disorder.

[0149] In certain embodiments, the disease or disorder is selected from the group consisting of age-related neurodegenerative disease, e.g., Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease, Frontotemporal Dementia, or a related disease or disorder.

[0150] In certain embodiments, the disease or disorder is a neuronal ceroid lipofuscinoses (NCLs) or Batten diseases, or a related disease or disorder.

[0151] In certain embodiments, the disease or disorder is a NPC, or a related disease or disorder.

[0152] In certain embodiments, the disease or disorder is a Charcot-Marie-Tooth disease (CMT), or a related disease or disorder.

[0153] In certain embodiments, the disease or disorder is age-related macular degeneration (AMD), or a related disease or disorder.

[0154] In certain embodiments, the disease or disorder is cystic fibrosis (CF), or a related disease or disorder.

[0155] In certain embodiments, the disease or disorder is autosomal dominant polycystic kidney disease (ADPKD), or a related disease or disorder.

[0156] In certain embodiments, the disease or disorder is selected from cancers in which TRPML1 is overexpressed in cancer cells.

[0157] In certain embodiments, the disease or disorder is Batten’s diseases.

[0158] In certain embodiments, the disease or disorder is muscular dystrophy, or a related disease or disorder.

[0159] In certain embodiments, the disease or disorder is oxidative stress or ROS, or a related disease or disorder.

[0160] In yet another aspect, the invention generally relates to a method for treating or reducing the effect of aging comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0161] In certain embodiments, the effect of aging comprises skin aging.

[0162] In certain embodiments, the effect of aging comprises photoaging.45SUBSTITUTE SHEET (RULE 26)

[0163] In yet another aspect, the invention generally relates to a method for treating or reducing oxidative stress or ROS related diseases or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a TRPML1 agonist or a composition comprising of a TRPML1 agonist disclosed herein.

[0164] In yet another aspect, the invention generally relates to a method for treating or reducing oxidative stress or ROS related diseases or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0165] In certain embodiments of methods of the invention, administration to a subject is via oral administration.

[0166] In certain embodiments of methods of the invention, administration to a subject is via topical administration.

[0167] In yet another aspect, the invention generally relates to use of a compound disclosed herein, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.

[0168] In certain embodiments of the use according to the invention, the disease or disorder is an neurodegenerative disease, e.g., Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease, Frontotemporal Dementia, or a related disease or disorder.

[0169] In certain embodiments, the disease or disorder is selected from cancers in which TRPML1 is overexpressed in cancer cells.

[0170] In certain embodiments, the disease or disorder is Batten’s disease.

[0171] In certain embodiments, the disease or disorder is muscular dystrophy, or a related disease or disorder.

[0172] In certain embodiments, the disease or disorder is oxidative stress or ROS, or a related disease or disorder.

[0173] In certain embodiments, the disease or disorder is skin aging.

[0174] In certain embodiments, the disease or disorder is photoaging.

[0175] The specific approaches and compounds disclosed herein are not intended to be limiting. The chemical structures in the schemes herein depict variables that are hereby defined commensurately with chemical group definitions (moieties, atoms, etc.) of the corresponding position in the compound formulae herein, whether identified by the same variable name {e.g, R1, R2, R, R’, X, etc.) or not. The suitability of a chemical group in a compound structure for use46SUBSTITUTE SHEET (RULE 26)in synthesis of another compound structure is within the knowledge of one of ordinary skill in the art. Additional methods of synthesizing compounds of the formulae herein and their synthetic precursors, including those within routes not explicitly shown in schemes herein, are within the means of chemists of ordinary skill in the art. Methods for optimizing reaction conditions, if necessary, minimizing competing by-products, are known in the art. The methods described herein may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compounds herein. In addition, various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser ’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.

[0176] The methods delineated herein contemplate converting compounds of one formula to compounds of another formula. The process of converting refers to one or more chemical transformations, which can be performed in situ, or with isolation of intermediate compounds. The transformations can include reacting the starting compounds or intermediates with additional reagents using techniques and protocols known in the art, including those in the references cited herein. Intermediates can be used with or without purification (e.g., filtration, distillation, sublimation, crystallization, trituration, solid phase extraction, and chromatography).

[0177] Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds.

[0178] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and / ra / AS-i somers, atropisomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl47SUBSTITUTE SHEET (RULE 26)group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0179] Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90: 10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomer ratios are contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures.

[0180] If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic methods well known in the art, and subsequent recovery of the pure enantiomers.

[0181] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the present invention include, for example, hydrates.

[0182] The invention also provides compositions comprising an effective amount of a compound of any of the formulae herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or prodrug, if applicable, of said compound; and an acceptable carrier. Preferably, a composition of this invention is formulated for pharmaceutical use (“a pharmaceutical composition”), wherein the carrier is a pharmaceutically acceptable carrier. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in amounts typically used in medicaments.

[0183] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer 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,48SUBSTITUTE SHEET (RULE 26)magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0184] The pharmaceutical compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. In certain embodiments, the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch). Other formulations may conveniently be presented in unit dosage form, e.g., tablets and sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17thed. 1985).

[0185] Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers or both, and then if necessary, shaping the product.

[0186] In certain preferred embodiments, the compound is administered orally. Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, or packed in liposomes and as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.

[0187] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets optionally may be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. Methods of formulating such slow or controlled release compositions of49SUBSTITUTE SHEET (RULE 26)pharmaceutically active ingredients, such as those herein and other compounds known in the art, are known in the art and described in several issued US Patents, some of which include, but are not limited to, US Patent Nos. 4,369,172; and 4,842,866, and references cited therein. Coatings can be used for delivery of compounds to the intestine (see, e.g., U.S. Patent Nos. 6,638,534, 5,217,720, and 6,569,457, 6,461,631, 6,528,080, 6,800,663, and references cited therein). A useful formulation for the compounds of this invention is the form of enteric pellets of which the enteric layer comprises hydroxypropyl methylcellulose acetate succinate.

[0188] In the case of tablets for oral use, carriers that are commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added.

[0189] Compositions suitable for topical administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.

[0190] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

[0191] Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are50SUBSTITUTE SHEET (RULE 26)mannitol, water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

[0192] The pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

[0193] The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0194] Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can 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 esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in51SUBSTITUTE SHEET (RULE 26)a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention.

[0195] Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal {e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment {e.g., the brain or central nervous system) relative to the parent species. Preferred prodrugs include derivatives where a group that enhances aqueous solubility or active transport through the gut membrane is appended to the structure of formulae described herein. (See, e.g., Alexander, et al. 1988 J Med Chem 31, 318-322; Bundgaard 1985 Elsevier: Amsterdam 1-92; Bundgaard, et al. 1987 J Med Chem 30, 451-454; Bundgaard, H. A Textbook of Drug Design and Development, Harwood Academic Publ.: Switzerland, 1991, 113-191; Digenis, et al. Handbook of Experimental Pharmacology 1975 28, 86-112; Friis, et al. A Textbook of Drug Design and Development, 2 ed.; Overseas Publ.: Amsterdam, 1996, 351-385; Pitman 1981 Med Res Rev 1, 189-214.)

[0196] Application of the subject therapeutics may be local, so as to be administered at the site of interest. Various techniques can be used for providing the subject compositions at the site of interest, such as injection, use of catheters, trocars, projectiles, pluronic gel, stents, sustained drug release polymers or other device which provides for internal access.

[0197] According to another embodiment, the invention provides a method of impregnating an implantable drug release device comprising the step of contacting said drug release device with a compound or composition of this invention. Implantable drug release devices include, but are not limited to, biodegradable polymer capsules or bullets, non-degradable, diffusible polymer capsules and biodegradable polymer wafers.

[0198] According to another embodiment, the invention provides an implantable medical device coated with a compound or a composition comprising a compound of this invention, such that said compound is therapeutically active.

[0199] In another embodiment, a composition of the present invention further comprises a second therapeutic agent. The second therapeutic agent includes any compound or therapeutic agent known to have or that demonstrates advantageous properties when administered alone or with a compound of any of the formulae herein. Drugs that could be usefully combined with52SUBSTITUTE SHEET (RULE 26)these compounds include other kinase inhibitors and / or other chemotherapeutic agents for the treatment of the diseases and disorders discussed above.

[0200] Such agents are described in detail in the art. Preferably, the second therapeutic agent is an agent useful in the treatment or prevention of cancer.

[0201] Even more preferably the second therapeutic agent co-formulated with a compound of this invention is an agent useful in the treatment of TRPML mediated disease / disorders.

[0202] In another embodiment, the invention provides separate dosage forms of a compound of this invention and a second therapeutic agent that are associated with one another. The term “associated with one another” as used herein means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of one another, consecutively or simultaneously).

[0203] In the pharmaceutical compositions of the invention, the compound of the present invention is present in an effective amount. As used herein, the term “effective amount” refers to an amount which, when administered in a proper dosing regimen, is sufficient to reduce or ameliorate the severity, duration or progression of the disorder being treated, prevent the advancement of the disorder being treated, cause the regression of the disorder being treated, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.

[0204] The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described in Freireich, et al. 1966 Cancer Chemother Rep 50: 219. Body surface area may be approximately determined from height and weight of the patient. (See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardley, N.Y., 1970, 537.) An effective amount of a compound of this invention can range from about 0.001 mg / kg to about 500 mg / kg, more preferably 0.01 mg / kg to about 50 mg / kg, more preferably 0.1 mg / kg to about 2.5 mg / kg. Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the patient, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician.

[0205] For pharmaceutical compositions that comprise a second therapeutic agent, an effective amount of the second therapeutic agent is between about 20% and 100% of the dosage normally utilized in a monotherapy regime using just that agent. Preferably, an effective amount53SUBSTITUTE SHEET (RULE 26)is between about 70% and 100% of the normal monotherapeutic dose. The normal monotherapeutic dosages of these second therapeutic agents are well known in the art. (See, e.g., Wells, etal., eds. 2000 Pharmacotherapy Handbook, 2ndEdition, Appleton and Lange, Stamford, Conn.; PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. 2000, each of which references are entirely incorporated herein by reference.

[0206] It is expected that some of the second therapeutic agents referenced above will act synergistically with the compounds of this invention. When this occurs, it will allow the effective dosage of the second therapeutic agent and / or the compound of this invention to be reduced from that required in a monotherapy. This has the advantage of minimizing toxic side effects of either the second therapeutic agent of a compound of this invention, synergistic improvements in efficacy, improved ease of administration or use and / or reduced overall expense of compound preparation or formulation.

[0207] The term “co-administered” as used herein means that the second therapeutic agent may be administered together with a compound of this invention as part of a single dosage form (such as a composition of this invention comprising a compound of the invention and a second therapeutic agent as described above) or as separate, multiple dosage forms. Alternatively, the additional agent may be administered prior to, consecutively with, or following the administration of a compound of this invention. In such combination therapy treatment, both the compounds of this invention and the second therapeutic agent(s) are administered by conventional methods. The co-administration of a composition of this invention comprising both a compound of the invention and a second therapeutic agent to a subject does not preclude the separate administration of that same therapeutic agent, any other second therapeutic agent or any compound of this invention to said subject at another time during a course of treatment.

[0208] Effective amounts of these second therapeutic agents are well known to those skilled in the art and guidance for dosing may be found in patents and published patent applications referenced herein, as well as in Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, 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, it is well within the skilled artisan’s purview to determine the second therapeutic agent’s optimal effective-amount range.54SUBSTITUTE SHEET (RULE 26)

[0209] In one embodiment of the invention where a second therapeutic agent is administered to a subject, the effective amount of the compound of this invention is less than its effective amount would be where the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount would be where the compound of this invention is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and / or reduced drug cost) will be apparent to those of skill in the art.

[0210] In yet another aspect, the invention provides the use of a compound of any of the formulae herein alone or together with one or more of the above-described second therapeutic agents in the manufacture of a medicament, either as a single composition or as separate dosage forms, for treatment or prevention in a subject of a disease, disorder or symptom set forth above. Another aspect of the invention is a compound of the formulae herein for use in the treatment or prevention in a subject of a disease, disorder or symptom thereof delineated herein.In other aspects, the methods herein include those further comprising monitoring subject response to the treatment administrations. Such monitoring may include periodic sampling of subject tissue, fluids, specimens, cells, proteins, chemical markers, genetic materials, etc. as markers or indicators of the treatment regimen. In other methods, the subject is prescreened or identified as in need of such treatment by assessment for a relevant marker or indicator of suitability for such treatment.

[0211] In one embodiment, the invention provides a method of monitoring treatment progress. The method includes the step of determining a level of diagnostic marker (Marker) (e.g., any target or cell type delineated herein modulated by a compound herein) or diagnostic measurement (e.g., screen, assay) in a subject suffering from or susceptible to a disorder or symptoms thereof delineated herein, in which the subject has been administered a therapeutic amount of a compound herein sufficient to treat the disease or symptoms thereof. The level of Marker determined in the method can be compared to known levels of Marker in either healthy normal controls or in other afflicted patients to establish the subject’s disease status. In preferred embodiments, a second level of Marker in the subject is determined at a time point later than the determination of the first level, and the two levels are compared to monitor the course of disease or the efficacy of the therapy. In certain preferred embodiments, a pre-treatment level of Marker55SUBSTITUTE SHEET (RULE 26)in the subject is determined prior to beginning treatment according to this invention; this pre- treatment level of Marker can then be compared to the level of Marker in the subject after the treatment commences, to determine the efficacy of the treatment.

[0212] In certain method embodiments, a level of Marker or Marker activity in a subject is determined at least once. Comparison of Marker levels, e.g., to another measurement of Marker level obtained previously or subsequently from the same patient, another patient, or a normal subject, may be useful in determining whether therapy according to the invention is having the desired effect, and thereby permitting adjustment of dosage levels as appropriate. Determination of Marker levels may be performed using any suitable sampling / expression assay method known in the art or described herein. Preferably, a tissue or fluid sample is first removed from a subject. Examples of suitable samples include blood, urine, tissue, mouth or cheek cells, and hair samples containing roots. Other suitable samples would be known to the person skilled in the art. 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 methods, real-time PCR, and the like.

[0213] The present invention also provides kits for use to treat diseases, disorders, or symptoms thereof, including those delineated herein. These kits comprise: a) a pharmaceutical composition comprising a compound of any of the formula herein or a salt thereof; or a prodrug, or a salt of a prodrug thereof; or a hydrate, solvate, or polymorph thereof, wherein said pharmaceutical composition is in a container; and b) instructions describing a method of using the pharmaceutical composition to treat the disease, disorder, or symptoms thereof, including those delineated herein.

[0214] The container may be any vessel or other sealed or sealable apparatus that can hold said pharmaceutical composition. Examples include bottles, divided or multi-chambered holders or bottles, wherein each division or chamber comprises a single dose of said composition, a divided foil packet wherein each division comprises a single dose of said composition, or a dispenser that dispenses single doses of said composition. The container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a “refill” of tablets for placement into a different container), or a blister56SUBSTITUTE SHEET (RULE 26)pack with individual doses for pressing out of the pack according to a therapeutic schedule. The container employed can depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle, which is in turn contained within a box. Preferably, the container is a blister pack.

[0215] The kit may additionally comprise information and / or instructions for the physician, pharmacist or subject. Such memory aids include numbers printed on each chamber or division containing a dosage that corresponds with the days of the regimen which the tablets or capsules so specified should be ingested, or days of the week printed on each chamber or division, or a card which contains the same type of information.

[0216] The following examples are meant to be illustrative of the practice of the invention and not limiting in any way.ExamplesAbbreviationsAbbreviation NameACN acetonitrileDCM dichloromethaneDHP 3,4-dihydro-2H-pyranDMF N,N-dimethylformamideDMSO dimethyl sulfoxideEtOAc ethyl acetateHPLC high-performance liquid chromatographyLC-MS liquid chromatography-mass spectrometryNIS N-iodosuccinimideNBS N-bromosuccinimideTBS tert-butyldimethylsilylTEA triethyl amineTFA trifluoroacetic acidTHF tetrahydrofuranTLC thin-layer chromatographyCompounds and Synthetic Methods

[0217] Compounds of the invention, including those specifically disclosed herein above and below, may be prepared as described in the following schemes.57SUBSTITUTE SHEET (RULE 26)Table 258SUBSTITUTE SHEET (RULE 26)59SUBSTITUTE SHEET (RULE 26)60SUBSTITUTE SHEET (RULE 26)61SUBSTITUTE SHEET (RULE 26)*ECso of TFEB activation (where data is provided): “+++” < 1 uM; “++” 1 uM to 10 uM;£;+” > 10 uMSynthetic MethodsIntermediate-Ll: (lZ)-2, 6-dichloro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride

[0218] Step 1. To a solution of 2, 6-di chlorobenzoyl chloride (5 g, 23.9 mmol, 3.42 mL, 1 eq) in toluene (100 mL) were added 4-methylbenzenesulfonohydrazide (4.22 g, 22.7 mmol, 0.95 eq) and diisopropylethylamine (3.70 g, 28.7 mmol, 4.99 mL, 1.2 eq). The mixture was stirred at 75 °C for 3 hours. LC-MS showed 2, 6-dichlorobenzoyl chloride was consumed completely and one main peak with the desired mass was detected. The reaction mixture was filtered, and the filter cake was dried in vacuum to give the desired 2, 6-dichloro-N'-(p-tolylsulfonyl) benzohydrazide (5.5 g, crude) as a yellow solid. MS (ESI): mass calcd. For C14H12CI2N2O3S 357.99, m / z found 359.1 [M+H]+.

[0219] Step 2'. A solution of 2, 6-dichloro-N'-(p-tolylsulfonyl) benzohydrazide (1.6 g, 4.45 mmol, 1 eq) in thionyl chloride (6.09 g, 51.2 mmol, 3.72 mL, 11.5 eq) was stirred at 75 °C for 1.5 hours. The reaction was cooled to 60 °C and an additional portion of 2, 6-dichloro-N'-(p- tolyl sulfonyl) benzohydrazide (1.60 g, 4.45 mmol, 1 eq) was added and the reaction was heated back to 75 °C for 1 hour. LC-MS (the sample quenched with piperidine) showed 2, 6-dichloro- N'-(p-tolylsulfonyl) benzohydrazide was consumed completely and the desired mass was detected. The reaction mixture was concentrated to give the desired (lZ)-2, 6-dichloro-N-(p- tolyl sulfonyl) benzohydrazonoyl chloride (1.7 g, crude) as a yellow gum. MS (ESI): mass calcd. For C14H11CI3N2O2S 375.96, m / z found 426.1 [M+H+49]+.62SUBSTITUTE SHEET (RULE 26)Intermediate-L2: (E)-2, 6-difluoro-N'-tosylbenzohydrazonoyl chloride

[0220] Step 1 : To a solution of 2, 6-difluorobenzoyl chloride (5 g, 28.3 mmol, 3.57 mL, 1 eq) in DCM (50 mL) were added TEA (7.16 g, 70.8 mmol, 9.85 mL, 2.5 eq) and 4- methylbenzenesulfonohydrazide (5.80 g, 31.2 mmol, 1.1 eq). The mixture was stirred at 15 °C for 12 hours. LC-MS showed 2, 6-difluorobenzoyl chloride was consumed completely and one main peak with the desired mass was detected. The crude was added HC1 (IM, 100 mL), the reaction mixture was concentrated under reduced pressure to give the desired N'-(2, 6- difluorobenzoyl)-4-methylbenzenesulfonohydrazide (5.0 g, crude) as a white solid. MS (ESI): mass calcd. For C14H12F2N2O3S 326.05, m / z found 327.2 [M+H]+.

[0221] Step 2: A solution of 2, 6-difluoro-N'-(p-tolylsulfonyl) benzohydrazide (700 mg, 2.15 mmol, 1 eq) in SOCL (10 mL) was stirred at 75 °C for 0.5 hour. TLC indicated 2, 6-difluoro-N'- (p-tolyl sulfonyl) benzohydrazide was consumed completely and one new spot was formed. The reaction mixture was concentrated under reduced pressure to give the desired (E)-2, 6-difluoro- N' -tosylbenzohydrazonoyl chloride (700 mg, crude) as a light yellow solid.Intermediate-L3: 4-Chloro-3-(3, 3-difluoro-2-methyl-azetidin-l-yl)-lH-indazole

[0222] Step 1: To a solution of 3, 3-difluoro-2-methyl-azetidine (150 mg, 1.04 mmol, 1 eq, HC1) in THF (2 mL) was added TEA (106 mg, 1.04 mmol, 145 μL, 1 eq) dropwise at 25 °C. After addition, the mixture was stirred at this temperature for 10 minutes, the solution of (1Z)- 2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (434 mg, 1.15 mmol, 1.1 eq) 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 showed 3, 3-difluoro-2-methyl-azetidine was consumed completely and one main peak with the desired mass was detected. Then it was separated between 20 mL of water63SUBSTITUTE SHEET (RULE 26)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 give the desired N-[(E)-[(2,6- dichlorophenyl)-(3, 3-difluoro-2-methyl-azetidin-l-yl) methylene] amino]-4-methyl- benzenesulfonamide (500 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C18H17CI2F2N3O2S 447.04, m / z found 448.2 [M+H]+.

[0223] Step 2: To a solution of N-[(E)-[(2, 6-dichlorophenyl)-(3, 3-difluoro-2-methyl- azetidin-l-yl) methylene] amino]-4-methyl-benzenesulfonamide (500 mg, 1.12 mmol, 1 eq) in DMF (10 mL) was added K2CO3(771 mg, 5.58 mmol, 5 eq). The mixture was stirred at 120 °C for 2 hours. LC-MS showed N- [(E)- [(2, 6-dichlorophenyl)-(3, 3-difluoro-2-methyl-azetidin-l-yl) methylene] amino]-4-methyl-benzenesulfonamide was consumed completely and the desired mass was detected. The reaction mixture was added to water (30 mL) and extracted with EtOAc (30 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired 4-chl oro-3 -(3,3 -difluoro-2- methyl-azetidin-l-yl)-l-(p-tolylsulfonyl)indazole (450 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C18H16CIF2N3O2S 411.06, m / z found 412.1 [M+H]+.

[0224] Step 3: To a solution of 4-chl oro-3 -(3, 3-difluoro-2-methyl-azetidin-l-yl)-l-(p- tolyl sulfonyl) indazole (450 mg, 1.09 mmol, 1 eq) in MeOH (5 mL) was added K2CO3(3.02 g, 21.9 mmol, 20 eq). The mixture was stirred at 70 °C for 0.5 hour. LC-MS showed 4-chl oro-3 -(3, 3-difluoro-2-methyl-azetidin-l-yl)-l-(p-tolylsulfonyl) indazole was consumed completely and one main peak with the desired mass was detected. The reaction mixture was added to water (20 mL) and extracted with EtOAc (10 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to give the desired 4-chloro-3-(3,3-difluoro-2-methyl-azetidin-l-yl)-lH-indazole (110 mg, crude) as a white solid. MS (ESI): mass calcd. For C11H10CIF2N3257.05, m / z found 258.0 [M+H]+.Intermediate-L4: Tert-butyl 4-chloro-3-iodo-lH-indazole-l-carboxylate64SUBSTITUTE SHEET (RULE 26)

[0225] Step 1. To a solution of 4-chloro-lH-indazole (5 g, 32.8 mmol, 1 eq) in DMF (20 mL) was added NIS (8.11 g, 36.1 mmol, 1.1 eq). The mixture was stirred at 70 °C for 3 hours. LC-MS showed 4-chloro-lH-indazole was consumed completely and the desired mass was detected. The crude was added H2O (50 mL) and extracted with MTBE (50 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired 4-chloro-3-iodo-lH-indazole (8 g, crude) as a yellow solid. MS (ESI): mass calcd. For C7H4CIIN2277.91 m / z found 278.8 [M+H]+.

[0226] Step 2'. To a solution of 4-chloro-3-iodo-lH-indazole (8 g, 28.7 mmol, 1 eq) in ACN (80 mL) were added tertbutoxy carbonyl tert-butyl carbonate (9.40 g, 43.1 mmol, 9.90 mL, 1.5 eq) and TEA (5.81 g, 57.5 mmol, 8.00 mL, 2 eq) and DMAP (3.51 g, 28.7 mmol, 1 eq). The mixture was stirred at 25 °C for 2 hours. LC-MS showed 4-chloro-3-iodo-lH-indazole was consumed completely and the desired mass was detected. The reaction mixture was concentrated to give the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-20% EtOAc / petroleum ether gradient @ 80 mL / min) to give the desired tert-butyl 4-chloro-3 -iodo-indazole- 1 -carboxylate (9.5 g, 25.1 mmol, 87.4% yield) as a yellow solid. MS (ESI): mass calcd. For C12H12CIIN2O2377.96 m / z found 322.8 [M+H-56]+.Intermediate-L5: 4-Chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole

[0227] Step 1 : A mixture of tert-butyl 4-chloro-3 -iodo-indazole- 1 -carboxylate (300 mg, 792 μmol, 1 eq), 3, 3, 4, 4-tetrafluoropyrrolidine (142 mg, 792μmol , 1 eq, HC1), Pd2(dba)3(72.6 mg, 79.2μmol , 0.1 eq), CS2CO3(775 mg, 2.38 mmol, 3 eq) and BINAP (49.3 mg, 79.2μmol , 0.1 eq) in toluene (2 mL) was degassed and purged with N2for 3 times. The mixture was stirred at 100 °C for 3 hours under N2atmosphere. LC-MS showed tert-butyl 4-chloro-3-iodo-indazole-l- carboxylate was consumed completely and the desired mass was detected. To the crude was added H2O (20 mL), and the resulting solution was extracted with EtOAc (15 mL X 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and65SUBSTITUTE SHEET (RULE 26)concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) give the desired tert-butyl 4-chloro-3-(3, 3, 4, 4- tetrafluoropyrrolidin-l-yl) indazole- 1 -carboxylate (200 mg, 508μmol , 64.1% yield) as a yellow oil. MS (ESI): mass calcd. For C16H16CIF4N3O2393.09 m / z found 338.1 [M+H-56]+.

[0228] Step 2: To a solution of tert-butyl 4-chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl) indazole- 1 -carboxylate (200 mg, 508μmol , 1 eq) in DCM (2 mL) was added TFA (1.45 g, 12.7 mmol, 943 μL, 25 eq). The mixture was stirred at 15 °C for 1 hour. LC-MS showed tert-butyl 4- chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl) indazole- 1 -carboxylate was consumed completely and the desired mass was detected. The reaction mixture was concentrated in vacuum to give the desired 4-chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole (200 mg, crude, TFA) as a brown oil. MS (ESI): mass calcd. For C11H8CIF4N3293.03 m / z found 294.0 [M+H]+.Intermediate-L6: Tert-butyl 4-fluoro-3-iodo-indazole-l-carboxylate

[0229] Step 1 To a solution of I2 (3.73 g, 14.7 mmol, 2.96 mL, 1 eq) in DMF (15 mL) were added 4-fluoro-lH-indazole (2 g, 14.7 mmol, 1 eq) and KOH (824 mg, 14.7 mmol, 1 eq). The mixture was stirred at 15 °C for 1 hour. LC-MS showed 4-fluoro-lH-indazole was remained and the desired compound was detected. The reaction mixture was quenched by addition sat. aq. NaHCO3, (30 mL) at 15 °C, and then diluted with EtOAc (50 mL) and extracted with H2O (30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired 4-fluoro-3-iodo-lH-indazole (5.16 g, crude) as a red solid. MS (ESI): mass calcd. For C7H4FIN2261.94, m / z found 262.9 [M+H]+.

[0230] Step 2'. To a solution of 4-fluoro-3-iodo-lH-indazole (500 mg, 1.91 mmol, 1 eq) and tert-butoxycarbonyl teit-butyl carbonate (541 mg, 2.48 mmol, 570 μL, 1.3 eq) in DCM (5 mL) were added TEA (1.93 g, 19.1 mmol, 2.66 mL, 10 eq) and DMAP (23.3 mg, 191μmol , 0.1 eq). The mixture was stirred at 15 °C for 2 hours. LC-MS showed 4-fluoro-3-iodo-lH-indazole was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 10 mL of H2O and 30 mL of EtOAc. The organic phase was separated, washed with 10 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the66SUBSTITUTE SHEET (RULE 26)crude product. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate =5 / 1 to 4 / 1) to give the desired tert-butyl 4-fluoro-3 -iodo-indazole- 1 -carboxylate (300 mg, 828μmol , 43.4% yield) as an orange solid. MS (ESI): mass calcd. For C12H12FIN2O2361.99, m / z found 306.9 [M+H-56]+.Intermediate-L7: (2S)-l-[4-chloro-l-(p-tolylsulfonyl) indazol-3-yl]-4, 4-difluoro- pyrrolidine-2-carbaldehyde

[0231] Step 1. To a solution of [(2S)-4, 4-difluoropyrrolidin-2-yl] methanol (0.7 g, 4.03 mmol, 1 eq, HC1) in THF (10 mL) was added TEA (1.22 g, 12.1 mmol, 1.68 mL, 3 eq), and then the solution of (E)-2,6-dichloro-N-tosylbenzohydrazonoyl chloride (1.68 g, 4.44 mmol, 1.1 eq) in THF (10 mL) was added dropwise at 0 °C. The mixture was stirred at 20 °C for 2 hours. LC- MS showed [(2S)-4, 4-difluoropyrrolidin-2-yl] methanol was consumed completely and one main peak with the desired mass was detected. The reaction mixture was added H2O (100 mL) and extracted with EtOAc (50 mL X 3). The combined organic phase was washed with brine (30 mL X 2), dried over Na2SO4, filtered, and concentrated in vacuum to give the desired N-[(E)- [(2, 6-dichlorophenyl)-[(2S)-4, 4-difluoro-2-(hydroxymethyl) pyrrolidin- 1 -yl] methylene] amino] - 4-methyl-benzenesulfonamide (2 g, crude) as an orange solid. MS (ESI): mass calcd. For C19H19CI2F2N3O3S 477.05, m / z found 478.1 [M+H]+.

[0232] Step 2\ To a solution of N-[(E)- [(2, 6-dichlorophenyl)-[(2S)-4, 4-difluoro-2- (hydroxymethyl) pyrrolidin-1- yl] methylene] amino]-4-methyl-benzenesulfonamide (2 g, 4.18 mmol, 1 eq) in DMF (20 mL) was added K2CO3(1.73 g, 12.5 mmol, 3 eq). The mixture was stirred at 100 °C for 4 hours. LC-MS showed N-[(E)- [(2, 6-dichlorophenyl)-[(2S)-4, 4-difluoro- 2-(hydroxymethyl) pyrrolidin- 1-yl] methylene] amino] - 4-methyl-benzenesulfonamide remained and the desired compound was detected. The reaction mixture was added H2O (200 mL) and extracted with EtOAc (100 mL X 3). The combined organic phase was washed with brine (100 mL X 2), dried over Na2SO4, filtered, and concentrated in vacuum to give the desired [(2S)-l-[4- chloro-l-(p-tolylsulfonyl) indazol-3-yl]-4, 4-difluoro-pyrrolidin-2-yl] methanol (1.5 g, crude) as67SUBSTITUTE SHEET (RULE 26)a yellow solid. MS (ESI): mass cal cd. For C19H18CIF2N3O3S 441.07, m / z found 460.2 [M+H+18]+.

[0233] Step 3. To a solution of pyridine; sulfur trioxide (630 mg, 3.96 mmol, 3.5 eq) in DCM (10 mL) and DMSO (2 mL) was added TEA (687 mg, 6.79 mmol, 945 μL, 6 eq). The mixture was stirred at 0 °C for 1 hour. Then [(2S)-1- [4-chloro-l-(p-tolylsulfonyl) indazol-3-yl]-4, 4- difluoro-pyrrolidin-2-yl] methanol (500 mg, 1.13 mmol, 1 eq) was added into the reaction mixture. The reaction mixture was stirred at 20 °C for 11 hours. LC-MS showed [(2S)- 1 - [4- chloro-l-(p-tolylsulfonyl) indazol-3-yl]-4, 4-difluoro-pyrrolidin-2-yl] methanol was consumed completely and one main peak with the desired mass was detected. The reaction mixture was added H2O (100 mL) and extracted with MTBE (50 mL X 3). The combined organic phase was washed with brine (50 mL X 2), dried over Na2SO4, filtered, and concentrated in vacuum to give the desired (2S)-l-[4-chloro-l-(p-tolylsulfonyl) indazol-3-yl]-4, 4-difluoro-pyrrolidine-2- carbaldehyde (500 mg, crude) as a purple solid. MS (ESI): mass calcd. For C19H16CIF2N3O3S 439.06, m / z found 440.1 [M+H]+.Intermediate-L8: l-((S)-l-(4-chloro-l-tosyl-lH-indazol-3-yl)-4,4-difluoropyrrolidin-2- yl)ethan-l-ol

[0234] Step 7: To a solution of (2S)-l-[4-chloro-l-(p-tolylsulfonyl)indazol-3-yl]-4,4- difluoro-pyrrolidine-2-carbaldehyde (500 mg, 1.14 mmol, 1 eq) in THF (10 mL) was added MeMgBr (3 M, 757 μL, 2 eq) under N2atmosphere. The mixture was stirred at 0 °C for 2 hours. LC-MS showed (S)-l-(4-chl oro-1 -tosyl- lH-indazol-3-yl)-4, 4-difluoropyrrolidine-2- carbaldehyde was consumed completely and one main peak with the desired mass was detected. The reaction mixture was quenched by HC1 (IM, 20 ml), then added H2O (20 mL) and extracted with EtOAc (10 mL X 3). The combined organic phase was washed with brine (10 mL X 2), dried over Na2SO4, filtered, and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 75 * 30 mm * 3 μm; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 45%-75% B over 8.0 min) to give the desired68SUBSTITUTE SHEET (RULE 26)l-((S)-l-(4-chloro-l-tosyl-lH-indazol-3-yl)-4,4-difhioropyrrolidin-2-yl)ethan-l-ol (80 mg, 157.9 μmol, 13.9% yield, 90% purity) as a white solid. MS (ESI): mass calcd. For C20H20CIF2N3O3S 455.09, m / z found 456.2 [M+H]+.Intermediate-L9: [(2R)-l-[4-chloro-l-(p-tolylsulfonyl) indazol-3-yl]-4, 4-difluoro- pyrrolidin-2-yl] methanol

[0235] Step 1 To a solution of [(2R)-4, 4-difluoropyrrolidin-2-yl]methanol (500 mg, 2.88 mmol, 1 eq, HC1) in THF (10 mL) were added TEA (1.17 g, 11.5 mmol, 1.60 mL, 4 eq) and (lE)-2, 6-dichloro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride (1.20 g, 3.17 mmol, 1.1 eq) at 0 °C. The mixture was stirred at 15 °C for 1 hour. LC-MS showed [(2R)-4, 4-difluoropyrrolidin- 2-yl] methanol was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 30 mL of H2O and 50 mL of EtOAc. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired N-[(E)-[(2,6-dichlorophenyl)-[(2R)-4, 4-difluoro-2- (hydroxymethyl)pyrrolidin-l-yl] methylene] amino]-4-methyl-benzenesulfonamide (1.38 g, crude) as a yellow solid. MS (ESI): mass calcd. For C19H19CI2F2N3O3S 477.0, m / z found 478.0 [M+H]+.

[0236] Step 2: To a solution of N-[(E)-[(2, 6-dichlorophenyl)-[(2R)-4, 4-difluoro-2- (hydroxymethyl) pyrrolidin-1 -yl] methylene] amino]-4-methyl-benzenesulfonamide (400 mg, 836 gmol, 1 eq) in DCM (5 mL) were added imidazole (114 mg, 1.67 mmol, 2 eq) and tert- butyl-chloro-dimethyl-silane (151 mg, 1.00 mmol, 124 μL, 1.2 eq) at 0 °C under N2. The mixture was stirred at 15 °C for 0.5 hour. LC-MS showed N-[(E)-[(2, 6-dichlorophenyl)-[(2R)-4, 4- difluoro-2- (hydroxymethyl) pyrrolidin-1 -yl] methylene] amino]-4-methyl-benzenesulfonamideSUBSTITUTE SHEET (RULE 26)was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 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 give the crude product. The residue was purified by flash silica gel chromatography (ISCO®;20 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate / petroleum ether gradient @ 60 mL / min) to give the desired (R,E)-N'-((2-(((tert-butyldimethylsilyl)oxy)methyl)- 4,4-difluoropyrrolidin-l-yl)(2,6-dichlorophenyl)methylene)-4-methylbenzenesulfonohydrazide (320 mg, 540 μmol , 64.6% yield) as a yellow solid. MS (ESI): mass calcd. For C25H33C12F2N3O3SSi 591.1, m / z found 592.1 [M+H]+.

[0237] Step 3: To a solution of (R,E)-N'-((2-(((tert-butyldimethylsilyl)oxy)methyl)-4,4- difluoropyrrolidin-l-yl)(2,6-dichlorophenyl)methylene)-4-methylbenzenesulfonohydrazide (320 mg, 540μmol , 1 eq) in DMF (6 mL) was added K3CO3(746 mg, 5.40 mmol, 10 eq). The mixture was stirred at 100 °C for 2 hours. LC-MS showed (R,E)-N'-((2-(((tert- butyldimethylsilyl)oxy)methyl)-4,4-difluoropyrrolidin-l-yl)(2,6-dichlorophenyl)methylene)-4- methylbenzenesulfonohydrazide was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 40 mL of H2O and 50 mL of EtOAc. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired tert-butyl-dimethyl-[[(2R)-l-[4-chloro-l-(p- tolyl sulfonyl) indazol-3-yl]-4, 4-difluoro-pyrrolidin-2-yl] methoxy] silane (210 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C25H32ClF2N3O3SSi 555.2, m / z found 556.1 [M+H]+.

[0238] Step 4. To a solution of tert-butyl-dimethyl-[[(2R)-l-[4-chloro-l-(p-tolylsulfonyl) indazol-3-yl]-4, 4-difluoro-pyrrolidin-2-yl] methoxy] silane (200 mg, 360μmol , 1 eq) in DCM (4 mL) was added TFA (3.07 g, 26.9 mmol, 2 mL, 74.9 eq). The mixture was stirred at 15 °C for 0.5 hour. LC-MS showed tert-butyl-dimethyl-[[(2R)-l-[4-chloro-l-(p-tolylsulfonyl) indazol-3- yl]-4, 4-difluoro-pyrrolidin-2-yl] methoxy] silane was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 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 give the crude product. The residue was purified by prep-TLC (silica gel, petroleum ether / Ethyl acetate = 1 / 1) to give the desired [(2R)- 1 -[4-chl oro-1 -(p-tolyl sulfonyl) indazol-3-yl]-4, 4-difluoro-pyrrolidin-2-yl] methanol (70 mg, 15870SUBSTITUTE SHEET (RULE 26)μmol, 44.1% yield) as a white solid. MS (ESI): mass calcd. For C19H18CIF2N3O3S 444.1, m / z found 445.0 [M+H]+.Intermediate-L 10 : 3-Bromo-4-chloro- l-tetrahydropyran-3-yl-indazole

[0239] Step 1 : To a solution of 4-chloro-lH-indazole (5 g, 32.8 mmol, 1 eq) in DMF (50 mL) was added NBS (6.42 g, 36.1 mmol, 1.1 eq) at 25 °C. The mixture was stirred at 70 °C for 3 hours. LC-MS showed 4-chloro-lH-indazole was consumed completely and the desired mass was detected. Pour the reaction to H2O (150 mL) at 25 °C and stir the mixture at 25 °C for 0.5 hour. Filter and washed the filter cake with H2O (100 mL X 2). Collect the solid and dry under reduced pressure to give the desired 3-bromo-4-chloro-lH-indazole (7.5 g, 32.40 mmol, 98.9% yield) as a yellow solid. MS (ESI): mass cal cd. For C7H4BrCIN2229.92, m / z found 230.9 [M+H]+.

[0240] Step 2\ To a solution of 3-bromo-4-chloro-lH-indazole (6.5 g, 28.1 mmol, 1 eq) in EtOAc (60 mL) were added TsOH.H2O (534 mg, 2.81 mmol, 0.1 eq) and DHP (3.54 g, 42.1 mmol, 3.85 mL, 1.5 eq) at 15 °C. The mixture was stirred at 80 °C for 0.5 hour. LC-MS showed a little 3-bromo-4-chloro-lH-indazole remained. Several new peaks were shown on LC-MS and the desired compound was detected. The reaction mixture was added to water (200 mL) and extracted with EtOAc (100 mL X 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / petroleum ether gradient @ 100 mL / min) to give the desired 3-bromo-4-chloro-l-tetrahydropyran-3-yl-indazole (6.1 g, 19.3 mmol, 68.8% yield) as a white solid. MS (ESI): mass calcd. For C12H12BrClN2O 313.98, m / z found 315.0 [M+H]+.Intermediate-Lll: 4-Chloro-3-(6, 6-difluoro-4-azaspiro [2.4] heptan-4-yl)-lH-indazole71SUBSTITUTE SHEET (RULE 26)

[0241] Step 1. To a solution of l-benzylpyrrolidine-2, 5-dione (3 g, 15.9 mmol, 1 eq) in THF (30 mL) were added Ti(i-PrO)4(22.5 g, 79.3 mmol, 23.4 mL, 5 eq) and EtMgBr (3 M, 18.5 mL, 3.5 eq) at 0 °C. The mixture was stirred at 20 °C for 12 hours. LC-MS showed 1- benzylpyrrolidine-2, 5-dione was consumed completely. BF3.Et2O (11.3 g, 79.3 mmol, 9.75 mL, 5 eq) was added to the mixture. The mixture was stirred at 20 °C for 4 hours. LC-MS showed 1- benzylpyrrolidine-2, 5-dione was consumed completely and one main peak with the desired mass was detected. The reaction mixture was quenched by 3N hydrochloric acid (30 mL) and extracted with EtOAc (60 mL X 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% TFA condition) to give the desired 4- benzyl-4-azaspiro [2.4] heptan-5-one (2 g, crude) as a yellow oil. MS (ESI): mass calcd. For C13H15NO 201.0, m / z found 202.2 [M+H]+.

[0242] Step 2\ To a solution of 4-benzyl-4-azaspiro [2.4] heptan-5-one (450 mg, 2.24 mmol, 1 eq) in THF (20 mL) was added LiHMDS (1 M, 8.94 mL, 4 eq) at -78 °C under N2. The mixture was stirred at -78 °C for 1 hour. NFSI (2.82 g, 8.94 mmol, 4 eq) in THF (10 mL) was added to the mixture at -78 °C. The mixture was stirred at 25 °C for 12 hours. LC-MS showed 4-benzyl-4- azaspiro [2.4] heptan-5-one remained. Several new peaks were shown on LC-MS and the desired compound was detected. The reaction mixture was quenched by addition saturated aqueous NH4CI (200 mL) at 0 °C, and extracted with EtOAc (300 mL X 3). The combined organic phase was washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated in vacuum. The72SUBSTITUTE SHEET (RULE 26)residue was purified by pre-HPLC (TFA condition; column: Phenomenex Luna Cl 8 75*30mm*3 μm; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 30%-55% B over 8.0 min) to give 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 C13H13F2NO 237.10, m / z found 238.2 [M+H]+.

[0243] Step 3: To a solution of 4-benzyl-6, 6-difluoro-4-azaspiro [2.4] heptan-5-one (110 mg, 464 μmol, 1 eq) in THF (3 mL) was added BH3-Me2S (10 M, 92.7 μL, 2 eq). The mixture was stirred at 40 °C for 12 hours. LC-MS showed 4-benzyl-6, 6-difluoro-4-azaspiro [2.4] heptan- 5-one was consumed completely and the desired compound was detected. MeOH (1 mL) was added dropwise to the mixture at 0 °C, then the mixture was stirred at 80 °C for 0.5 hour. The reaction mixture was quenched by addition HC1 (IM, 1 mL) and concentrated under reduced pressure to give a residue. The residue was purified by pre-HPLC (TFA condition; column: Phenomenex Luna C18 75*30mm*3 μm; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 20%- 45% B over 8.0 min) to give the desired 4-benzyl-6, 6-difluoro-4-azaspiro [2.4] heptane (85 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C13H15F2N 223.12, m / z found 224.2 [M+H]".

[0244] Step 4. Two reactions were carried out in parallel. A mixture of 4-benzyl-6, 6- difluoro-4-azaspiro [2.4] heptane (30 mg, 134 μmol, 1 eq), Pd(OH)2 / C (40 mg, 28.5 μm,o 1l0% purity, 2.12 e'1eq) in MeOH (5 mL) was degassed and purged with H215 psi) for 3 times, and then the mixture was stirred at 25 °C for 5 min under H2atmosphere. LC-MS showed 4-benzyl- 6, 6-difluoro-4-azaspiro [2.4] heptane was consumed completely, and the desired mass was detected. Two reactions were combined for workup. The reaction mixture was filtered, and concentrated under reduced pressure to give 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]+.

[0245] Step 5: To a solution of 6, 6-difluoro-4-azaspiro [2.4] heptane (35 mg, 263 μm,o 1l eq) in THF (1 mL) was added dropwise TEA (266 mg, 2.63 mmol, 366 μL, 10 eq) at 25 °C. After addition, the mixture was stirred at this temperature for 10 min, and then (lZ)-2,6- dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (99.3 mg, 263 μmoll 1 eq) in THF (1 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 20 min. LC-MS showed 6, 6-difluoro-4-azaspiro [2.4] heptane was consumed completely and one main peak with the desired mass was detected. Then it was separated between 20 mL of water and 40 mL of ethyl acetate. The organic phase was separated, washed with 30 mL of brine, dried over Na2SO4,73SUBSTITUTE SHEET (RULE 26)filtered, and concentrated under reduced pressure to give the desired N-[(E)-[(2,6- dichlorophenyl)-(6,6-difluoro-4-azaspiro[2.4]heptan-4-yl)methylene]amino]-4-methyl- benzenesulfonamide (140 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C20H19CI2F2N3O2S 473.05, m / z found 474.0 [M+H]+.

[0246] 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-methyl- benzenesulfonamide (70 mg, 148 μmol, 1 eq) in DMF (3 mL) was added K2CO3(102 mg, 738 μmol, 5 eq). The mixture was stirred at 100 °C for 2 hours. LC-MS showed N-[(E)-[(2, 6- dichlorophenyl)-(6, 6-difluoro-4-azaspiro [2.4] heptan-4-yl) methylene] amino]-4-methyl- benzenesulfonamide was consumed completely and the desired mass was detected. Two reactions were combined for workup. The reaction mixture was added to water (5 mL) and extracted with EtOAc (3 mL X 3). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired 4- chloro-3-(6,6-difluoro-4-azaspiro[2.4]heptan-4-yl)-l-(p-tolylsulfonyl)indazole (120 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C20H18CIF2N3O2S 437.08, m / z found 438.1 [M+H]+.

[0247] Step 7: To a solution of 4-chloro-3-(6, 6-difluoro-4-azaspiro [2.4] heptan-4-yl)-l-(p- tolyl sulfonyl) indazole (120 mg, 274 μmoll 1 eq) in MeOH (3 mL) was added K2CO3(189 mg, 1.37 mmol, 5 eq). The mixture was stirred at 60 °C for 0.5 hour. LC-MS showed 4-chloro-3-(6, 6-difluoro-4-azaspiro [2.4] heptan-4-yl)-l-(p-tolyl sulfonyl) indazole was consumed completely and the desired mass was detected. The reaction mixture was added to water (5 mL) and extracted with EtOAc (3 mL X 3). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by / irep-TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to give the desired 4-chloro-3-(6, 6-difluoro-4-azaspiro [2.4] heptan-4-yl)-lH-indazole (25 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C13H12CIF2N3283.07, m / z found 284.0 [M+H]+.Intermediate-Rl: 4-(l, 1-Difluoroethyl) benzenesulfonyl chloride74SUBSTITUTE SHEET (RULE 26)

[0248] Step 1 KOH (3.25 g, 57.9 mmol, 1 eq) was added to a solution of phenylmethanethiol (7.91 g, 63.7 mmol, 7.46 mL, 1.1 eq) in EtOH (100 mL). The mixture was heated to reflux until the KOH was completely dissolved and then cooled to 25 °C. A solution of l-(4-fluorophenyl) ethanone (8 g, 57.9 mmol, 7.02 mL, 1 eq) in EtOH (20 mL) was added dropwise to the mixture and the mixture was heated to 100 °C for 7 hours. TLC (petroleum ether / ethyl acetate = 5 / 1) indicated 1 -(4-fluorophenyl) ethanone was consumed completely and one new spot was formed. The crude was added H2O (100 mL) and extracted with EtOAc (100 mL X 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 5 / 1) to give the desired l-(4- benzylsulfanylphenyl) ethanone (14 g, crude) as a brown oil.

[0249] Step 2: A solution of l-(4-benzylsulfanylphenyl) ethanone (12 g, 49.5 mmol, 1 eq) in DAST (120 mL) was stirred at 70 °C for 1 hour. TLC (petroleum ether / ethyl acetate = 5 / 1) indicated l-(4-benzylsulfanylphenyl) ethanone was consumed completely and two new spots were formed. The reaction mixture was partitioned between water (200 mL) and EtOAc (150 mL X 3). The organic phase was separated, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 SepaFlash® Silica Flash Column, Eluent of 0-5% EtOAc / petroleum ether gradient @ 80 mL / min) to give the desired l-benzylsulfanyl-4-(l, 1- difluoroethyl) benzene (2.5 g, 9.46 mmol, 19.1% yield) as a white solid.

[0250] Step 3. To a solution of l-benzylsulfanyl-4-(l, 1 -difluoroethyl) benzene (2.5 g, 9,46 mmol, 1 eq) in AcOH (20 mL) and H2O (5 mL) was added NCS (5.05 g, 37.8 mmol, 4 eq) at 0 °C. The mixture was stirred at 20 °C for 1 hour. LC-MS showed l-benzylsulfanyl-4-(l, 1- difluoroethyl) benzene was consumed completely and the desired mass was detected (the sample quenched with piperidine). The reaction mixture was filtered, and the filter liquor was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~5% EtOAc / petroleum ether gradient @ 60 mL / min) to give the desired 4-(l, 1 -difluoroethyl) benzenesulfonyl chloride (1.33 g, 5.53 mmol, 58.4% yield) as a yellow oil. MS (ESI): mass calcd. For C8H7F2SO2C1 239.98, mass found 290.1[M+H+49]+.75SUBSTITUTE SHEET (RULE 26)Intermediate-R2: 3-(l, 1-Difluoroethyl) bicycle [1.1.1] pentane-l-sulfonyl fluoride

[0251] Step 1 : To the mixture of 3-methoxycarbonylbicyclo[l.l.l]pentane-l-carboxylic acid(2 g, 11.8 mmol, 1 eq), N-methoxymethanamine (1.15 g, 11.8 mmol, 1 eq, HC1) and DIPEA (9.11 g, 70.5 mmol, 12.3 mL, 6 eq) in DCM (50 mL) was added T3P (12.7 g, 20.0 mmol, 11.9 mL, 50% purity, 1.70 eq) at 0 °C under the atmosphere of nitrogen. The mixture was stirred at 20 °C for 12 hours. TLC showed 3 -methoxy carbonylbicyclo [1.1.1] pentane- 1 -carboxylic acid was consumed completely and a new spot was formed. The reaction was added DCM (50 mL). The mixture was washed with water (50 mL) and HC1 (50 mL, IM). The organic phase was separated, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-50% ethyl acetate / petroleum ether gradient @ 60 mL / min) to give 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. 1H NMR (Chloroform-; / ) 5 3.69 (s, 3H), 3.67 (s, 3H), 3.18 (s, 3H), 2.38 (s, 6H).

[0252] 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 eq) in THF (18 mL) was added MeMgBr (3 M, 2.81 mL, 1 eq) at -20 °C under the atmosphere of nitrogen. The mixture was stirred at 15 °C for 176SUBSTITUTE SHEET (RULE 26)hour. TLC indicated methyl 3-[methoxy (methyl) carbamoyl] bicycle [1.1.1] pentane-1- carboxylate was consumed completely and one new spot was formed. The reaction mixture was quenched by addition saturated aqueous NH4CI (50 mL) at 0°C slowly under N2and stirred at 25 °C for 15 minutes. THF was removed in vacuum. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL X 3). The combined organic phase was washed with brine (30 mL X 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-50% ethyl acetate / petroleum ethergradient @ 80 mL / min) to give the desired methyl 3 -acetylbicyclo[l.l.l]pentane-l -carboxylate (700 mg, 4.16 mmol, 49.3% yield) as a light yellow solid.

[0253] Step 3 : To a solution of methyl 3 -acetylbicyclo [1.1.1] pentane- 1 -carboxylate (700 mg, 4.16 mmol, 1 eq) in DCM (10 mL) was added DAST (6.71 g, 41.6 mmol, 5.50 mL, 10 eq) at -78 °C. The mixture was stirred at 15 °C for 12 hours. TLC indicated methyl 3 -acetylbicyclo [1.1.1] pentane- 1 -carboxylate was consumed completely and one new spot was formed. The reaction was quenched by saturated sodium bicarbonate solution (50 ml) and extracted with EtOAc (50 mL X 3). The organic phase was separated, washed with brine (30 mL X 2), dried over Na2SO4, filtered, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-50% ethyl acetate I petroleum ether gradient @ 80 mL / min) to give the desired methyl 3-(l, 1 -difluoroethyl) bicycle [1.1.1] pentane- 1 -carboxylate (450 mg, 2.37 mmol, 56.9% yield) as a light-yellow solid. 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).

[0254] Step 4: To a solution of methyl 3-(l, 1 -difluoroethyl) bicycle [1.1.1] pentane-1- carboxylate (450 mg, 2.37 mmol, 1 eq) in H2O (1 mL), MeOH (1 mL) and THF (3 mL) was added LiOH (113 mg, 4.73 mmol, 2 eq). The mixture was stirred at 15 °C for 3 hours. TLC indicated methyl 3-(l, 1 -difluoroethyl) bicycle [1.1.1] pentane- 1 -carboxylate was consumed completely and one new spot was formed. The pH value of the reaction mixture was adjusted to 3-4 with IN HC1, then the reaction mixture was partitioned between H2O (30 mL) and EtOAc (20 mL X 3). The organic phase was separated, washed with brine (15 mL X 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired 3-(l, 1- difluoroethyl) bicycle [1.1.1] pentane- 1 -carboxylic acid (300 mg, crude) as a white solid.77SUBSTITUTE SHEET (RULE 26)

[0255] Step 5 : To the mixture of 3-(l, 1 -difluoroethyl) bicycle [1.1.1] pentane- 1 -carboxylic acid (280 mg, 1.59 mmol, 1 eq) and DMF (11.6 mg, 159 μmoll 12.2 μL, 0.1 eq) in DCM (3 mL) was added (COC1)2(242 mg, 1.91 mmol, 167 μL, 1.2 eq) at 15 °C and the mixture was stirred at 15 °C for 1 hour. TLC indicated 3-(l, 1 -difluoroethyl) bicycle [1.1.1] pentane- 1 -carboxylic acid was consumed completely and a new spot was detected. The reaction was concentrated under reduced pressure to give the desired 3-(l, 1 -difluoroethyl) bicycle [1.1.1] pentane- 1 -carbonyl chloride (300 mg, crude) as a yellow oil.

[0256] Step 6: To the mixture of 3-(l, 1 -difluoroethyl) bicycle [1.1.1] pentane- 1 -carbonyl chloride (300 mg, 1.54 mmol, 1 eq) in DCM (2 mL) was added sodium; 1-oxidopyri din- 1-ium -2- thiolate (252 mg, 1.70 mmol, 207 μL, 1.1 eq) at -5 °C and the mixture was stirred at -5 °C for 2 hours. TLC indicated 3-(l, 1 -difluoroethyl) bicycle [1.1.1] pentane- 1 -carbonyl chloride was consumed completely and a new spot was detected. The reaction was concentrated under reduced pressure to give the desired (2-thioxo-l -pyridyl) 3-(l, 1 -difluoroethyl) bicycle [1.1.1] pentane- 1- carboxylate (430 mg, crude) as a yellow solid.

[0257] Step 7: The mixture of (2-thioxo-l -pyridyl) 3-(l, 1 -difluoroethyl) bicycle [1.1.1] pentane- 1 -carboxylate (430 mg, 1.51 mmol, 1 eq) and 2-(2 -pyridyldisulfanyl) pyridine (996 mg, 4.52 mmol, 3 eq) in toluene (20 mL) was degassed with Ar for 3 times and irradiated with a 2000 W halogen lamp under argon atmosphere at 20 °C for 2 hours. LCMS showed (2-thioxo-l- pyridyl) 3-(l, 1-difluoroethyl) bicycle [1.1.1] pentane- 1 -carboxylate was consumed completely and the desired mass was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-50% ethyl acetate / petroleum ether gradient @ 80 mL / min) to give the desired 2-[[3-(l, 1 -difluoroethyl)- 1 -bicyclo [1.1.1] pentanyl] sulfanyl] pyridine (162 mg, crude) as a colorless oil. MS (ESI): mass calcd. For C12H13F2SN 241.07 m / z found 242.0 [M+H]+.

[0258] Step 8: To the mixture of 2-[[3-(l, 1 -difluoroethyl)- 1 -bicyclo [1.1.1] pentanyl] sulfanyl] pyridine (160 mg, 663 μmoll 1 eq) in DCM (10 mL) was added m-CPBA (404 mg, 1.99 mmol, 85% purity, 3 eq) at 20 °C and the mixture was stirred at 20 °C for 1 hour. LCMS showed 2-[[3-(l, 1 -difluoroethyl)-1 -bicyclo [1.1.1] pentanyl] sulfanyl] pyridine was consumed completely and the desired mass was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;78SUBSTITUTE SHEET (RULE 26)40 g SepaFlash® Silica Flash Column, Eluent of 0-50% ethyl acetate / petroleum ether gradient @ 80 mL / min) to give the desired 2-[[3-(l, 1 -difluoroethyl)-1 -bicyclo [1.1.1] pentanyl] sulfanyl] pyridine (162 mg, crude) as a colorless oil. MS (ESI): mass calcd. For C12H13F2SNO2273.06 m / z found 274.0 [M+H]+.

[0259] Step 9: To the mixture ofNaH (22.0 mg, 549 μmol, 60% purity, 1.5 eq) in THF (2 mL) was added EtSH (0.3 g, 4.83 mmol, 357 μL, 13.2 eq) at 0 °C and the mixture was stirred at 0 °C for 1 hour. To the mixture was added 2-[[3-(l, 1 -difluoroethyl)- 1 -bicyclo [1.1.1] pentanyl] sulfonyl] pyridine (100 mg, 366 μmoll 1 eq) and the mixture was stirred at 20 °C for 11 hours. TLC showed 2-[[3-(l, 1 -difluoroethyl)- 1 -bicyclo [1.1.1] pentanyl] sulfonyl] pyridine was consumed completely and a new spot was detected. The mixture was diluted with MTBE (10 mL), the precipitate was filtered, washed with MTBE (10 mL), and dried in vacuo to give the desired [3-(l, 1 -difluoroethyl)- 1 -bicyclo [1.1.1] pentanyl] sulfinyloxy sodium (40 mg, crude) as a white solid which was used into next directly.

[0260] Step 10: To the mixture of [3-(l, 1 -difluoroethyl)- 1 -bicyclo [1.1.1] pentanyl] sulfinyloxysodium (40 mg, 183 μmol, 1 eq) in ACN (2 mL) was added NFSI (86.7 mg, 275 μmol, 1.5 eq) at 20 °C and the mixture was stirred at 20 °C for 4 hours. TLC showed [3-(l, 1- difluoroethyl)-l -bicyclo [1.1.1] pentanyl] sulfinyloxysodium was consumed completely and a new spot was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-50% ethyl acetate I petroleum ether gradient @ 40 mL / min) to give the desired 3-(l, 1 -difluoroethyl) bicycle [1.1.1] pentane- 1 -sulfonyl fluoride (27.9 mg, 130 μ,mol 71.1% yield) as a white solid.NMR (Chloroform-d) δ : 2.47 (s, 6H), 1.62 (m, 3H).Intermediate-R3: 3-(Trifluoromethyl) bicycle [1.1.1] pentane-l-sulfonyl fluoride79SUBSTITUTE SHEET (RULE 26)

[0261] Step 1: To a solution of 3 -(trifluoromethyl) bicycle [1.1.1] pentane- 1 -carboxylic acid (2 g, 11.1 mmol, 1 eq) in DCM (30 mL) was added DMF (81.2 mg, 1.11 mmol, 85.4 μL, 0.1 eq) was degassed and purged with N2for 3 times. To the mixture was added (COCI)? (1.83 g, 14.4 mmol, 1.26 mL, 1.3 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour under N2atmosphere. TLC (petroleum ether / ethyl acetate = 3 / 1) indicated 3 -(trifluoromethyl) bicycle [1.1.1] pentane- 1 -carboxylic acid was consumed completely and one new spot was formed (quenched with MeOH 0.5 mL). The reaction mixture was concentrated to give the desired 3- (trifluorom ethyl) bicycle [1.1.1] pentane- 1 -carbonyl chloride (2 g, crude) as a yellow oil.

[0262] Step 2 : The mixture of sodium; 1-oxidopyri din- l-ium-2 -thiolate (2.55 g, 17.1 mmol,2.09 mL, 1.7 eq) in toluene (5 mL) was degassed and purged with Ar for 3 times. To the mixture was added 3 -(trifluoromethyl) bicycle [1.1.1] pentane- 1 -carbonyl chloride (2 g, 10.1 mmol, 1 eq) at -10 °C. The mixture was stirred at 0 °C for 1 hour under Ar atmosphere in dark. LCMS showed 3 -(trifluoromethyl) bicycle [1.1.1] pentane- 1 -carbonyl chloride was consumed completely and the desired mass was detected. The reaction mixture was concentrated to give the desired (2-thioxo-l -pyridyl) 3 -(trifluoromethyl) bicycle [1.1.1] pentane- 1 -carboxylate (2 g, crude) as a yellow oil. MS (ESI): mass calcd. For C12H10F3NO2S 289.04 m / z found 290.2 [M+H]+.

[0263] Step 3 : The mixture of (2-thioxo-l -pyridyl) 3 -(trifluoromethyl) bicycle [1.1.1] pentane- 1 -carboxylate (2 g, 6.91 mmol, 1 eq) in toluene (50 mL) was degassed and purged with Ar for 3 times. To the mixture was added 2-(2 -pyridyldisulfanyl) pyridine (3.81 g, 17.3 mmol, 2.5 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hours under argon atmosphere under 1000 w lamp. LCMS showed (2-thioxo-l -pyridyl) 3 -(trifluoromethyl) bicycle [1.1.1] pentane-1-80SUBSTITUTE SHEET (RULE 26)carboxylate was consumed completely and the desired mass was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was added water (30 mL) and extracted with EtOAc (3 X 50 mL). The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 97 / 3 to 90 / 10) to give 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 C11H10F3NS 245.05 m / z found 246.2 [M+H]+.

[0264] Step 4: The mixture of 2-[[3-(trifluoromethyl)-l -bicyclo [1.1.1] pentanyl] sulfanyl] pyridine (1.3 g, 5.30 mmol, 1 eq) in DCM (50 mL) was added m-CPBA (3.23 g, 15.9 mmol, 85% purity, 3 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hours. LCMS showed 2-[[3- (trifluorom ethyl)- 1 -bicyclo [1.1.1] pentanyl] sulfanyl] pyridine was consumed completely and the desired mass was detected. The reaction mixture was quenched by addition sat. aq. Na2SO3(30 mL) at 0 °C and extracted with DCM (3 X 50 mL), then the combined organic layers were washed with sat. aq. Na2CO3(20 mL). The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate =10 / 1 to 5 / 1). The reaction mixture was concentrated to give the desired 2-[[3-(trifluoromethyl)-l-bicyclo [1.1.1] pentanyl] sulfonyl] pyridine (1.1 g, 3.97 mmol, 74.9% yield) as a white solid. MS (ESI): mass calcd. For C11H10F3NO2S 277.04 m / z found 278.2 [M+H]+.

[0265] Step 5: The mixture ofNaH (238 mg, 5.95 mmol, 60% purity, 1.5 eq) in THF (15 mL) was degassed and purged with Ar for 3 times. EtSH (986 mg, 15.9 mmol, 1.17 mL, 4 eq) was added dropwise to the mixture. The mixture was stirred at 0 °C for 1 hour. To the mixture was added 2-[[3-(trifhioromethyl)-l-bicyclo [1.1.1] pentanyl] sulfonyl] pyridine (1.1 g, 3.97 mmol, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 11 hours under Ar atmosphere. TLC (petroleum ether / ethyl acetate = 3 / 1) indicated 2-[[3-(trifluoromethyl)-l-bicyclo [1.1.1] pentanyl] sulfonyl] pyridine was consumed completely and one new spot was formed. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction mixture was washed with MTBE (10 mL) and the filter cake was concentrated under reduced pressure to give a residue. The reaction mixture was concentrated to give the desired [3 -(trifluoromethyl)- 1- bicyclo [1.1.1] pentanyl] sulfinyloxysodium (500 mg, 2.25 mmol, 56.7% yield) as a white solid which was used in the next step.

[0266] Step 6: To a solution of [3 -(trifluoromethyl)- 1 -bicyclo [1.1.1] pentanyl] sulfinyloxysodium (500 mg, 2.25 mmol, 1 eq) in ACN (20 mL) was added N-(benzenesulfonyl)-81SUBSTITUTE SHEET (RULE 26)N-fluoro-benzenesulfonamide (1.06 g, 3.38 mmol, 1.5 eq). The mixture was stirred at 25 °C for 2 hours. TLC (petroleum ether / ethyl acetate = 1 / 1) indicated [3 -(trifluoromethyl)- 1 -bicyclo [1.1.1] pentanyl] sulfmyloxysodium was consumed completely and one new spot was formed. The residue was added water (30 mL) and extracted with EtOAc (3 X 50 mL). The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate =20 / 1 to 10:1) to give the desired 3 -(trifluoromethyl) bicycle [1.1.1] pentane-l-sulfonyl fluoride (130 mg, 596 μmol, 26.5% yield) as a white solid which was used in the next step.Intermediated: 3-Fluorobicyclo [1.1.1] pentane-l-sulfonyl fluoride

[0267] Step 1: To a solution of 3 -fluorobicyclo [1.1.1] pentane- 1 -carboxylic acid (3.6 g, 27.7 mmol, 1 eq) in DCM (100 mL) were added DMF (202 mg, 2.77 mmol, 213 μL, 0.1 eq) and (COC1)2(5.27 g, 41.5 mmol, 3.63 mL, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour under N2atmosphere. TLC (petroleum ether / ethyl acetate = 3 / 1) indicated 3 -fluorobicyclo [1.1.1] pentane- 1 -carboxylic acid was consumed completely and one new spot was formed (quenched with MeOH 0.5 mL). The reaction mixture was concentrated to give the desired 3- fluorobicyclo [1.1.1] pentane- 1 -carbonyl chloride (3.6 g, crude) as a yellow oil.

[0268] Step 2 : The mixture of sodium; 1-oxidopyri din- l-ium-2 -thiolate (4.34 g, 29.1 mmol, 3.55 mL, 1.2 eq) in toluene (50 mL) was degassed and purged with Ar for 3 times. To the mixture was added 3 -fluorobicyclo [1.1.1] pentane- 1 -carbonyl chloride (3.6 g, 24.2 mmol, 1 eq) at -10 °C. The mixture was stirred at 0 °C for 1 hour under Ar atmosphere in dark. LCMS showed sodium; 1-oxidopyri din- l-ium-2 -thiolate was consumed completely and the desired mass was detected. The reaction mixture was concentrated to give the desired (2-thioxo-l-82SUBSTITUTE SHEET (RULE 26)pyridyl) 3 -fluorobicyclo [1.1.1] pentane- 1 -carboxylate (3.6 g, crude) as a yellow oil. MS (ESI): mass calcd. For C11H10FNO2S 239.04 m / z found 240.2 [M+H]+.

[0269] Step 3 : The mixture of (2-thioxo-l -pyridyl) 3 -fluorobicyclo [1.1.1] pentane-1- carboxylate (3.6 g, 15.1 mmol, 1 eq) in toluene (100 mL) was degassed and purged with Ar for 3 times. To the mixture was added 2-(2-pyridyldisulfanyl) pyridine (8.29 g, 37.6 mmol, 2.5 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hours under argon atmosphere under 1000 w lamp. LCMS showed (2-thioxo-l -pyridyl) 3-fluorobicyclo [1.1.1] pentane-1 -carboxylate was consumed completely and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove toluene. The residue was added water (30 mL) and extracted with EtOAc (3 X 50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 93 / 7 to 90 / 10) to give the desired 2-[(3-fluoro-l-bicyclo [1.1.1] pentanyl) sulfanyl] pyridine (600 mg, 3.07 mmol, 20.4% yield) as a yellow solid. MS (ESI): mass calcd. For C10H10FNS 195.05 m / z found 196.2 [M+H]+.

[0270] Step 4: To a solution of 2-[(3 -fluoro- 1 -bicyclo [1.1.1] pentanyl) sulfanyl] pyridine (600 mg, 3.07 mmol, 1 eq) in DCM (20 mL) was added TM-CPBA (1.87 g, 9.22 mmol, 85% purity, 3 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hours. LCMS showed 2-[(3 -fluoro- 1- bicyclo [1.1.1] pentanyl) sulfonyl] pyridine was consumed completely and the desired mass was detected. The reaction mixture was quenched by addition sat. aq. Na2SO3(30 mL) at 0 °C and extracted with DCM (3 X 50 mL). The combined organic layers were washed with sat. aq. Na2CC>3 (20 mL). The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give the desired 2-[(3-fluoro-l-bicyclo [1.1.1] pentanyl) sulfonyl] pyridine (500 mg, 2.20 mmol, 71.6% yield) as a white solid. MS (ESI): mass calcd. For C10H10FNO2S 227.04 m / z found 228.2 [M+H]+.

[0271] Step 5: The mixture ofNaH (132 mg, 3.30 mmol, 60% purity, 1.5 eq) in THF (20 mL) was degassed and purged with Ar for 3 times. EtSH (2.05 g, 33.0 mmol, 2.44 mL, 15 eq) was added dropwise to the mixture at 0 °C. The mixture was stirred at 0 °C for 1 hour. To the mixture was added 2-[(3-fluoro-l-bicyclo [1.1.1] pentanyl) sulfonyl] pyridine (500 mg, 2.20 mmol, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 11 hours under Ar atmosphere. TLC (petroleum ether / ethyl acetate = 3 / 1) indicated 2-[(3-fluoro-l-bicyclo [1.1.1] pentanyl) sulfonyl]83SUBSTITUTE SHEET (RULE 26)pyridine was consumed completely and one new spot was formed. The reaction mixture concentrated under reduced pressure to give a residue. The reaction mixture was washed with MTBE (10 mL) and the filter cake was concentrated under reduced pressure to give 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.

[0272] Step 6: To a solution of (3 -fluoro- 1 -bicyclo [1.1.1] pentanyl) sulfinyloxysodium (340 mg, 1.97 mmol, 1 eq) in ACN (15 mL) was added N-(benzenesulfonyl)-N-fluoro- benzenesulfonamide (934 mg, 2.96 mmol, 1.5 eq). The mixture was stirred at 25 °C for 2 hours. TLC (petroleum ether / ethyl acetate = 1 / 1) indicated (3 -fluoro- 1 -bicyclo [1.1.1] pentanyl) sulfinyloxysodium was consumed completely and one new spot was formed. The residue was added water (30 mL) and extracted with EtOAc (3 X 50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give the desired 3 -fluorobicyclo [1.1.1] pentane- 1-sulfonyl fluoride (100 mg, 595 μmoll 30.1% yield) as a white solid which was used in the next step.Intermediate-R5: [4-(l, 1-Difluoroethyl) phenyl] sulfinyloxysodiumStep 1

[0273] Step 1 : To a solution of 4-(l, 1 -difluoroethyl) benzenesulfonyl chloride (1 g, 4.16 mmol, 1 eq) in H2O (10 mL) were added NaHCO3(698 mg, 8.31 mmol, 323 μL, 2 eq) and Na2SO3(1.05 g, 8.31 mmol, 2 eq). The mixture was stirred at 80 °C for 2 hours. TLC (petroleum ether / ethyl acetate = 3 / 1) indicated 4-(l, 1 -difluoroethyl) benzenesulfonyl chloride was consumed completely and one new spot was formed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was added MeOH (20 mL). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the desired [4-(l, 1 -difluoroethyl) phenyl] sulfinyloxysodium (1 g, crude) as a white solid.84SUBSTITUTE SHEET (RULE 26)Compound 1: 4-Chloro-3-(7, 7-difluoro-3-azabicyclo [4.1.0] heptan-3-yl)-l-[4-(l, 1- difluoroethyl) phenyl] sulfonyl-indazole

[0274] Step 1: To the solution of 7, 7-difluoro-3-azabicyclo [4.1.0] heptane (100 mg, 590 μmol, 1 eq, HC1) and TEA (597 mg, 5.90 mmol, 821 μL, 10 eq) in THF (1 mL) was added (1E)- 2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (334 mg, 884 μmoll 1.5 eq) at 0 °C and the solution was stirred at 20 °C for 0.5 hour. LCMS showed (lE)-2, 6-dichloro-N-(p- tolyl sulfonyl) benzohydrazonoyl chloride was consumed completely and the desired mass was detected. The reaction was concentrated to give the desired N-[(E)-[(2, 6-dichlorophenyl)-(7, 7- difluoro-3 -azabicyclo [4.1.0] heptan-3-yl) methylene] amino]-4-methyl-benzenesulfonamide (260 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C20H19CI2F2N3O2S 473.05, m / z found 474.1 [M+H]+.

[0275] 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-methyl-benzenesulfonamide (260 mg, 548 μm,o 1l eq) in DMF (5 mL) was added K2CO3(1.52 g, 11.0 mmol, 20 eq). The mixture was stirred at 100 °C for 2 hours. LC-MS showed N- [(E)- [(2, 6-dichlorophenyl)-(7, 7-difluoro-3-azabicyclo [4.1.0] heptan-3-yl) methylene] amino]-4-methyl-benzenesulfonamide remained and the desired mass was detected. The reaction mixture was added to water (20 mL) and extracted with EtOAc (10 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired 4-chloro-3-(7, 7-difluoro-3- azabicyclo [4.1.0] heptan-3-yl)-l-(p-tolylsulfonyl) indazole (240 mg, crude) as an orange oil. MS (ESI): mass calcd. For C20H18CIF2N3O2S 437.08, m / z found 438.0 [M+H]+.85SUBSTITUTE SHEET (RULE 26)

[0276] Step 3: To a solution of 4-chloro-3-(7, 7-difluoro-3-azabicyclo [4.1.0] heptan-3-yl)-l- (p-tolyl sulfonyl) indazole (240 mg, 548 μmoll 1 eq) in MeOH (5 mL) was added K2CO3(1.52 g, 11.0 mmol, 20 eq). The mixture was stirred at 70 °C for 1 hour. LC-MS showed 4-chloro-3-(7, 7-difluoro-3-azabicyclo [4.1.0] heptan-3-yl)-l-(p-tolylsulfonyl) indazole was consumed completely and the desired mass was detected. The reaction mixture was added to water (20 mL) and extracted with EtOAc (10 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to give the desired 4-chloro-3-(7, 7-difluoro-3-azabicyclo [4.1.0] heptan-3-yl)-lH-indazole (110 mg, crude) as an orange oil. MS (ESI): mass calcd. For C13H12CIF2N3283.07, m / z found 284.0 [M+H]+.

[0277] Step 4: To a solution of 4-(l, 1 -difluoroethyl) benzenesulfonyl chloride (67.9 mg, 282 μmol, 2 eq) and 4-chloro-3-(7, 7-difluoro-3-azabicyclo [4.1.0] heptan-3-yl)-lH-indazole (40 mg, 141μmol , 1 eq) in DCM (2 mL) was added dropwise TEA (71.3 mg, 705 μmoll 98.1 μL, 5 eq) and DMAP (1.72 mg, 14.1 μmol, 0.1 eq). The mixture was stirred at 20 °C for 1 hour. LC-MS showed 4-chloro-3-(7, 7-difluoro-3-azabicyclo [4.1.0] heptan-3-yl)-lH-indazole was consumed completely and the desired mass was detected. The reaction mixture was concentrated to give the crude product. The residue was purified byprep-HPLC (TFA condition; column: Phenomenex Luna C18 75 * 30 mm * 3 μm; mobile phase: [water (TFA)-ACN]; B%: 45%-75%,8min) to give the desired 4-chloro-3-(7, 7-difluoro-3-azabicyclo [4.1.0] heptan-3-yl)-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-indazole (13.9 mg, 28.5 μmoll 20.2% yield, 100.00% purity) as a white solid. ^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 (br m, 1H), 3.28 (br m, 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% (220 nm), 92.48% (210 nm), 100.00% (254 nm). MS (ESI): mass calcd. For C21H18CIF4N3O2S 487.07, m / z found 488.1 [M+H]+.Compound 2: 4-Chloro-3-(3, 3-difluoroazetidin-l-yl)-l-((4-(l, 1-difluoroethyl) phenyl) sulfonyl)-lH-indazole86SUBSTITUTE SHEET (RULE 26)

[0278] Step 1: To a solution of 3, 3 -difluoroazetidine (137 mg, 1.06 mmol, 1 eq, HC1) in DCM (5 mL) were added TEA (1.07 g, 10.6 mmol, 1.47 mL, 10 eq) and (lE)-2,6-dichloro-N-(p- tolylsulfonyl)benzohydrazonoyl chloride (0.4 g, 1.06 mmol, 1 eq) at -78 °C. The mixture was stirred at 0 °C for 0.5 hour. LCMS showed (lE)-2, 6-dichloro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride was complete and the desired MS was detected. The reaction mixture was added H2O (5 mL) at 0 °C, and extracted with EtOAc (3 X 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired N-[(E)-[(2,6-dichlorophenyl)-(3,3-difluoroazetidin-l-yl)methylene]amino]-4-methyl- benzenesulfonamide (0.45 g, crude) as a yellow oil. MS (ESI): mass calcd. For C17H15CI2F2N3O2S 433.02 m / z found 434.0 [M+H]+,

[0279] Step 2: To a solution of N-[(E)-[(2, 6-dichlorophenyl)-(3, 3-difluoroazetidin-l-yl) methylene] amino]-4-methyl-benzenesulfonamide (0.4 g, 921 μmoll 1 eq) in DMF (5 mL) was added K2CO3(382 mg, 2.76 mmol, 3 eq). The mixture was stirred at 100 °C for 12 hours. LCMS showed N-[(E)-[(2, 6-dichlorophenyl)-(3, 3-difluoroazetidin-l-yl) methylene] amino]-4-methyl- benzenesulfonamide was complete and the desired mass was detected. The reaction mixture was added H2O (5 mL) at 0°C, and extracted with EtOAc (3 X 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired 4- chloro-3-(3, 3-difluoroazetidin-l-yl)-l-(p-tolylsulfonyl) indazole (0.4 g, crude) as a yellow oil. MS (ESI): mass calcd. For C17H14CIF2N3O2S 397.05 m / z found 398.0 [M+H]+.

[0280] Step 3: To a solution of 4-chloro-3-(3, 3-difluoroazetidin-l-yl)-l-(p-tolylsulfonyl) indazole (0.3 g, 754 μmol, 1 eq) in MeOH (4 mL) was added K2CO3(208 mg, 1.51 mmol, 2 eq). The mixture was stirred at 50 °C for 2 hours. LCMS showed 4-chloro-3-(3, 3-difluoroazetidin-l- yl)-l -(p-tolyl sulfonyl) indazole was complete and the desired mass was detected. The reaction87SUBSTITUTE SHEET (RULE 26)mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 3 / 1) to give the desired 4- chloro-3-(3, 3-difluoroazetidin-l-yl)-lH-indazole (0.1 g, 410 μmol, 54.4% yield) as a yellow solid. MS (ESI): mass calcd. For C10H8C1F2N3243.04 m / z found 244.0 [M+H]+.

[0281] Step 4: To a solution of 4-chloro-3-(3,3-difluoroazetidin-l-yl)-lH-indazole (80 mg, 328μmol , 1 eq) and TEA (332 mg, 3.28 mmol, 457 μL, 10 eq) in DCM (1 mL) was added 4- (l,l-difluoroethyl)benzenesulfonyl chloride (237 mg, 985 μmol, 3 eq) and DMAP (4.01 mg, 32.8 μmol, 0.1 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour. LCMS showed 4-chloro-3-(3, 3-difluoroazetidin-l-yl)-lH-indazole was consumed completely and the desired mass was detected. The reaction mixture was quenched with saturated NH4CI (5 mL) at 0 °C, and extracted with EtOAc (3 X 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75 * 30 mm * 3 μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 50% - 80% B over 8.0 min) to give the desired 4-chl oro-3 -(3,3 -difluoroazeti din- 1-yl)- l-[4-(l,l-difluoroethyl)phenyl]sulfonyl-indazole (56.6 mg, 126 μmol, 38.3% yield, 99.87% purity) as a white solid. 1H NMR. ( DMSO-d6) δ 8.08 (d, J= 8.5 Hz, 1H), 7.99 (br d, J= 8.1 Hz, 2H), 7.78 (br d, J= 8.4 Hz, 2H), 7.66 (t, J= 8.1 Hz, 1H), 7.47 (d, J= 7.8 Hz, 1H), 4.64 (br t, J= 12.9 Hz, 4H), 1.94 (br t, J= 19.1 Hz, 3H). HPLC: 99.87% (220 nm), 99.68% (215 nm), 100.00% (254 nm). MS (ESI): mass calcd. For C18H14CIF4N3O2S 447.04 m / z found 448.0 [M+H]+.Compound 3: 4-Chloro-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-3-(3-fhioro-l-bicyclo[1.1.1] pentanyl) indazole88SUBSTITUTE SHEET (RULE 26)

[0282] Step 1 : To a solution of 3 -fluorobicyclo [1.1.1] pentane- 1 -carboxylic acid (5 g, 38.4 mmol, 1 eq) in DMF (50 mL) were added DIPEA (19.9 g, 154 mmol, 26.8 mL, 4 eq), HATU (21.9 g, 57.6 mmol, 1.5 eq) at 20 °C under the atmosphere of N2. The mixture was stirred at 20 °C for 1 hour. To a solution was added N-methoxymethanamine hydrochloride (5.62 g, 57.6 mmol, 1.5 eq) at 20 °C and the mixture was stirred at 20 °C for 11 hours. TLC indicated 3- fluorobicyclo [1.1.1] pentane- 1 -carboxylic acid was consumed completely and one new spot was formed. The residue was diluted with H2O (50 mL) and extracted with EtOAc (100 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / petroleum ether gradient @ 80 mL / min) to give 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.

[0283] Step 2 : To the solution of 1 -chi oro-3 -fluoro-benzene (603 mg, 4.62 mmol, 495 μL,1.6 eq) in THF (6 mL) was added w-BuLi (2.5 M, 1.85 mL, 1.6 eq) at -78 °C and the solution was stirred at -78 °C for 0.5 hour under the atmosphere of nitrogen. To the solution was added 3- fluoro-N-methoxy-N-methyl-bicyclo [1.1.1] pentane- 1 -carboxamide (500 mg, 2.89 mmol, 1 eq) at -78 °C and the solution was stirred at -78 °C for 1 hour. TLC showed 3-fluoro-N-methoxy-N- methyl-bicyclo [1.1.1] pentane- 1 -carboxamide a new spot was detected. To the solution was added NH4CI solution (0.5 mL) and extracted with EtOAc (2 X 5 mL). The combined organics were concentrated to get a residue. The residue was purified by / v'cyi-TLC (silica gel, petroleum ether I ethyl acetate = 3 / 1) to give the desired (2-chloro-6-fluoro-phenyl)-(3-fluoro-l-bicyclo [1.1.1] pentanyl) methanone (450 mg, crude) as a yellow oil.

[0284] Step 3: A mixture of (2-chloro-6-fluoro-phenyl)-(3 -fluoro- 1 -bicyclo [1.1.1] pentanyl) methanone (300 mg, 1.24 mmol, 1 eq) in NH2NH2.H2O (6 mL) was stirred at 100 °C for 3 hours. LC-MS showed (2-chloro-6-fluoro-phenyl)-(3-fluoro-l-bicyclo [1.1.1] pentanyl) methanone was consumed completely and one main peak with the desired mass was detected. The reaction mixture was diluted with H2O (30 ml) and extracted with EtOAc (20 mL X 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to give the desired 4- chloro-3 -(3 -fluoro- 1 -bicyclo [1.1.1] pentanyl)-lH-indazole (40 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C12H10CIFN2236.05, m / z found 237.0 [M+H]+.89SUBSTITUTE SHEET (RULE 26)

[0285] Step 4: To a solution of 4-chloro-3 -(3 -fluoro- 1 -bicyclo[ 1.1. l]pentanyl)-lH-indazole (30 mg, 127 μmol, 1 eq) and 4-(l,l-difluoroethyl)benzenesulfonyl chloride (45.8 mg, 190 μmoll 1.5 eq) in DCM (2 mL) was added TEA (38.5 mg, 380 μmoll 52.9 μL, 3 eq) and DMAP (1.55 mg, 12.7 μmol, 0.1 eq). The mixture was stirred at 20 °C for 1 hour. LC-MS showed 4-chloro-3- (3 -fluoro- 1 -bicyclo [1.1.1] pentanyl)-lH-indazole was consumed completely and one main peak with the desired mass was detected. The reaction mixture was concentrated to give the crude product. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 75 * 30 mm *3 μm; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 55% - 90% B over 8.0 min) to give the desired 4-chloro-l-[4-(l,l-difluoroethyl)phenyl]sulfonyl-3-(3-fluoro-l- bicyclo[l.l. l]pentanyl)indazole (11.3 mg, 25.6 μmol, 20.2% yield, 99.11% purity) as a white solid. Tl NMR (400 MHz, DMSO-d6) δ 8.15 (d, J= 8.4 Hz, 1H), 8.10 (br d, J= 8.3 Hz, 2H), 7.83 (br d, J= 8.3 Hz, 2H), 7.69 (t, J= 8.1 Hz, 1H), 7.55 (d, J= 7.7 Hz, 1H), 2.63 (d, J= 2.1 Hz, 6H), 1.95 (t, J= 19.1 Hz, 3H). HPLC: 99.11% (220 nm), 99.21% (210 nm), 99.09% (254 nm). MS (ESI): mass calcd. For C20H16CIF3N2O2S 440.06, m / z found 441.1 [M+H]+.Compound 4: 4-Chloro-3-(3, 3-difluorocyclobutyl)-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-indazole

[0286] Step 1 : To a solution of 3, 3 -difluorocyclobutanecarboxylic acid (300 mg, 2.20 mmol, 1 eq) in DCM (5 mL) were added N-methoxymethanamine hydrochloride (886 mg, 6.61 mmol, 3 eq, HC1), HATU (2.51 g, 6.61 mmol, 3 eq) and DIEA (2.28 g, 17.6 mmol, 3.07 mL, 8 eq). The mixture was stirred at 20 °C for 12 hours. LC-MS showed 3, 3 -difluorocyclobutanecarboxylic90SUBSTITUTE SHEET (RULE 26)acid was consumed completely and the desired mass was detected. The reaction mixture was added to water (20 mL) and extracted with EtOAc (10 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=l / O to 0 / 1) to give the desired 3, 3-difluoro-N-methoxy-N- methyl-cyclobutanecarboxamide (300 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C7H11F2NO2179.08, m / z found 180.0 [M+H]+.

[0287] Step 2 : To the solution of 1 -chi oro-3 -fluoro-benzene (175 mg, 1.34 mmol, 143 μL,1.2 eq) in THF (6 mL) was addedN-BuLi (2.5 M, 536 μL, 1.2 eq) at -78 °C and the solution was stirred at -78 °C for 0.5 hour under the atmosphere of nitrogen. To the solution was added 3,3- difluoro-N-methoxy-N-methyl-cyclobutanecarboxamide (200 mg, 1.12 mmol, 1 eq) at -78 °C and the solution was stirred at -78 °C for 1 hour. TLC (petroleum ether / ethyl acetate = 3 / 1) showed 3, 3 -difluoro-N-m ethoxy -N-methyl-cyclobutanecarboxamide remained and a new spot was detected. To the solution was added NH4CI solution (0.5 mL) and extracted with EtOAc (2 X 5 mL). The combined organics were concentrated to get a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to give the desired (2-chloro-6-fluoro- phenyl)-(3, 3 -difluorocyclobutyl) methanone (100 mg, crude) as a yellow oil.

[0288] Step 3 : A mixture of (2-chloro-6-fluoro-phenyl)-(3, 3 -difluorocyclobutyl) methanone(100 mg, 402 μmol, 1 eq) in NH2NH2.H2O (2 mL) was stirred at 100 °C for 3 hours. TLC indicated (2-chloro-6-fluoro-phenyl)-(3, 3 -difluorocyclobutyl) methanone was consumed completely and one new spot was formed. The reaction was clean according to TLC. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mL X 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to give the desired 4-chloro-3-(3, 3-difluorocyclobutyl)-lH-indazole (40 mg, crude) as a white solid. .

[0289] Step 4: To a solution of 4-chloro-3-(3, 3-difluorocyclobutyl)-lH-indazole (35 mg, 144μmol, 1 eq) and 4-(l,l-difluoroethyl)benzenesulfonyl chloride (52.1 mg, 216 μmoll 1.5 eq) in DCM (1 mL) were added TEA (43.8 mg, 433 μmoll 60.2 μL, 3 eq) and DMAP (1.76 mg, 14.4μmol , 0.1 eq). The mixture was stirred at 20 °C for 0.5 hours. LC-MS showed 4-chloro-3-(3, 3- difluorocyclobutyl)-lH-indazole was consumed completely and one main peak with the desired mass was detected. The reaction mixture was concentrated to give the crude product. The residue91SUBSTITUTE SHEET (RULE 26)was purified by prepH-PLC (TFA condition; column: Phenomenex Luna C18 75 * 30 mm * 3 μm; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 55% - 80% B over 8.0 min) to give the desired 4-chloro-3-(3, 3-difluorocyclobutyl)-l-[4-(l, 1 -difluoroethyl) phenyl] sulfonyl-indazole (4.3 mg, 9.41 μmol, 6.52% yield, 97.76% purity) as a white solid. 1H NMR (400 MHz, DMSO- d6) δ 8.12 (dd, J= 8.4, 17.1 Hz, 3H), 7.82 (d, J= 8.4 Hz, 2H), 7.70 (t, J= 8.1 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 4.03 (br dd, J= 7.5, 9.0 Hz, 1H), 3.21 - 3.07 (m, 2H), 3.07 - 2.94 (m, 2H), 1.96 (t, J= 19.1 Hz, 3H). HPLC: 97.76% (220 nm), 98.82% (210 nm), 98.60% (254 nm). MS (ESI): mass calcd. For C19H15CIF4N2O2S 446.05, m / z found 447.0 [M+H]+.Compound 5: 4-Chloro-l-((4-(l, 1-difluoroethyl) phenyl) sulfonyl)-3-(3, 3- difluoropyrrolidin-l-yl)-lH-indazole

[0290] Step 1 : A mixture of tert-butyl 4-chloro-3 -iodo-indazole- 1 -carboxylate (300 mg, 792 μmol, 1 eq), 3, 3 -difluoropyrrolidine (137 mg, 951 μm,ol 1.2 eq, HC1), Pd2(dba)s (72.6 mg, 79.2 μmol, 0.1 eq), CS2CO3(775 mg, 2.38 mmol, 3 eq) and BINAP (49.3 mg, 79.2 μm, 0ol.1 eq) in toluene (5 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100 °C for 3 hours under N2atmosphere. LC-MS showed tert-butyl 4-chl oro-3 -iodo-indazole- 1- carboxylate was consumed completely and the desired mass was detected. The crude was added H2O (20 mL) and extracted with EtOAc (15 mL X 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) give the desired tert-butyl 4-chloro-3-(3, 3-difluoropyrrolidin-l-yl) indazole- 1 -carboxylate (200 mg, 559 μmol, 70.5% yield) as a yellow oil. MS (ESI): mass calcd. For C16H18CIF2N3O2357.11 m / z found 358.1 [M+H]+.

[0291] Step 2: To a solution of tert-butyl 4-chl oro-3 -(3, 3-difluoropyrrolidin-l-yl) indazole- 1-carboxylate (200 mg, 559 μmol, 1 eq) in DCM (2 mL) was added TFA (1.59 g, 14.0 mmol, 1.04 mL, 25 eq). The mixture was stirred at 15 °C for 0.5 hour. LC-MS showed tert-butyl 4- chloro-3-(3, 3-difluoropyrrolidin-l-yl) indazole- 1 -carboxylate was consumed completely and the92SUBSTITUTE SHEET (RULE 26)desired mass was detected. The reaction mixture was concentrated in vacuum to give the desired 4-chloro-3-(3, 3-difluoropyrrolidin-l-yl)-lH-indazole (200 mg, crude, TFA) as a brown oil. MS (ESI): mass calcd. For C11H10CIF2N3257.05 m / z found 258.1 [M+H]+.

[0292] Step 3: To a solution of 4-chloro-3-(3, 3-difluoropyrrolidin-l-yl)-lH-indazole (100 mg, 269 μmol, 1 eq, TFA) and 4-(l,l-difluoroethyl)benzenesulfonyl chloride (97.1 mg, 404 μmol, 1.5 eq) in DCM (2 mL) were added TEA (81.7 mg, 807 μmol 112 μL, 3 eq) and DMAP (3.29 mg, 26.9 μmol, 0.1 eq). The mixture was stirred at 15 °C for 1 hour. LC-MS showed 4- chloro-3-(3, 3-difluoropyrrolidin-l-yl)-lH-indazole was consumed completely and the desired mass was detected. The crude was added H2O (20 mL) and extracted with DCM (15 mL X 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition, column: Phenomenex Luna Cl 8 75 * 30 mm * 3 μm; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 55% - 85% B over 8.0 min) give the desired 4-chloro-l-[4-(l,l- difluoroethyl)phenyl]sulfonyl-3-(3,3-difluoropyrrolidin-l-yl)indazole (13.2 mg, 28.6 μmoll 10.6% yield, 100.00% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J= 8.5 Hz, 1H), 7.96 (d, J= 8.4 Hz, 2H), 7.75 (d, J= 8.4 Hz, 2H), 7.65 (t, J= 8.1 Hz, 1H), 7.48 (d, J= 7.6 Hz, 1H), 3.88 (t, J= 13.1 Hz, 2H), 3.70 (t, J= 7.2 Hz, 2H), 2.50 - 2.41 (m, 2H), 1.92 (t, J = 19.1 Hz, 3H). HPLC: 100.00% (220 nm), 100.00% (215 nm), 100.00 (254 nm). MS (ESI): mass calcd. For C19H16CIF4N3O2S 461.06 m / z found 462.1 [M+H] .Compound 6: 4-Chloro-l-((4-(l, 1-difluoroethyl) phenyl) sulfonyl)-3-(3, 3, 4, 4- tetrafluoropyrrolidin-l-yl)-lH-indazole

[0293] Step 1: To a solution of 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidin-l-yl)-lH-indazole (100 mg, 245 μmol, 1 eq, TFA) and 4-(l,l-difluoroethyl)benzenesulfonyl chloride (88.6 mg, 368 μmol, 1.5 eq) in DCM (2 mL) were added TEA (74.5 mg, 736 μmoll 102 μL, 3 eq) and DMAP (3.00 mg, 24.5 μmol, 0.1 eq). The mixture was stirred at 15 °C for 1 hour. LC-MS showed 4-SUBSTITUTE SHEET (RULE 26)chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole was consumed completely and the desired mass was detected. The crude was added H2O (20 mL) and extracted with DCM (15 mL X 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (TFA condition, column: Phenomenex Luna C18 75 * 30 mm * 3 μm; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 55% - 85% B over 8.0 min) give the desired 4-chloro-l-[4- (l,l-difluoroethyl)phenyl]sulfonyl-3-(3,3,4,4-tetrafluoropyrrolidin-l-yl)indazole (14.6 mg, 29.1 μmol, 11.9% yield, 99.25% purity) as a white solid.(400 MHz, DMSO-d6) δ 8.15 (d, J = 8.5 Hz, 1H), 8.06 (d, J= 8.5 Hz, 2H), 7.82 (d, J= 8.5 Hz, 2H), 7.73 (t, J= 8.1 Hz, 1H), 7.57 (d, J= 7.6 Hz, 1H), 4.35 - 4.22 (m, 4H), 1.98 (t, J= 19.1 Hz, 3H). HPLC: 99.25% (220 nm), 98.53% (215 nm), 100.00 (254 nm). MS (ESI): mass calcd. For C19H14CIF6N3O2S 497.04 m / z found 498.1 [M+H]+.Compound 7: 4-Chloro-l-[4-(l,l-difluoroethyl)phenyl]sulfonyl-3-[(2R)-3,3-difluoro-2- methyl-azetidin-l-yl] indazoleCompound 8: 4-Chloro-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-3-[(2S)-3, 3-difluoro-2- methyl-azetidin-l-yl] indazole

[0294] Step 1: To a solution of 4-chloro-3-(3,3-difluoro-2-methyl-cyclobutyl)-lH-indazole (110 mg, 429 μmol, 1 eq) and 4-(l,l-difluoroethyl)benzenesulfonyl chloride (155 mg, 643 μmoll 1.5 eq) in DCM (1 mL) were added TEA (130 mg, 1.29 mmol, 179 μL, 3 eq) and DMAP (5.24 mg, 42.9 μmol, 0.1 eq). The mixture was stirred at 20 °C for 0.5 hour. LC-MS showed 4-chloro- 3 -(3, 3-difluoro-2-methyl-cyclobutyl)-lH-indazole was consumed completely and one main peak with the desired mass was detected. The reaction mixture was added to water (20 mL), extracted with DCM (10 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to give the desired 4-94SUBSTITUTE SHEET (RULE 26)chl oro-3 -(3 ,3 -difluoro-2-methylazetidin- 1 -yl)- 1 -((4-( 1 , 1 -difluoroethyl)phenyl)sulfonyl)- 1H- indazole (110 mg) as a white solid, which was further separated by SFC (condition: column: ChiralPak IH, 250*30mm, 10um;mobile phase: [CO2-fPA(0.1%NH3H2O)]; B%:15%, isocratic elution mode) to give two isomers. The structures were assigned arbitrarily. 4-chloro-l-[4-(l, 1- difluoroethyl) phenyl] sulfonyl-3-[(2R)-3, 3-difluoro-2-methyl-azetidin-l-yl] indazole (21.0 mg, 44.5μmol , 10.4% yield, 97.91% purity, Rt = 0.806 minutes; E.E. by chiral HPLC (%) = 99.98%) was isolated as a white solid. 1HMR (400 MHz, DMSO-d6) δ 8.13 (d, J= 8.5 Hz, IH), 8.01 (d, J= 8.3 Hz, 2H), 7.83 (d, J= 8.4 Hz, 2H), 7.72 (t, J= 8.1 Hz, IH), 7.54 (d, J= 7.8 Hz, IH), 5.04 - 4.91 (m, IH), 4.77 (q, J= 11.5 Hz, IH), 4.57 - 4.41 (m, IH), 1.98 (t, J= 19.1 Hz, 3H), 1.29 (d, J= 6.5 Hz, 3H). HPLC: 97.91% (220 nm), 97.64% (210 nm), 96.97% (254 nm). MS (ESI): mass calcd. For C19H16CIF4N3O2S 461.06, m / z found 462.0 [M+H]+.4-chloro-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-3-[(2S)-3, 3-difhioro-2-methyl-azetidin-l-yl] indazole (21.1 mg, 45.0 μmol, 10.5% yield, 98.52% purity, Rt = 0.908 minutes; E.E. by chiral HPLC (%) = 94.60%) was isolated as a white solid.JH NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 8.4 Hz, IH), 8.01 (d, J= 8.4 Hz, 2H), 7.83 (d, J= 8.4 Hz, 2H), 7.72 (t, J= 8.1 Hz, IH), 7.54 (d, J= 7.6 Hz, IH), 5.06 - 4.91 (m, IH), 4.77 (q, J= 11.3 Hz, IH), 4.57 - 4.42 (m, IH), 1.98 (t, J = 19.1 Hz, 3H), 1.29 (d, J= 6.5 Hz, 3H). HPLC: 98.52% (220 nm), 98.41% (210 nm), 97.10% (254 nm). MS (ESI): mass calcd. For C19H16CIF4N3O2S 461.06, m / z found 462.0 [M+H]+.Compound 9: 4-Chloro-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-3-(3-fluoroazetidin-l-yl) indazole

[0295] Step 1: To a solution of (lE)-2, 6-dichloro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride (800 mg, 2.12 mmol, 1 eq) in DCM (10 mL) were added TEA (2.14 g, 21.2 mmol, 2.9595SUBSTITUTE SHEET (RULE 26)mL, 10 eq) and 3 -fluoroazetidine hydrochloride (284 mg, 2.54 mmol, 1.2 eq) at -78 °C. The mixture was stirred for 0.5 hour and then the mixture was stirred at 0 °C for 0.5 hour. LCMS showed (lE)-2, 6-dichloro-4-fluoro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride was consumed completely and the desired mass was detected. The reaction mixture was concentrated to give the desired N-[(E)-[(2, 6-dichlorophenyl)-(3-fluoroazetidin-l-yl) methylene] amino]-4- methyl-benzenesulfonamide (880 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C17H16C12FN3O2S 415.03 m / z found 415.9 [M+H]+.

[0296] Step 2 : To a solution of N-[(E)-[(2, 6-dichlorophenyl)-(3-fluoroazetidin-l-yl) methylene] amino]-4-methyl-benzenesulfonamide (880 mg, 2.11 mmol, 1 eq) in DMF (10 mL) was added K2CO3(876 mg, 6.34 mmol, 3 eq). The mixture was stirred at 100 °C for 12 hours. LCMS showed N-[(E)-[(2, 6-dichlorophenyl)-(3-fluoroazetidin-l-yl) methylene] amino]-4- methyl-benzenesulfonamide was consumed completely and the desired mass was detected. The residue was added water (10 mL) and extracted with EtOAc (3 X 10 mL). The combined organics were concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to give the desired 4- chloro-3-(3-fluoroazetidin-l-yl)-l-(p-tolylsulfonyl) indazole (280 mg, 737 μmol, 34.9% yield) as a yellow oil. MS (ESI): mass calcd. For C17H15CIFN3O2S 379.06 m / z found 379.9 [M+H]+.

[0297] Step 3: To a solution of 4-chloro-3-(3-fluoroazetidin-l-yl)-l-(p-tolylsulfonyl) indazole (280 mg, 737 μmol, 1 eq) in MeOH (3 mL) was added K2CO3(204 mg, 1.47 mmol, 2 eq). The mixture was stirred at 50 °C for 1 hour. LCMS showed 4-chloro-3-(3-fluoroazetidin-l- yl)-l -(p-tolyl sulfonyl) indazole was consumed completely and the desired mass was detected. The reaction was concentrated to get a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100 / 1 to 3 / 1) to give the desired 4- chloro-3-(3-fluoroazetidin-l-yl)-lH-indazole (90 mg, 399 μmol, 54.1% yield) as a white solid. MS (ESI): mass calcd. For C10H9CIFN3225.05 m / z found 225.9 [M+H]~.

[0298] Step 4: To a solution of 4-chloro-3-(3-fluoroazetidin-l-yl)-lH-indazole (80 mg, 355 μmol, 1 eq) in DCM (1 mL) were added TEA (179 mg, 1.77 mmol, 247 μL, 5 eq) and DMAP (4 mg, 35.5 μmol, 0.1 eq), 4-( 1,1 -difluoroethyl )benzenesulfonyl chloride (171 mg, 709 μ,m 2o elq). The mixture was stirred at 25 °C for 1 hour. LCMS showed 4-chloro-3-(3-fluoroazetidin-l-yl)- IH-indazole was consumed completely and the desired mass was detected. The reaction was concentrated to get a residue. The residue was purified by prepH-PLC (column: Waters Xbridge96SUBSTITUTE SHEET (RULE 26)C18 150 * 50 mm * 10 μm; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 40% - 70% B over 8.0 min) to give the desired 4-chloro-l-[4-(l,l-difluoroethyl)phenyl]sulfonyl-3-(3- fluoroazetidin-l-yl)indazole (16 mg, 36.9 μmol, 10.4% yield, 99.23% purity) as a white solid. 1H NMR (400 MHz, DMSOd6) 5 8.07 (d, J= 8.4 Hz, IH), 7.97 (br d, J= 8.1 Hz, 2H), 7.78 (br d, J = 8.2 Hz, 2H), 7.65 (br t, J= 8.1 Hz, IH), 7.46 (br d, J= 7.7 Hz, IH), 5.59 - 5.35 (m, IH), 4.60 - 4.43 (m, 2H), 4.34 - 4.17 (m, 2H), 1.95 (brt, J= 19.1 Hz, 3H). MS (ESI): mass calcd. For C18H15CIF3N3O2S 429.05 m / z found 430.0 [M+H]+.Compound 10: 4-Chloro-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-3-(3-fluoro-3-methyl- azetidin-l-yl) indazole

[0299] Step 1: The mixture of 3-fluoro-3-methyl-azetidine (319 mg, 2.54 mmol, 1.2 eq, HC1) in DCM (8 mL) were added TEA (1.07 g, 10.6 mmol, 1.47 mL, 5 eq) and (lE)-2,6-dichloro-N- (p-tolylsulfonyl)benzohydrazonoyl chloride (800 mg, 2.12 mmol, 1 eq) was added the mixture at -78 °C. The mixture was stirred at 0 °C for 0.5 hour. LCMS showed (lE)-2, 6-dichloro-N-(p- tolyl sulfonyl) benzohydrazonoyl chloride was consumed completely and the desired mass was detected. The reaction mixture was quenched by addition sat. aq. NH4CI (30 mL) at 0 °C, and extracted with DCM (3 X 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The reaction mixture was concentrated to give the desired N-[(E)-[(2, 6-dichlorophenyl)-(3-fhroro-3-methyl-azetidin-l-yl) methylene] amino]-4-methyl- benzenesulfonamide (800 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C18H18CI2FN3O2S 429.05 m / z found 430.1 [M+H]+.97SUBSTITUTE SHEET (RULE 26)

[0300] Step 2 : The mixture ofN-[(E)-[(2, 6-dichlorophenyl)-(3-fluoro-3-methyl-azetidin-l- yl) methylene] amino]-4-methyl-benzenesulfonamide (800 mg, 1.86 mmol, 1 eq) in DMF (6 mL) was added K2CO3(771 mg, 5.58 mmol, 3 eq). The mixture was stirred at 100 °C for 12 hours. LCMS showed N-[(E)-[(2, 6-dichlorophenyl)-(3-fluoro-3-methyl-azetidin-l-yl) methylene] amino]-4-methyl-benzenesulfonamide was consumed completely and the desired mass was detected. The reaction mixture was concentrated to give the desired 4-chloro-3-(3-fluoro-3- methyl-azetidin-l-yl)-l-(p-tolylsulfonyl) indazole (700 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C18H17CIFN3O2S 393.07 m / z found 394.1 [M+H]+.

[0301] Step 3: The mixture of 4-chloro-3-(3-fluoro-3-methyl-azetidin-l-yl)-l-(p- tolyl sulfonyl) indazole (800 mg, 2.03 mmol, 1 eq) in MeOH (10 mL) was added K2CO3(561 mg, 4.06 mmol, 2 eq). The mixture was stirred at 50 °C for 1 hour. LCMS showed 4-chloro-3-(3- fluoro-3-methyl-azeti din- 1-yl)- 1 -(p-tolyl sulfonyl) indazole was consumed completely and the desired mass was detected. The reaction was concentrated to get a residue. The residue was added water (30 mL) and extracted with EtOAc (3 X 50 mL). The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) The reaction mixture was concentrated to give the desired 4-chloro-3-(3-fluoro-3-methyl-azetidin-l-yl)-lH- indazole (200 mg, 834 μmol, 47.0% yield) as a yellow oil. MS (ESI): mass calcd. For C11H11CIFN3239.06 m / z found 240.2 [M+H]+.

[0302] Step 4: The mixture of 4-chloro-3-(3-fluoro-3-methyl-azetidin-l-yl)-lH-indazole (200 mg, 834 μmol, 1 eq) in DCM (10 mL) were added TEA (253 mg, 2.50 mmol, 348 μL, 3 eq) and DMAP (10.2 mg, 83.5 μmol, 0.1 eq) at 0 °C. The mixture was stirred 25 °C for 1 hour. LCMS showed 4-chloro-3-(3-fluoro-3-methyl-azetidin-l-yl)-lH-indazole was consumed completely and the desired mass was detected. The reaction was concentrated to get a residue. The residue was purified by prepH-PLC (column: Waters Xbridge Cl 8 150 * 50 mm * 10 μm; mobile phase: [H2O(10M ]; gradient: 60% - 90% B over 8.0 min) to give the desired 4-chloro- 1 - [4-( 1 , 1 -difluoroethyl)phenyl]sulfonyl-3-(3-fluoro-3-methyl-azetidin- 1 - yl)indazole (82.2 mg, 171 μmol, 20.5% yield, 92.23% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-cL) δ 8.07 (d, J= 8.4 Hz, 1H), 7.95 (d, J= 8.6 Hz, 2H), 7.77 (d, J= 8.6 Hz, 2H), 7.65 (t, J= 8.1 Hz, 1H), 7.46 (d, .7= 7.6 Hz, 1H), 4.38 - 4.14 (m, 4H), 1.94 (t, J= 19.1 Hz, 3H), 1.68 - 1.49 (m, 3H) HPLC: 96.32% (220 nm), 96.20% (215 nm), 92.23% (254 nm). MS (ESI): mass calcd. For C19H17CIF3N3O2S 443.07 m / z found 444.3 [M+H]+.98SUBSTITUTE SHEET (RULE 26)Compound 11: 4-Chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-l-[4-(trifluoromethyl) phenyl] sulfonyl-indazoleStep 1

[0303] Step J: To a solution of 4-chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole (50 mg, 170 μmol, 1 eq) and 4-(trifluoromethyl)benzenesulfonyl chloride (62.5 mg, 255 μm,ol 1.5 eq) in DCM (1 mL) were added TEA (86.2 mg, 851 qmol, 119 μL. 5 eq) and DMAP (2.08 mg, 17.0 μmol, 0.1 eq). The mixture was stirred at 15 °C for 0.5 hour. LC-MS showed 4-chloro- 3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 10 mL of FLO and 10 mL of EtOAc. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by prep-TLC (silica gel, petroleum ether I ethyl acetate = 3 / 1) to give the desired 4- chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-l-[4-(trifluorom ethyl) phenyl] sulfonyl-indazole (15.5 mg, 29.2 μmol, 17.2% yield, 94.67% purity) as a white solid. 1H NMR (400 MHz, DMSO- d6) δ 8.10 (d, J= 8.4 Hz, 3H), 7.95 (d, J= 8.4 Hz, 2H), 7.69 (t, J= 8.1 Hz, 1H), 7.53 (d, J= 7.8 Hz, 1H), 4.23 (br t, J= 12.1 Hz, 4H). HPLC: 94.67% (220 nm), 100.0% (215 nm), 94.83% (254 nm). MS (ESI): mass calcd. For C18H11CIF7N3O2S 501.0, m / z found 502.0 [M+H]+.Compound 12: 4-Chloro-l-[4-(difluoromethyl) phenyl] sulfonyl-3-(3, 3, 4, 4- tetrafluoropyrrolidin-l-yl) indazole99SUBSTITUTE SHEET (RULE 26)

[0304] Step 1 : To a solution of 4-chloro-3-(3,3,4,4-tetrafluoropyrrolidin-l-yl)-lH-indazole(100 mg, 341 μmol, 1 eq) and 4-formylbenzenesulfonyl chloride (105 mg, 511 μmoll 1.5 eq) in DCM (1 mL) were added TEA (103 mg, 1.02 mmol, 142 μL, 3 eq) and DMAP (4.16 mg, 34.1 gmol, 0.1 eq). The mixture was stirred at 15 °C for 0.5 hour. LC-MS showed 4-chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 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 give the crude product. The residue was purified by prep- TLC (silica gel, petroleum ether / ethyl acetate = 1 / 1) to give the desired 4-[4-chloro-3-(3, 3, 4, 4- tetrafluoropyrrolidin-l-yl) indazol-l-yl] sulfonylbenzaldehyde (27 mg, 58.5 μmoll 17.2% yield) as a white solid. MS (ESI): mass calcd. Lor C18H12CIF4N3O3S 461.1, m / z found 462.1 [M+H]+.

[0305] Step 2\ To a solution of 4-[4-chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl) indazol-l- yl] sulfonylbenzaldehyde (24 mg, 52.0 μmoll 1 eq) in DAST (0.3 mL). The mixture was stirred at 15 °C for 1 hour. LC-MS showed 4-[4-chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl) indazol- l-yl] sulfonylbenzaldehyde was consumed completely and the desired mass was detected. The reaction was quenched by Sodium bicarbonate in LEO (10 ml), then the mixture was extracted with EtOAc (20 mL). The organic phase was separated, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by pre-pT-LC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to give the desired 4- chloro-l-[4-(difluoromethyl) phenyl] sulfonyl-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl) indazole (12.3 mg, 24.4 gmol, 46.9% yield, 95.84% purity) as a white solid. 1H NMR (400 MHz, DMSO- d6) δ 8.09 (d, J= 8.6 Hz, 1H), 8.03 (d, J= 8.3 Hz, 2H), 7.76 (d, J= 8.1 Hz, 2H), 7.67 (t, J= 8.1 Hz, 1H), 7.51 (d, 7.7 Hz, 1H), 7.25 - 6.93 (m, 1H), 4.23 (br t, J= 12.2 Hz, 4H). HPLC:95.84% (220 nm), 94.80% (215 nm), 96.15% (254 nm). MS (ESI): mass calcd. For C18H12CIF6N3O2S 483.0, m / z found 484.0 [M+H]+.Compound 13: l-((4-(l, 1-Difluoroethyl) phenyl) sulfonyl)-4-fluoro-3-(3, 3, 4, 4- tetrafluoropyrrolidin-l-yl)-lH-indazole tooSUBSTITUTE SHEET (RULE 26)

[0306] Step 1 : A mixture of tert-butyl 4-fluoro-3 -iodo-indazole- 1 -carboxylate (100 mg, 278 μmol, 1 eq), 3, 3, 4, 4-tetrafluoropyrrolidine (50 mg, 278 μmoll 1 eq, HC1), Pd2(dba)s (25.5 mg, 27.9μmol , 0.1 eq), CS2CO3(272 mg, 835 μm,o 3l eq) and BINAP (17.3 mg, 27.9 μm, 0ol.1 eq) in toluene (2 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100 °C for 3 hours under N2atmosphere. LC-MS showed teit-butyl 4-fluoro-3-iodo-indazole- 1 -carboxylate was consumed completely and the desired mass was detected. The crude was added H2O (20 mL) and extracted with EtOAc (15 mL X 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) give the desired tert-butyl 4-fluoro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl) indazole- 1 -carboxylate (100 mg, 265 μmol, 95.17% yield) as a yellow oil. MS (ESI): mass calcd. For C16H16F5N3O2377.12 m / z found 378.1 [M+H]+.

[0307] Step 2'. To a solution of tert-butyl 4-fluoro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l- yl)indazole-l -carboxylate (100 mg, 265 μmol, 1 eq) in DCM (1 mL) was added TFA (453 mg, 3.98 mmol, 295 μL, 15 eq) at 0 °C. The mixture was stirred at 15°C for 0.5 hour. LC-MS showed tert-butyl 4-fluoro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl) indazole- 1 -carboxylate was consumed completely and the desired mass was detected. The reaction mixture was concentrated in vacuum to give the desired 4-fluoro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole (100 mg, crude, TFA) as a brown oil. MS (ESI): mass calcd. For C11H8F5N3277.06 m / z found 278.0 [M+H]+.

[0308] Step 3: To a solution of 4-fluoro-3-(3,3,4,4-tetrafluoropyrrolidin-l-yl)-lH-indazole (80 mg, 289 μmol, 1 eq) and 4-(l,l-difluoroethyl)benzenesulfonyl chloride (69.5 mg, 289 μmoll 1 eq) in DCM (0.5 mL) were added TEA (58.4 mg, 577 μmoll 80.3 μL, 2 eq) and DMAP (3.53 mg, 28.9 μmol, 0.1 eq). The mixture was stirred at 15 °C for 0.5 hour. LC-MS showed 4-fluoro- 3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole was consumed completely and the desired mass was detected. The crude was added H2O (20 mL) and extracted with DCM (15 mL X 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and101SUBSTITUTE SHEET (RULE 26)concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) give the desired l-[4-(l, 1 -difluoroethyl) phenyl] sulfonyl-4-fluoro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl) indazole (3.2 mg, 6.65 μm,ol 2.30% yield, 100% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J= 8.5 Hz, 2H), 8.00 (d, J= 8.5 Hz, 1H), 7.82 (d, J= 8.5 Hz, 2H), 7.79 - 7.73 (m, 1H), 7.31 (dd, J= 8.1, 11.3 Hz, 1H), 4.39 - 4.26 (m, 4H), 1.99 (t, J= 19.1 Hz, 3H). HPLC: 100.00% (220 nm), 100.00% (215 nm), 100.00 (254 nm). MS (ESI): mass calcd. For C19H14F7N3O2S 481.07 m / z found 482.1 [M+H]+.Compound 14: 4-Chloro-l-[[3-(l, l-difluoroethyl)-l- bicycle [1.1.1] pentanyl] sulfonyl]-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl) indazole

[0309] Step 1: To a solution of 4-chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole (50 mg, 170 μmol, 1 eq) and 3-(l, 1 -difluoroethyl) bicycle [1.1.1] pentane- 1 -sulfonyl fluoride (36.5 mg, 170 μmol, 1 eq) in ACN (3 mL) were added bis[bis(trifluoromethylsulfonyl) amino] calcium (307 mg, 511 μmol, 3 eq), TEA (86.2 mg, 851 μmoll 119 μL, 5 eq) and CS2CO3(277 mg, 851 μmol, 5 eq). The mixture was stirred at 90 °C for 12 hours. LC-MS showed 4-chloro-3- (3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole was consumed completely and the desired mass was detected. The reaction mixture was filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18 75 * 30mm *3 μm; mobile phase: [H2O (0.1% TFA) - ACN]; gradient: 65% - 95% B over 8.0 minutes) to give the desired 4-chloro-l-[[3-(l, 1 -difluoroethyl)- 1 -bicyclo [1.1.1] pentanyl] sulfonyl]-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl) indazole (6.7 mg, 13.7 μmoll 8.07% yield, 100.00% purity) as a white solid.(400 MHz, DMSO-d6) δ 7.91 (d, J= 8.50 Hz, 1 H) 7.62 - 7.70 (m, 1 H) 7.55 (d, . / = 7.63 Hz, 1 H) 4.27 (br t, J= 12.95 Hz, 4 H) 2.12 (s, 6 H) 1.51 (t, J= 18.89 Hz, 3 H). HPLC: 100.00% (220 nm), 100.00% (215 nm), 100.00% (254 nm). MS (ESI): mass calcd. For C18H16CIF6N3O2S 487.06 m / z found 488.1 [M+H]+.102SUBSTITUTE SHEET (RULE 26)Compound 15: 4-Chloro-l-[[3-(l, l-difluoroethyl)-l-bicyclo [1.1.1] pentanyl] sulfonyl]-3-(3, 3-difluoro-2-methyl-azetidin-l-yl) indazole

[0310] Step 1: To a solution of 4-chloro-3-(3, 3-difluoro-2-methyl-azetidin-l-yl)-lH- indazole (70 mg, 272 μmol, 1 eq) and 3-(l,l-difluoroethyl)bicyclo[l. l.l]pentane-l-sulfonyl fluoride (58.2 mg, 272 μmol, 1 eq) in ACN (3 mL) were added bis[bis(trifluoromethylsulfonyl)amino]calcium (163 mg, 272 μmoll 1 eq), TEA (137 mg, 1.36 mmol, 189 μL, 5 eq) and CS2CO3(443 mg, 1.36 mmol, 5 eq). The mixture was stirred at 90 °C for 12 hours. LC-MS showed 4-chloro-3-(3, 3-difluoro-2-methyl-azetidin-l-yl)-lH-indazole was consumed completely and the desired mass was detected. The reaction mixture was filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prHepP-LC (TFA condition; according to LCMS; method: column: Phenom enex Luna €18 75 * 30 mm * 3 μm; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 65%-95% B over 8.0 min) to give the desired 4-chloro-l-[[3-(l,l-difluoroethyl)-l-bicyclo[l. l.l]pentanyl]sulfonyl]-3-(3,3-difluoro-2- methyl-azetidin-l-yl)indazole (1.6 mg, 3.54 μmol, 1.33% yield, 100.0% purity) as a white solid. 1H NMR (DMSO-d6) δ 7.86 (br d, J= 8.4 Hz, 1H), 7.62 (br t, J= 8.0 Hz, 1H), 7.53 - 7.46 (m, 1H), 5.01 - 4.86 (m, 1H), 4.77 (q, 11.6 Hz, 1H), 4.62 - 4.48 (m, 1H), 2.09 (s, 6H), 1.51 (br t,J= 18.9 Hz, 3H), 1.35 (br d, J = 6.4 Hz, 3H). HPLC: 100.0% (220 nm), 99.72% (215 nm), 100.0% (254 nm). MS (ESI): mass calcd. For C18H18CIF4N3O2S 451.1 m / z found 452.1 [M+H]+.Compound 16: 4-Chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-l-[[3-(trifluoromethyl)-l- bicyclo [1.1.1] pentanyl] sulfonyl] indazole103SUBSTITUTE SHEET (RULE 26)

[0311] Step l : To a solution of 4-chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole(10 mg, 34.1 μmol, 1 eq) and 3 -(trifluoromethyl) bicycle [1.1.1] pentane- 1 -sulfonyl fluoride (8.92 mg, 40.9 μmol, 1.2 eq) in ACN (1.5 mL) were added bis [bis (trifluoromethylsulfonyl) amino] calcium (24.5 mg, 40.9 μmoll 1.2 eq), CS2CO3(55.5 mg, 170 μm, o 5l eq) and TEA (17.2 mg, 170 μmol, 23.7 μL, 5 eq). The mixture was stirred at 80 °C for 12 hours. LCMS showed 4- chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole was consumed completely and the desired mass was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75 * 30 mm * 3 μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 45% - 75% B over 8.0 min) to give the desired 4-chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-l-[[3-(trifluoromethyl)-l-bicyclo [1.1.1] pentanyl] sulfonyl]indazole (5.9 mg, 12.0 μmoll 35.2% yield, 100.00% purity) as a yellow solid. ^NMR (400 MHz, DMSO-d6) δ 7.84 (d, J= 8.3 Hz, 1H), 7.60 (t, 8.1 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 4.22 (br t, J= 12.2 Hz, 4H), 2.29 (s, 6H). HPLC: 99.75% (220 nm), 99.49% (215 nm), 100.00% (254 nm). MS (ESI): mass calcd. For C17H13CIF7N3O2S 491.03 m / z found 492.00 [M+H]+.Compound 17: 4-Chloro-l-[(3-fluoro-l-bicyclo [1.1.1] pentanyl) sulfonyl] -3-(3, 3, 4, 4- tetrafluoropyrrolidin-l-yl) indazole

[0312] Step 1: To a solution of 4-chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole (10 mg, 34.1 μmol, 1 eq) and 3 -fluorobicyclo [1.1.1] pentane- 1 -sulfonyl fluoride (6.9 mg, 40.9 μmol, 1.2 eq) in ACN (1.5 mL) were added bis [bis (trifluoromethylsulfonyl) amino] calcium (24.5 mg, 40.9 μmol, 1.2 eq), CS2CO3(55.5 mg, 170 μm,o 5l eq) and TEA (17.2 mg, 170 μm, ol 23.7 μL, 5 eq). The mixture was stirred at 80 °C for 12 hours. LCMS showed 4-chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole was consumed completely and the desired mass was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75 * 30 mm * 3 μm; mobile phase:104SUBSTITUTE SHEET (RULE 26)[H2O(0.1%TFA)-ACN]; gradient: 40% - 70% B over 8.0 min) to give the desired 4-chloro-l-[(3- fluoro-1 -bicyclo [1.1.1] pentanyl)sulfonyl]-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl) indazole (4.9 mg, 11.1 μmol, 32.57% yield, 97.44% purity) as a white solid.rH NMR (400 MHz, DMSO-cL) δ 7.90 (d, J= 8.5 Hz, 1H), 7.67 (t, J= 8.1 Hz, 1H), 7.57 (d, J= 7.5 Hz, 1H), 4.34 - 4.20 (m, 4H), 2.45 (d, J= 2.3 Hz, 6H). HPLC: 97.44% (220 nm), 96.90% (215 nm), 99.84% (254 nm). MS (ESI): mass calcd. For C16H13CIFSN3O2S 441.03 m / z found 442.00 [M+H]+.Compound 18: 4-Chloro-3-(3, 3-difluoro-2-methylazetidin-l-yl)-l-((3-(trifluoromethyl) bicycle [1.1.1] pentan-l-yl) sulfonyl) -IH-indazole

[0313] Step 1. To a solution of 4-chloro-3-(3,3-difluoro-2-methyl-azetidin-l-yl)-lH-indazole (20 mg, 77.6 μmol, 1 eq) and 3 -(trifluoromethyl)bicyclo[l. l.l]pentane-l -sulfonyl fluoride (25.4 mg, 116 μmol, 1.5 eq) in ACN (2 mL) were added bis [bis (trifluoromethyl sulfonyl) amino] calcium (55.9 mg, 93.1 μmol, 1.2 eq), TEA (39.3 mg, 388 μmoll 54.0 μL, 5 eq) and CS2CO3(126 mg, 388 μmol, 5 eq). The mixture was stirred at 80 °C for 12 hours. LC-MS showed 4-chloro-3- (3, 3 -difluoro-2-methyl-azetidin-l-yl)- IH-indazole was consumed completely and the desired mass was detected. The crude was added H2O (20 mL) and extracted with EtOAc (15 mL X 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition, column: Phenom enex Luna C18 75 * 30 mm *3 μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 50% - 80% B over 8.0 min) give the desired 4-chloro-3-(3, 3- difluoro-2-methylazetidin-l-yl)-l-((3-(trifluoromethyl) bicycle [1.1.1] pentan-l-yl) sulfonyl) - IH-indazole (10.5 mg, 23.0 μmol, 29.7% yield, 100.00% purity) as a white solid. 1H NMR (400 MHz, DMSO-t / e) δ 7.86 (d, J= 8.0 Hz, 1H), 7.63 (t, J= 8.1 Hz, 1H), 7.51 (d, J= 7.1 Hz, 1H), 5.01 - 4.88 (m, 1H), 4.83 - 4.73 (m, 1H), 4.57 (dt, J= 10.7, 13.4 Hz, 1H), 2.33 (s, 6H), 1.36 (d, J = 6.5 Hz, 3H). HPLC: 100.00% (220 nm), 100.00% (215 nm), 100.00 (254 nm). MS (ESI): mass calcd. For C17H15CIF5N3O2S 455.05 m / z found 456.1 [M+H] .105SUBSTITUTE SHEET (RULE 26)Compound 19: 4-Chloro-3-(3, 3-difluoro-2-methylazetidin-l-yl)-l-((3-fluorobicyclo [1.1.1] pentan-l-yl) sulfonyl)-lH-indazole

[0314] Step 1 : To a solution of 4-chloro-3-(3,3-difluoro-2-methyl-azetidin-l-yl)-lH-indazole (10 mg, 38.8 μmol, 1 eq) and 3 -fluorobicyclo[l.l.l]pentane-l -sulfonyl fluoride (9.79 mg, 58.2 μmol, 1.5 eq) in ACN (2 mL) were added bis[bis(trifluoromethylsulfonyl) amino]calcium (28.0 mg, 46.6 μmol, 1.2 eq), TEA (19.6 mg, 194 μmoll 27.0 μL, 5 eq) and CS2CO3(63.2 mg, 194 μmol, 5 eq). The mixture was stirred at 80 °C for 12 hours. LC-MS showed 4-chloro-3-(3, 3- difluoro-2-methyl-azetidin-l-yl)-lH-indazole was consumed completely and the desired mass was detected. The crude was added H2O (20 mL) and extracted with EtOAc (15 mL X 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by / 2 / X72-HPLC (TFA condition, column: Phenomenex Luna Cl 8 75 * 30 mm * 3 μm; mobile phase:[H2O(0.1%TFA)-ACN]; gradient: 45%-75% B over 8.0 min) to give the desired 4-chloro-3-(3,3- difluoro-2-methyl-azetidin- 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. 1H NMR (400 MHz, DMSO-d6) 8 7.91 (d, J= 8.3 Hz, 1H), 7.69 (t, J= 8.1 Hz, 1H), 7.57 (d, J= 7.5 Hz, 1H), 5.06 - 4.92 (m, 1H), 4.89 - 4.78 (m, 1H), 4.63 (dt, J= 10.8, 13.4 Hz, 1H), 2.49 (d, J= 2.3 Hz, 6H), 1.42 (d, J= 6.5 Hz, 3H). HPLC: 100.00% (220 nm), 100.00% (215 nm), 100.00 (254 nm). MS (ESI): mass calcd. For CI6HI5C1F3N3O2S 405.05 m / z found 406.1 [M+H] .Compound 20: 4-Chloro-3-(6, 6-difluoro-3-azabicyclo [3.1.0] hexan-3-yl)-l-[4-(l, 1- difluoroethyl) phenyl] sulfonyl-indazoleSUBSTITUTE SHEET (RULE 26)

[0315] Step 1 : To a solution of 6, 6-difluoro-3 -azabicyclo [3.1.0] hexane (150 mg, 964 μm, ol 1 eq, HC1) in THF (2 mL) was added dropwise TEA (976 mg, 9.64 mmol, 1.34 mL, 10 eq) at 25 °C. After addition, the mixture was stirred at this temperature for 10 minutes. (lZ)-2,6-dichloro- N-(p-tolylsulfonyl)benzohydrazonoyl chloride (401 mg, 1.06 mmol, 1.1 eq) 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 showed 6, 6-difluoro-3 -azabicyclo [3.1.0] hexane was consumed completely and one main peak with the desired mass was detected. The reaction mixture was separated between 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 give the desired N-[(Z)-[(2, 6-dichlorophenyl)-(6, 6-difluoro-3 -azabicyclo [3.1.0] hexan-3-yl) methylene] amino]-4-methyl-benzenesulfonamide (440 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C19H17CI2F2N3O2S 459.04 m / z found 460.2 [M+H]+.

[0316] Step 2\ To a solution of N-[(Z)-[(2, 6-dichlorophenyl)-(6, 6-difluoro-3-azabicyclo [3.1.0] hexan-3-yl) methylene] amino]-4-methyl-benzenesulfonamide (440 mg, 956 μm,o 1l eq) in DMF (10 mL) was added K2CO3(661 mg, 4.78 mmol, 5 eq). The mixture was stirred at 100 °C for 12 hours. LC-MS showed N-[(Z)-[(2, 6-dichlorophenyl)-(6, 6-difluoro-3 -azabicyclo [3.1.0] hexan-3-yl) methylene] amino]-4-methyl-benzenesulfonamide was consumed completely and the desired mass was detected. The reaction mixture was added to water (30 mL) and extracted with EtOAc (30 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired 4- chloro-3-(6, 6-difluoro-3 -azabicyclo [3.1.0] hexan-3-yl)-l-(p-tolyl sulfonyl) indazole (400 mg,107SUBSTITUTE SHEET (RULE 26)crude) as a yellow oil. MS (ESI): mass calcd. For C19H16CIF2N3O2S 423.06 m / z found 424.1 [M+H]+.

[0317] Step 3: To a solution of 4-chloro-3-(6, 6-difluoro-3 -azabicyclo [3.1.0] hexan-3-yl)-l- (p-tolyl sulfonyl) indazole (400 mg, 944 μmoll 1 eq) in MeOH (10 mL) was added K2CO3(652 mg, 4.72 mmol, 5 eq). The mixture was stirred at 60 °C for 0.5 hour. LC-MS showed 4-chloro-3- (6, 6-difluoro-3 -azabicyclo [3.1.0] hexan-3-yl)-l-(p-tolyl sulfonyl) indazole was consumed completely and the desired mass was detected. The reaction mixture was added to water (30 mL) and extracted with EtOAc (30 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to give the desired 4-chloro-3-(6, 6-difluoro-3 -azabicyclo [3.1.0] hexan-3-yl)-lH-indazole (80 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C12H10CIF2N3269.05 m / z found 270.2 [M+H]+.

[0318] Step 4. To a solution of 4-chloro-3-(6, 6-difluoro-3 -azabicyclo [3.1.0] hexan-3-yl)- IH-indazole (30 mg, 111 μmol, 1 eq) and 4-(l, 1 -difluoroethyl) benzenesulfonyl chloride (40.2 mg, 167 μmol, 1.5 eq) in DCM (1 mL) were added TEA (33.8 mg, 334 μm,o 4l 6.5 LIL, 3 eq) and DMAP (1.36 mg, 11.1 μmol, 0.1 eq). The mixture was stirred at 20 °C for 0.5 hour. LC-MS showed 4-chloro-3-(6, 6-difluoro-3 -azabicyclo [3.1.0] hexan-3-yl)-lH-indazole was consumed completely and one main peak with the desired mass was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by / vep-HPLC (TFA condition; column: Phenomenex Luna Cl 8 80 * 30 mm * 3 μm; mobile phase:[H2O(0.1%TFA)-ACN]; gradient: 50%-80% B over 8.0 min) to give the desired 4-chloro-3-(6, 6-difluoro-3 -azabicyclo [3.1.0] hexan-3-yl)-l-[4-(l, 1 -difluoroethyl) phenyl] sulfonyl-indazole (6.0 mg, 12.1 μmol, 10.9% yield, 95.51% purity) as a yellow solid. 1H NMR (400 MHz, DMSO- ds) δ 8.10 (d, J= 8.4 Hz, 1H), 7.95 (d, J= 8.4 Hz, 2H), 7.76 (d, J= 8.6 Hz, 2H), 7.64 (t, J= 8.1 Hz, 1H), 7.49 (d, J= 7.7 Hz, 1H), 4.01 (d, J= 11.0 Hz, 2H), 3.84 - 3.75 (m, 2H), 2.62 (br d, J= 11.7 Hz, 2H), 1.94 (t, J= 19.1 Hz, 3H). HPLC: 95.51% (220 nm), 95.21% (215 nm), 96.48 (254 nm). MS (ESI): mass calcd. For C20H16CIF4N3O2S 473.06 m / z found 474.0 [M+H]".Compound 21: 4-Chloro-3-(2, 2-difluoro-5-azaspiro [2.3] hexan-5-yl)-l-[4-(l, 1- difluoroethyl) phenyl] sulfonyl-indazole108SUBSTITUTE SHEET (RULE 26)

[0319] Step 1: To a solution of (lE)-2, 6-dichloro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride (364 mg, 964 μmol, 1 eq) and TEA (976 mg, 9.64 mmol, 1.34 mL, 10 eq) in THF (10 mL) was added 2, 2-difluoro-5-azaspiro [2.3] hexane (150 mg, 964 μm,ol 1 eq, HC1) at -15 °C and the mixture was stirred at 20 °C for 12 hours. LCMS showed (lE)-2, 6-dichloro-N-(p- tolyl sulfonyl) benzohydrazonoyl chloride was consumed completely and the desired mass was detected. The reaction was concentrated under reduced pressure to give the desired N-[(E)-[(2, 6- dichlorophenyl)-(2, 2-difluoro-5-azaspiro [2.3] hexan-5-yl) methylene] amino]-4-methyl- benzenesulfonamide (443 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C19H17N3SO2CI2F2459.04 m / z found 460.1 [M+H]+,

[0320] Step 2: The mixture of N-[(E)-[(2, 6-dichlorophenyl)-(2, 2-difluoro-5-azaspiro [2.3] hexan-5-yl) methylene] amino]-4-methyl-benzenesulfonamide (443 mg, 962 μmoll 1 eq) and K2CO3(1.33 g, 9.62 mmol, 10 eq) in DMF (4 mL) was stirred at 100 °C for 3 hours. LCMS showed N-[(E)-[(2, 6-dichlorophenyl)-(2, 2-difluoro-5-azaspiro [2.3] hexan-5-yl) methylene] amino]-4-methyl-benzenesulfonamide remained and the desired mass was detected. The reaction was poured into ice-water (50 mL) and extracted with MTBE (3 X 20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, fdtered, and concentrated under reduced pressure to give the desired 4-chloro-3-(2, 2-difluoro-5 -azaspiro [2.3] hexan-5-yl)- l-(p-tolyl sulfonyl) indazole (400 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C19H16N3SO2CIF2423.06 m / z found 424.2 [M+H]+.

[0321] Step 3: The mixture of 4-chloro-3-(2, 2-difluoro-5-azaspiro [2.3] hexan-5-yl)-l-(p- tolyl sulfonyl) indazole (400 mg, 944 μmoll 1 eq) and K2CO3(261 mg, 1.89 mmol, 2 eq) in109SUBSTITUTE SHEET (RULE 26)MeOH (4 mL) was stirred at 40 °C for 0.5 hour. LCMS showed 4-chloro-3-(2, 2-difluoro-5- azaspiro [2.3] hexan-5-yl)-l-(p-tolyl sulfonyl) indazole was consumed completely and the desired mass was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was added water (50 mL) and extracted with MTBE (3 X 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified byprep-TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to give the desired 4-chloro-3-(2, 2-difluoro-5 -azaspiro [2.3] hexan-5- yl)-lH-indazole (130 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C12H10N3CIF2269.05 m / z found 270.1 [M+H]+.

[0322] Step 4: To a solution of 4-(l, 1 -difluoroethyl) benzenesulfonyl chloride (66.9 mg, 278 μmol, 1.5 eq) in DCM (2 mL) and 4-chloro-3-(2, 2-difluoro-5-azaspiro [2.3] hexan-5-yl)-lH- indazole (50 mg, 185 μmol, 1 eq) in DCM (2 mL) were added TEA (56.3 mg, 556 μm,o 3l eq) and DMAP (2.27 mg, 18.5 μmol, 0.1 eq). The mixture was stirred at 20 °C for 12 hours. LCMS showed 4-chloro-3-(2, 2-difluoro-5-azaspiro [2.3] hexan-5-yl)-lH-indazole was consumed completely and the desired mass was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by / ?rqp-TLC (silica gel, petroleum ether I ethyl acetate = 3 / 1) to give the desired 4-chloro-3-(2, 2-difluoro-5-azaspiro [2.3] hexan-5-yl)-l- [4-(l, 1 -difluoroethyl) phenyl] sulfonyl-indazole (20 mg, 41.3 μm,o 2l 2.3% yield, 97.86% purity) as a white solid.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 (br m, 2H). HPLC: 97.86% (220 nm), 97.09% (215 nm), 95.74% (254 nm). MS (ESI): mass calcd. For C20H16CIN3SO2F4473.06 m / z found 474.1 [M+H]+.Compound 22: 4-Chloro-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-3-(3, 4- difluoropyrrolidin-l-yl) indazole110SUBSTITUTE SHEET (RULE 26)

[0323] Step 1: To the mixture of (lE)-2, 6-dichloro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride (921 mg, 2.44 mmol, 1 eq) and TEA (2.47 g, 24.4 mmol, 3.39 mL, 10 eq) in THF (10 mL) was added 3, 4-difluoropyrrolidine (350 mg, 2.44 mmol, 1 eq, HC1) at -15 °C. The mixture was stirred at 20 °C for 12 hours. LCMS showed (lE)-2, 6-dichloro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride was consumed completely and the desired mass was detected. The reaction was concentrated under reduced pressure to give the desired N-[(E)-[(2, 6- dichlorophenyl)-(3, 4-difluoropyrrolidin-l-yl) methylene] amino]-4-methyl-benzenesulfonamide (1.09 g, crude) as a yellow oil. MS (ESI): mass calcd. For C18H17N3SO2CI2F2447.04 m / z found448.1 [M+H]+.

[0324] Step 2 : The mixture of N-[(E)-[(2, 6-dichlorophenyl)-(3, 4-difluoropyrrolidin-l-yl) methylene] amino]-4-methyl-benzenesulfonamide (1.09 g, 2.43 mmol, 1 eq) and K2CO3(3.36 g, 24.3 mmol, 10 eq) in DMF (10 mL) was stirred at 100 °C for 3 hours. LCMS showed N-[(E)-[(2, 6-dichlorophenyl)-(3, 4-difluoropyrrolidin-l-yl) methylene] amino]-4-methyl- benzenesulfonamide remained and the desired mass was detected. The reaction was poured into ice-water (50 mL) and extracted with MTBE (3 X 20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired 4-chloro-3-(3, 4-difluoropyrrolidin-l-yl)-l-(p-tolyl sulfonyl) indazole (1 g, crude) as a yellow solid. MS (ESI): mass calcd. For C18H16N3SO2CIF2411.06 m / z found412.1 [M+H]+.

[0325] Step 3: The mixture of 4-chloro-3-(3, 4-difluoropyrrolidin-l-yl)-l-(p-tolylsulfonyl) indazole (1 g, 2.43 mmol, 1 eq) and K2CO3(671 mg, 4.86 mmol, 2 eq) in MeOH (10 mL) was ill SUBSTITUTE SHEET (RULE 26)stirred at 40 °C for 0.5 hour. LCMS showed 4-chloro-3-(3, 4-difluoropyrrolidin-l-yl)-l-(p- tolyl sulfonyl) indazole was consumed completely and the desired mass was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was added water (50 mL) and extracted with MTBE (3 X 20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to give the desired 4-chloro-3-(3, 4-difluoropyrrolidin-l-yl)-lH-indazole (250 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C11H10CIN3F2257.05 m / z found 258.1 [M+H]+.

[0326] Step 4: To a solution of 4-(l, 1-difluoroethyl) benzenesulfonyl chloride (140 mg, 582 μmol, 1.5 eq) and 4-chloro-3-(3, 4-difhioropyrrolidin-l-yl)-lH-indazole (100 mg, 388 μmoll 1 eq) in DCM (2 mL) were added TEA (118 mg, 1.16 mmol, 3 eq) and DMAP (4.74 mg, 38.8 μmol, 0.1 eq). The mixture was stirred at 20 °C for 12 hours. LCMS showed 4-chloro-3-(3, 4- diftaoropyrrolidin-l-yl)-lH-indazole was consumed completely and the desired mass was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by / ?rep-TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to give the desired 4- chloro-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-3-(3, 4-difluoropyrrolidin-l-yl) indazole (24.0 mg, 51.4 μmol, 13.2% yield, 98.87% purity) as a white solid. 1H NMR (DMSO-d6) 6 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% (220 nm), 98.43% (215 nm), 99.38% (254 nm). MS (ESI): mass calcd. For C19H16CIF4N3O2S 461.06 m / z found 462.1 [M+H]+.Compound 23: A meso form of 4-chloro-l-((4-(l, 1-difluoroethyl) phenyl) sulfonyl)-3-((3R,4R)-3, 4-difluoropyrrolidin-l-yl)-lH-indazole

[0327] Step 1. A mixture of tert-butyl 4-chloro-3 -iodo-indazole- 1 -carboxylate (527 mg, 1.39 mmol, 1 eq), a meso form of 3, 4-difluoropyrrolidine (200 mg, 1.39 mmol, 1 eq, HC1), Pd2(dba)s112SUBSTITUTE SHEET (RULE 26)(128 mg, 139 μmol, 0.1 eq), CS2CO3(1.36 g, 4.18 mmol, 3 eq) and BINAP (86.8 mg, 139 μ,mol 0.1 eq) in toluene (10 mL) was degassed and purged with N2for 3 times. The mixture was stirred at 100 °C for 3 hours under N2atmosphere. LC-MS showed tert-butyl 4-chl oro-3 -iodo-indazole- 1 -carboxylate was consumed completely and the desired mass was detected. The crude was added H2O (20 mL) and extracted with EtOAc (20 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to give the desired meso form of tert-butyl 4-chloro-3-(3, 4- difhioropyrrolidin-l-yl) indazole- 1 -carboxylate (150 mg, 419 μm,o 3l0.1% yield) as a yellow oil. MS (ESI): mass calcd. For C16H18CIF2N3O2357.11 m / z found 358.1 [M+H]+.

[0328] Step 2: To a solution of a meso form of tert-butyl 4-chloro-3-((3R, 4R)-3, 4- difluoropyrrolidin-l-yl) indazole- 1 -carboxylate (250 mg, 699 μm,o 1l eq) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 15 °C for 0.5 hour. TLC (petroleum ether / ethyl acetate = 3 / 1) indicated a meso form of tert-butyl 4-chl oro-3 -((3R, 4R)-3, 4-difluoropyrrolidin-l- yl) indazole- 1 -carboxylate was consumed completely and one new spot was formed. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) give the desired meso form of 4- chloro-3-(3, 4-difluoropyrrolidin-l-yl)-lH-indazole (250 mg, crude, TFA) as a brown solid.

[0329] Step 3: To a solution of a meso form of 4-chl oro-3 -((3R, 4R)-3, 4-difluoropyrrolidin- l-yl)-lH-indazole (20.0 mg, 53.8 μmol, 1 eq, TFA) and 4-(l, 1 -difluoroethyl) benzenesulfonyl chloride (13.0 mg, 53.8 μmol, 1 eq) in DCM (1 mL) were added TEA (27.2 mg, 269 μm,o 3l 7.5 μL, 5 eq) and DMAP (657 μg, 5.38 μmoll 0.1 eq). The mixture was stirred at 15 °C for 0.5 hour. LC-MS showed a meso form of 4-chl oro-3 -((3R, 4R)-3, 4-difluoropyrrolidin-l-yl)-lH-indazole was consumed completely and the desired mass was detected. The crude was added H2O (20 mL) and extracted with DCM (15 mL X 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to give the desired meso form of 4-chloro-l-[4-(l, 1 -difluoroethyl) phenyl] sulfonyl-3-((3R, 4R)- 3, 4-difluoropyrrolidin-l-yl) indazole (2 mg, 4.14 μmoll 7.69 % yield, 95.53% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) 5 8.14 (d, J= 8.0 Hz, 1H), 8.00 (d, J= 8.5 Hz, 2H), 7.80 (d, J= 8.5 Hz, 2H), 7.70 (t, J= 8.1 Hz, 1H), 7.54 (d, J= 7.4 Hz, 1H), 5.62 - 5.39 (m, 2H), 4.25 -113SUBSTITUTE SHEET (RULE 26)4.03 (m, 2H), 3.82 - 3.66 (m, 2H), 1.97 (t, . / = 19.1 Hz, 3H). HPLC: 95.93% (220 nm), 95.88% (215 nm), 100.00 (254 nm). MS (ESI): mass calcd. For C19H16CIF4N3O2S 461.06 m / z found 462.1 [M+H]+.Compound 24: 4-Chloro-3-(7, 7-difluoro-2-azaspiro [3.3] heptan-2-yl)-l-[4-(l, 1- difluoroethyl) phenyl] sulfonyl-indazole

[0330] Step 1. To a solution of tert-butyl 7-oxo-2-azaspiro [3.3] heptane-2-carboxylate (500 mg, 2.37 mmol, 1 eq) in DCM (6 mL) was added DAST (1.91 g, 11.8 mmol, 1.56 mL, 5 eq) at 0 °C. The mixture was stirred at 15 °C for 1 hour. TLC indicated tert-butyl 7-oxo-2-azaspiro [3.3] heptane-2-carboxylate was consumed completely one new spot was formed. The reaction mixture was partitioned between 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 give the crude product. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to give the desired tert-butyl 7, 7-difluoro-2-azaspiro [3.3] heptane-2-carboxylate (160 mg, 686 μmol, 28.9% yield) as a white oil. 1H NMR (400 MHz, DMSO-cA) δ 4.22 (d, J= 9.3 Hz, 2H), 3.76 (d, J= 9.3 Hz, 2H), 2.44 (tt, J= 8.6, 12.3 Hz, 2H), 2.05 - 1.94 (m, 2H), 1.43 (s, 9H).

[0331] Step 2: To a solution of tert-butyl 7, 7-difluoro-2-azaspiro [3.3] heptane-2- carboxylate (160 mg, 686 μmol, 1 eq) in DCM (3 mL) was added TFA (1.96 g, 17.2 mmol, 1.27 mL, 25 eq). The mixture was stirred at 15 °C for 1 hour. TLC indicated tert-butyl 7, 7-difluoro-2-114SUBSTITUTE SHEET (RULE 26)azaspiro [3.3] heptane-2-carboxylate was consumed completely and one new spot was formed. The reaction mixture was filtered, and the filter liquor was concentrated under reduced pressure to give the desired 7, 7-difluoro-2-azaspiro [3.3] heptane (300 mg, crude, TFA) as a black oil.

[0332] Step 3 : To a solution of (lE)-2, 6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (550 mg, 1.46 mmol, 1.2 eq) and 7, 7-difluoro-2-azaspiro[3.3]heptane (300 mg, 1.21 mmol, 1 eq, TFA) in THF (8 mL) was added TEA (614 mg, 6.07 mmol, 845 μL, 5 eq) at 0 °C. The mixture was stirred at 15 °C for 2 hours. LC-MS showed 7, 7-difluoro-2-azaspiro [3.3] heptane was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 30 mL of FLO and 50 mL of EtOAc. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired N-[(E)-[(2, 6-dichlorophenyl)-(7, 7-difluoro-2-azaspiro [3.3] heptan- 2-yl) ] amino]-4-methyl-benzenesulfonamide (490 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C20H19CI2F2N3O2S 473.1, m / z found 474.1 [M+H]+.

[0333] Step 4: To a solution of N-[(E)-[(2, 6-dichlorophenyl)-(7, 7-difluoro-2-azaspiro [3.3] heptan-2-yl) methylene] amino]-4-methyl-benzenesulfonamide (470 mg, 991 μm,ol 1 eq) in DMF (5 mL) was added K2CO3(685 mg, 4.95 mmol, 5 eq). The mixture was stirred at 100 °C for 2 hours. LC-MS showed N- [(E)- [(2, 6-dichlorophenyl)-(7, 7-difluoro-2-azaspiro [3.3] heptan-2-yl) methylene] amino]-4-methyl-benzenesulfonamide was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 20 mL of H2O and 30 mL of EtOAc. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired 4-chloro-3-(7, 7- difluoro-2-azaspiro [3.3] heptan-2-yl)-l-(p-tolylsulfonyl)indazole (280 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C20H18CIF2N3O2S 437.1, m / z found 438.1 [M+H]+.

[0334] Step 5: To a solution of 4-chloro-3-(7, 7-difluoro-2-azaspiro [3.3] heptan-2-yl)-l-(p- tolyl sulfonyl) indazole (280 mg, 639 μmoll 1 eq) in MeOH (3 mL) was added K2CO3(442 mg, 3.20 mmol, 5 eq). The mixture was stirred at 40 °C for 1 hour. LC-MS showed 4-chloro-3-(7, 7- difluoro-2-azaspiro [3.3] heptan-2-yl)-l-(p-tolyl sulfonyl) indazole was consumed completely and the desired mass was detected. The reaction mixture was filtered, and the filter liquor was concentrated under reduced pressure to give a residue. The residue was partitioned between 10 mL of H2O and 10 mL of EtOAc. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product.115SUBSTITUTE SHEET (RULE 26)The crude was purified by pre-pT-LC (silica gel, petroleum ether I ethyl acetate = 1 / 1) to give the desired 4-chloro-3-(7, 7-difluoro-2-azaspiro [3.3] heptan-2-yl)-lH-indazole (70 mg, 247 μm,ol 38.6% yield) as a yellow oil. MS (ESI): mass calcd. For C13H12CIF2N3283.1 m / z found 284.1 [M+H]+.

[0335] Step 6: To a solution of 4-chloro-3-(7, 7-difluoro-2-azaspiro [3.3] heptan-2-yl)-lH- indazole (30 mg, 106 μmol, 1 eq) and 4- (l,l-difluoroethyl)benzenesulfonyl chloride (38.2 mg, 159 μmol, 1.5 eq) in DCM (1 mL) were added TEA (21.4 mg, 212 μmoll 29.4 μL, 2 eq) and DMAP (1.29 mg, 10.6 μmol, 0.1 eq). The mixture was stirred at 15 °C for 1 hour. LC-MS showed 4-chloro-3-(7, 7-difluoro-2-azaspiro [3.3] heptan-2-yl)-lH-indazole was consumed completely and the desired mass was detected. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL X 3). The combined organic phase was washed with brine (10 mL X 3), dried over Na2SO4, filtered, and concentrated in vacuum to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether I ethyl acetate = 2 / 1) to give the desired 4-chloro-3-(7, 7-difluoro-2-azaspiro [3.3] heptan-2-yl)-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-indazole (4.1 mg, 8.37 μmoll 13.6% yield, 99.62% purity) as a white solid. 1H NMR (400 MHz, DM SO-4) 5 8.05 (d, J= 8.4 Hz, 1H), 7.92 (d, J= 8.3 Hz, 2H), 7.74 (d, J= 8.4 Hz, 2H), 7.63 (t, J= 8.1 Hz, 1H), 7.45 (d, J= 7.7 Hz, 1H), 4.34 (d, J= 9.3 Hz, 2H), 4.13 (d, J= 9.3 Hz, 2H), 2.49 - 2.41 (m, 2H), 2.04 (br t, J= 8.3 Hz, 2H), 1.91 (t, J= 19.1 Hz, 3H). HPLC: 99.62% (220 nm), 99.38% (215 nm), 100.00% (254 nm). MS (ESI): mass calcd. For C21H18CIF4N3O2S 487.1 m / z found 488.1 [M+H]+.Compound 25: 4-Chloro-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-3-(7-fluoro-5-azaspiro[2.4] heptan-5-yl) indazole116SUBSTITUTE SHEET (RULE 26)

[0336] Step 1 : To a solution of 7-fluoro-5-azaspiro [2.4] heptane hydrochloride (100 mg, 660 μmol, 1 eq) in THF (10 mL) were added TEA (133 mg, 1.32 mmol, 184 μL, 2 eq) and (lE)-2, 6- dichloro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride (299 mg, 792 μmoll 1.2 eq) at 0 °C. The mixture was stirred at 15 °C for 2 hours. LC-MS showed (lE)-2, 6-dichloro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride was consumed completely and the desired mass was detected. The reaction mixture was concentrated to give the desired N-[(Z)-[(2, 6-dichlorophenyl)-(7-fluoro-5- azaspiro [2.4] heptan-5-yl) methylene] amino]-4-methylbenzenesulfonamide (1 g, crude) as a yellow solid. MS (ESI): mass calcd. For C20H20CI2FN3O2S 455.06, m / z found 456.3 [M+H]+.

[0337] Step 2: To a solution of N-[(Z)-[(2, 6-dichlorophenyl)-(7-fluoro-5-azaspiro [2.4] heptan-5-yl) methylene] amino]-4-methyl-benzenesulfonamide (1.0 g, 2.19 mmol, 1 eq) in DMF (10 mL) was added K2CO3(3.03 g, 21.9 mmol, 10 eq). The mixture was stirred at 100 °C for 2 hours. LC-MS showed N-[(Z)-[(2, 6-dichlorophenyl)-(7-fluoro-5-azaspiro [2.4] heptan-5-yl) methylene] amino]-4-methyl-benzenesulfonamide was consumed completely and the desired mass was detected. The reaction mixture was diluted with H2O (20 mL) and extracted with MTBE (20 mL X 3). The combined organic phase was washed with brine (20 mL X 3), dried over Na2SO4, filtered, and concentrated in vacuum to give the desired 4-chloro-3-(7-fluoro-5- azaspiro[2.4]heptan-5-yl)-l-(p-tolylsulfonyl)indazole (380 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C20H19CIFN3O2S 419.09, m / z found 420.3 [M+H]+.

[0338] Step 3: To a solution of 4-chloro-3-(7-fluoro-5-azaspiro [2.4] heptan-5-yl)-l-(p- tolyl sulfonyl) indazole (380 mg, 905 μmoll 1 eq) in MeOH (5 mL) was added K2CO3(1.25 g, 9.05 mmol, 10 eq). The mixture was stirred at 45 °C for 1 hour. LC-MS showed 4-chloro-3-(7- fluoro- 5 -azaspiro [2.4] heptan-5-yl)-l-(p-tolylsulfonyl) indazole was consumed completely and the desired mass was detected. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL X 3). The combined organic phase was washed with brine (10 mL X 3), dried over Na2SO4, filtered, and concentrated in vacuum to give a residue. The residue was purified by p / 'cp-TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to give the desired 4- chloro-3-(7-fluoro-5-azaspiro [2.4] heptan-5-yl)-lH-indazole (90 mg, 338 μmoll 37.4% yield) as a white solid. MS (ESI): mass calcd. For C13H13CIFN3265.08, m / z found 266.2 [M+H]+.

[0339] Step 4: To a solution of 4-chloro-3-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)-lH- indazole (90 mg, 338 μmol, 1 eq) and 4-(l , 1 - difluoroethyl)benzenesulfonyl chloride (122 mg, 508μmol , 1.5 eq) in DCM (2 mL) were added TEA (68 mg, 677 μmoll 94 μL, 2 eq) and DMAP117SUBSTITUTE SHEET (RULE 26)(4.14 mg, 33 μmol, 0.1 eq). The mixture was stirred at 15 °C for 1 hour. LC-MS showed 4- chloro-3-(7-fluoro-5-azaspiro [2.4] heptan-5-yl)-lH-indazole was consumed completely and the desired mass was detected. The reaction mixture was added to H2O (30 mL) and extracted with EtOAc (30 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPhC (TFA condition; column: Phenomenex Luna C18 75 * 30 mm * 3 μm; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 50%-80% B over 8.0 min) to give the desired 4- chloro-l-[4-(l,l-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. 'HNMR (400 MHz, DMSO-<A) 6 8.13 - 8.03 (m, 1H), 7.92 (d, J= 8.3 Hz, 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% (220 nm), 82.12% (215 nm), 96.26% (254 nm). MS (ESI): mass calcd. For C21H19CIF3N3O2S 469.08 m / z found 470.0 [M+H]+.Compound 26: 4-Chloro-l-((4-(l, 1-difluoroethyl) phenyl) sulfonyl)-3-((3R, 4R)-3, 4- difluoropyrrolidin-l-yl)-lH-indazoleCompound 27: 4-Chloro-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-3-[(3S, 4S)-3, 4- difluoropyrrolidin-l-yl] indazole

[0340] Step 1 : The meso form of 4-chloro-l-((4-(l,l-difluoroethyl)phenyl)sulfonyl)-3- ((3S,4S)-3,4-difluoropyrrolidin-l-yl)-lH-indazole (60 mg, 130 μmol, 1 eq) was separated by chiral SFC (column: Daicel ChiralPak IG (250 * 30 mm, 10 μm); mobile phase: [Heptane- EtOH]; gradient: 5%-70% B over 12.0 min) to give two isomers. The structures were assigned arbitrarily. 4-Chloro- 1 -((4-(l , 1 -difluoroethyl)phenyl)sulfonyl)-3-((3R,4R)-3,4- difluoropyrrolidin-l-yl)-lH-indazole (11.3 mg, 24.0 μmol, 18.5% yield, 98.24% purity, Rt = 3.968 minutes; E.E. by chiral HPLC (%) = 100.00%) was isolated as a white solid. 1H NMR (400 MHz, DMSO-rC) δ 8.14 (d, J= 8.5 Hz, 1H), 8.00 (d, J= 8.5 Hz, 2H), 7.80 (d, J= 8.5 Hz,118SUBSTITUTE SHEET (RULE 26)2H), 7.70 (t, . / = 8.1 Hz, 1H), 7.54 (d, J= 7.6 Hz, 1H), 5.62 - 5.38 (m, 2H), 4.25 - 4.04 (m, 2H), 3.82 - 3.66 (m, 2H), 1.97 (t, J= 19.1 Hz, 3H). HPLC: 98.24% (220 nm), 97.92% (215 nm), 98.66% (254 nm). MS (ESI): mass calcd. For C19H16CIF4N3O2S 461.06 m / z found 462.1 [M+H]+.4-Chloro-l-[4-(l,l-difluoroethyl)phenyl]sulfonyl-3-[(3S,4S)-3,4-difluoropyrrolidin-l- yl]indazole (9.7 mg, 20.8 μmol, 16.0% yield, 99.21% purity, Rt = 4.222 minutes; E.E. by chiral HPLC (%) = 95.68%) was isolated as a white solid.1HNMR (400 MHz, DMSO-tC) 5 8.14 (br d, J= 8.5 Hz, 1H), 8.00 (br d, J= 8.0 Hz, 2H), 7.80 (br d, J= 7.9 Hz, 2H), 7.74 - 7.67 (m, 1H), 7.54 (br d, J= 7.7 Hz, 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% (220 nm), 99.12% (215 nm), 97.45% (254 nm). MS (ESI): mass calcd. For C19H16CIF4N3O2S 461.06 m / z found 462.1 [M+H] .Compound 28: 4-Chloro-3-(7, 7-difluoro-5-azaspiro [2.4] heptan-5-yl)-l-[4-(l, 1- difluoroethyl) phenyl] sulfonyl-indazole

[0341] Step 1 : To a solution of tert-butyl 7-oxo-5-azaspiro [2.4] heptane-5-carboxylate (1.61 g, 7.62 mmol, 1 eq) in DCM (17 mL) was added DAST (18.4 g, 114 mmol, 15.1 mL, 15 eq) at 0°C. The mixture was stirred at 35 °C for 12 hours. TLC indicated tert-butyl 7-oxo-5-azaspiro[2.4] heptane-5-carboxylate remained and one major new spot with lower polarity was detected.119SUBSTITUTE SHEET (RULE 26)The reaction was quenched by sat. aq. NaHCO3(20 mL), then 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 give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 2 g SepaFlash® Silica Flash Column, Eluent of 0-15% ethyl acetate / petroleum ether gradient @ 60 mL / min) to give 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.

[0342] Step 2 : To the mixture of tert-butyl 7, 7-difluoro-5 -azaspiro [2.4] heptane-5- carboxylate (580 mg, 2.49 mmol, 1 eq) in DCM (9 mL) was added TFA (4.61 g, 40.4 mmol, 3 mL, 16.2 eq). The mixture was stirred at 20 °C for 1 hour. TLC indicated tert-butyl 7, 7-difluoro- 5-azaspiro [2.4] heptane-5-carboxylate was consumed completely and a new spot was formed. The reaction was concentrated under reduced pressure to give the desired 7, 7-difluoro-5- azaspiro [2.4] heptane (610 mg, crude, TFA) as a light brown oil.

[0343] Step 3 : To the mixture of 7,7-difluoro-5-azaspiro[2.4]heptane (300 mg, 1.21 mmol, 1 eq, TFA) and TEA (2.18 g, 21.5 mmol, 3 mL, 17.8 eq) in THF (5 mL) was added (lE)-2,6- dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (458 mg, 1.21 mmol, 1 eq) at -15 °C. The mixture was stirred at 20 °C for 12 hours. LCMS showed (lE)-2, 6-dichloro-N-(p- tolyl sulfonyl) benzohydrazonoyl chloride was consumed completely and the desired mass was detected. The reaction was concentrated under reduced pressure to give the desired N-[(E)-[(2, 6- dichlorophenyl)-(7, 7-difluoro-5-azaspiro [2.4] heptan-5-yl) methylene] amino]-4- methylbenzenesulfonamide (575 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C20H19CI2F2N3O2S 473.05, m / z found 474.1 [M+H]+.

[0344] Step 4: The 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 eq) and K2CO3(3.35 g, 24.2 mmol, 20 eq) in DMF (10 mL) was stirred at 100 °C for 3 hours. LCMS showed N-[(E)-[(2, 6-dichlorophenyl)-(7, 7-difluoro-5-azaspiro [2.4] heptan-5- yl) methylene] amino]-4-methyl-benzenesulfonamide was consumed completely and the desired mass was detected. The reaction was poured into ice-water (50 mL) and extracted with MTBE (3 X 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired 4-chloro-3-(7, 7-difluoro-5-azaspiro120SUBSTITUTE SHEET (RULE 26)[2.4] heptan-5-yl)- l-(p-tolyl sulfonyl) indazole (530 mg, 1.21 mmol, 99.9% yield) as a yellow oil. MS (ESI): mass calcd. For C20H18CIF2N3O2S 437.08 m / z found 438.1 [M+H]+.

[0345] Step 5: The mixture of 4-chloro-3-(7, 7-difluoro-5-azaspiro [2.4] heptan-5-yl)-l-(p- tolyl sulfonyl) indazole (530 mg, 1.21 mmol, 1 eq) and K2CO3(334 mg, 2.42 mmol, 2 eq) in MeOH (5 mL) was stirred at 40 °C for 0.5 hour. LCMS showed 4-chloro-3-(7, 7-difluoro-5- azaspiro [2.4] heptan-5-yl)-l-(p-tolyl sulfonyl) indazole was consumed completely and the desired mass was detected. The reaction was concentrated to get a residue. The reaction was poured into ice-water (10 mL) and extracted with MTBE (3 X 10 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to give the desired 4-chloro-3-(7, 7-difluoro-5 -azaspiro [2.4] heptan- 5-yl)-lH-indazole (90 mg, 317 μmol, 26.2% yield) as a yellow solid. MS (ESI): mass calcd. For C13H12CIF2N3283.07 m / z found 284.1 [M+H]+.

[0346] Step 6: To a solution of 4-chloro-3-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-lH- indazole (50 mg, 176 μmol, 1 eq) and 4- (l,l-difluoroethyl)benzenesulfonyl chloride (63.6 mg, 264μmol , 1.5 eq) in DCM (2 mL) were added TEA (35.7 mg, 352 μmoll 49 μL, 2 eq) and DMAP (2.15 mg, 17.6 μmol, 0.1 eq) at 0 °C. The mixture was stirred at 15 °C for 2 hours. LC- MS showed 4-chloro-3-(7, 7-difluoro-5-azaspiro [2.4] heptan-5-yl)-lH-indazole was consumed completely and the desired mass was detected. The reaction mixture was added to H2O (30 mL) and extracted with EtOAc (30 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1) to give the desired 4-chloro-3-(7, 7-difluoro-5 -azaspiro [2.4] heptan-5-yl)-l-[4-(l, 1 -difluoroethyl) phenyl] sulfonyl-indazole (35 mg, 71.5 μmoll 40.6% yield, 99.64% purity) as a white solid.1HNMR (400 MHz, 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% (220 nm), 97.61% (215 nm), 99.64% (254 nm). MS (ESI): mass calcd. For C21H18ClF4N3O2S 487.07 m / z found 488.0 [M+H]+.121SUBSTITUTE SHEET (RULE 26)Compound 29: 3-(7, 7-Difluoro-5-azaspiro [2.4] heptan-5-yl)-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-4-fluoro-indazole

[0347] Step 1 : To the mixture of 7,7-difluoro-5-azaspiro[2.4]heptane (300 mg, 1.21 mmol, 1 eq, TFA) and TEA (2.18 g, 21.5 mmol, 3 mL, 17.8 eq) in THF (5 mL) was added (lE)-2,6- difluoro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (418 mg, 1.21 mmol, 1 eq) at -15 °C and the mixture was stirred at 20 °C for 1 hour. LCMS showed 7,7-difluoro-5-azaspiro[2.4]heptane was consumed completely and the desired mass was detected. The reaction was concentrated under reduced pressure to give the desired N-[(E)-[(7, 7-difluoro-5 -azaspiro [2.4] heptan-5-yl)- (2, 6-difluorophenyl) methylene] amino]-4-methylbenzenesulfonamide (535 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C20H19F4N3O2S 441.11, m / z found 442.1 [M+H]+.

[0348] Step 2: The 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 eq) and K2CO3(3.35 g, 24.2 mmol, 20 eq) in DMF (10 mL) was stirred at 100 °C for 3 hours. LCMS showed N-[(E)-[(7, 7-difluoro-5-azaspiro [2.4] heptan-5-yl)-(2, 6- difluorophenyl) methylene] amino]-4-methyl-benzenesulfonamide was consumed completely and the desired mass was detected. The reaction was poured into ice-water (50 mL) and extracted with MTBE (3 X 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired 3-(7, 7-difluoro-5-azaspiro [2.4] heptan-5-yl)-4-fluoro-l-(p-tolylsulfonyl) indazole (510 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C2OHI8F3N302S 421.11, m / z found 422.1 [M+H]+.

[0349] Step 3: The mixture of 3-(7, 7-difluoro-5-azaspiro [2.4] heptan-5-yl)-4-fluoro-l-(p- tolyl sulfonyl) indazole (510 mg, 1.21 mmol, 1 eq) and K2CO3(335 mg, 2.42 mmol, 2 eq) in122SUBSTITUTE SHEET (RULE 26)MeOH (5 mL) was stirred at 40 °C for 0.5 hour. LCMS showed 3-(7, 7-difluoro-5-azaspiro [2.4] heptan-5-yl)-4-fluoro-l-(p-tolylsulfonyl) indazole was consumed completely and the desired mass was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether I ethyl acetate = 3 / 1) to give the desired 3-(7,7-difhioro-5-azaspiro[2.4]heptan-5-yl)-4-fluoro-lH-indazole (130 mg, 486 μm,ol 40.2% yield) as a yellow solid. MS (ESI): mass calcd. For C13H12F3N3267.1, m / z found 268.1 [M+H]+.

[0350] Step 4: To a solution of 3-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-4-fluoro-lH- indazole (50 mg, 187 μmol, 1 eq) and 4- (l,l-difluoroethyl)benzenesulfonyl chloride (67.5 mg, 281μmol , 1.5 eq) in DCM (2 mL) were added TEA (37.9 mg, 374 μmoll 52.1 μL, 2 eq) and DMAP (2.29 mg, 18.7 μmol, 0.1 eq) at 0 °C. The mixture was stirred at 15 °C for 2 hours. LC- MS showed 3-(7, 7-difluoro-5-azaspiro [2.4] heptan-5-yl)-4-fluoro-lH-indazole was consumed completely and the desired mass was detected. The reaction mixture was added to H2O (30 mL) and extracted with EtOAc (30 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate =3 / 1) to give the desired 3-(7, 7-difluoro-5 -azaspiro [2.4] heptan-5-yl)-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-4-fluoro-indazole (44 mg, 93.0 μmol, 49.71% yield, 99.64% purity) as a white solid.1HNMR (400 MHz, DMSO-d6) 5 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% (220 nm), 98.93% (215 nm), 99.64% (254 nm). MS (ESI): mass calcd. For C21H18F5N3O2S 471.1 m / z found 472.0 [M+H]+.Compound 30: 4-Chloro-l-[4-(l, 1-difluoroethyl) phenyl] snlfonyl-3-(3-fluoro-4-methyl- pyrrolidin-l-yl) indazole123SUBSTITUTE SHEET (RULE 26)

[0351] Step 1 : To a solution of tert-butyl 3 -methyl-4-oxo-pyrrolidine-l -carboxylate (1 g,5.02 mmol, 1 eq) in EtOH (10 mL) was added NaBIL (380 mg, 10.0 mmol, 2 eq) at 0 °C. The mixture was stirred at 20 °C for 1 hour. TLC indicated tert-butyl 3-methyl-4-oxo-pyrrolidine-l- carboxylate was consumed completely and one new spot was formed. The residue was diluted with HC1 (1 N, 5 mL) and the resulting mixture was allowed to return to room temperature. The EtOH was evaporated in vacuum. The reaction mixture was added to water (20 mL) and extracted with DCM (20 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate =1 / 0 to 0 / 1) to give the desired tert-butyl 3 -hydroxy -4-methyl-pyrrolidine-l -carboxylate (1 g, crude) as colorless oil.

[0352] Step 2\ To a solution of tert-butyl 3 -hydroxy-4-methyl-pyrrolidine-l -carboxylate (1 g, 4.97 mmol, 1 eq) in DCM (20 mL) was added DAST (2.40 g, 14.9 mmol, 1.97 mL, 3 eq) at 0 °C. The mixture was stirred at 20 °C for 1 hour. TLC indicated tert-butyl 3-hydroxy-4-methyl- pyrrolidine-1 -carboxylate was consumed completely and two new spots were formed. The reaction mixture was quenched by addition sat. NaHCO3aq. (40 mL) and extracted with DCM (10 mL X 4). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by124SUBSTITUTE SHEET (RULE 26)column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give the desired tert-butyl 3 -fluoro-4-methyl-pyrrolidine-l -carboxylate (190 mg, crude) as a colorless oil.

[0353] Step 3 : To a solution of tert-butyl 3 -fluoro-4-methyl-pyrrolidine-l -carboxylate (190 mg, 935 μmol, 1 eq) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 20 °C for 1 hour. TLC indicated tert-butyl 3 -fluoro-4-methyl-pyrrolidine-l -carboxylate was consumed completely and one new spot was formed. The reaction mixture was concentrated to give the desired 3-fluoro-4-methyl-pyrrolidine (200 mg, crude, TFA) as a yellow oil.

[0354] Step 4. To a solution of 3-fluoro-4-methyl-pyrrolidine (200 mg, 921 μm,ol 1 eq, TFA) in THF (3 mL) was added dropwise TEA (932 mg, 9.21 mmol, 1.28 mL, 10 eq) at 25 °C. After addition, the mixture was stirred at this temperature for 10 minutes. (lZ)-2, 6-dichloro-N- (p-tolyl sulfonyl) benzohydrazonoyl chloride (522 mg, 1.38 mmol, 1.5 eq) 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 showed 3-fluoro-4-methyl-pyrrolidine was consumed completely and one main peak with the desired mass was detected. The mixture was separated between 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 give the desired N-[(E)-[(2, 6- dichlorophenyl)-(3-fluoro-4-methyl-pyrrolidin-l-yl) methylene] amino]-4-methyl- benzenesulfonamide (400 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C19H20CI2FN3O2S 443.06 m / z found 444.0 [M+H]+.

[0355] Step 5: To a solution of N-[(E)-[(2, 6-dichlorophenyl)-(3-fluoro-4-methyl-pyrrolidin- 1-yl) methylene] amino]-4-methyl-benzenesulfonamide (400 mg, 900 μm,ol 1 eq) in DMF (10 mL) was added K2CO3(622 mg, 4.50 mmol, 5 eq). The mixture was stirred at 100 °C for 12 hours. LC-MS showed N-[(E)-[(2, 6-dichlorophenyl)-(3-fluoro-4-methyl-pyrrolidin-l-yl) methylene] amino]-4-methyl-benzenesulfonamide was consumed completely and the desired mass was detected. The reaction mixture was added to water (30 mL) and extracted with EtOAc (30 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired 4-chloro-3-(3-fluoro-4- methyl-pyrrolidin-l-yl)-l-(p-tolylsulfonyl)indazole (360 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C19H19CIFN3O2S 407.09 m / z found 408.1 [M+H]+.

[0356] Step 6: To a solution of 4-chloro-3-(3-fluoro-4-methyl-pyrrolidin-l-yl)-l-(p- tolyl sulfonyl) indazole (460 mg, 1.13 mmol, 1 eq) in MeOH (10 mL) was added K2CO3(779 mg,125SUBSTITUTE SHEET (RULE 26)5.64 mmol, 5 eq). The mixture was stirred at 70 °C for 1 hour. LC-MS showed 4-chloro-3-(3- fluoro-4-methyl-pyrrolidin-l-yl)-l-(p-tolylsulfonyl) indazole was consumed completely and the desired mass was detected. The reaction mixture was added to water (30 mL) and extracted with EtOAc (30 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, fdtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 2 / 1) to give the desired 4- chloro-3-(3-fluoro-4-methyl-pyrrolidin-l-yl)-lH-indazole (190 mg, 749 μmol, 66.4% yield) as a yellow oil. MS (ESI): mass calcd. For C12H13CIFN3253.08 m / z found 254.1 [M+H]+.

[0357] Step 7: To a solution of 4-chloro-3-(3-fluoro-4-methyl-pyrrolidin-l-yl)-lH-indazole (190 mg, 749 μmol, 1 eq) and 4-(l, 1 -difluoroethyl) benzenesulfonyl chloride (270 mg, 1.12 mmol, 1.5 eq) in DCM (1 mL) were added TEA (227 mg, 2.25 mmol, 313 μL, 3 eq) and DMAP (9.15 mg, 74.9 μmol, 0.1 eq). The mixture was stirred at 20 °C for 0.5 hour. LC-MS showed 4- chloro-3-(3-fluoro-4-methyl-pyrrolidin-l-yl)-lH-indazole was consumed completely and one main peak with the desired mass was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 75 * 30 mm * 3 μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 50%-80% B over 8.0 min ) to give the desired 4-chloro-l-[4-(l, 1 -difluoroethyl) phenyl] sulfonyl-3-(3-fluoro-4-methyl-pyrrolidin-l-yl) indazole (28 mg, 60.4 μmoll 8.06% yield, 98.70% purity) as a yellow solid.NMR (400 MHz, DMSO-d6) δ 8.07 (d, J= 8.4 Hz, 1H), 7.92 (br d, J = 8.2 Hz, 2H), 7.73 (br d, J= 8.2 Hz, 2H), 7.61 (br t, J= 8.1 Hz, 1H), 7.45 (br d, J= 7.6 Hz, 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= 19.1 Hz, 3H), 1.60 - 1.45 (m, 1H), 1.10 (br d, J= 6.7 Hz, 2H). HPLC: 98.70% (220 nm), 99.85% (215 nm), 98.73% (254 nm). MS (ESI): mass calcd. For C20H19CIF3N3O2S 457.08 m / z found 458.0 [M+H]+.Compound 31: 4-Chloro-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-3-(3, 3-difluoro-4- methyl-pyrrolidin-l-yl) indazole126SUBSTITUTE SHEET (RULE 26)

[0358] Step 1 : To a solution of tert-butyl 3 -methyl-4-oxo-pyrrolidine-l -carboxylate (500 mg, 2.51 mmol, 1 eq) in DCM (5 mL) was added DAST (2,02 g, 12,6 mmol, 1.66 mL, 5 eq) at 0 °C. The mixture was stirred at 15 °C for 1 hour. TLC indicated tert-butyl 3-methyl-4-oxo- pyrrolidine-1 -carboxylate was consumed completely and one new spot was formed. The reaction was quenched by sat. aq. NaHCCL (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 give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 1 g SepaFlash® Silica Flash Column, Eluent of 0-15% EtOAc / petroleum ether gradient @ 40 mL / min) to give the desired tert-butyl 3, 3-difluoro-4-methyl-pyrrolidine-l- carboxylate (400 mg, 1.81 mmol, 72.1% yield) as a yellow oil.JH NMR (400 MHz, CHLOROFORM-5 3.95 (br d, J= 4.5 Hz, IH), 3.80 - 3.59 (m, 3H), 3.15 - 3.01 (m, IH), 1.46 (s, 9H), 1.11 (br d, .7= 6.8 Hz, 3H).

[0359] Step 2\ To a solution of tert-butyl 3, 3 -difluoro-4-methyl-pyrrolidine-l -carboxylate (350 mg, 1.58 mmol, 1 eq) in DCM (5 mL) was added TFA (3.61 g, 31.6 mmol, 2.35 mL, 20 eq). The mixture was stirred at 20 °C for 1 hour. TLC indicated tert-butyl 3, 3-difluoro-4-methyl- pyrrolidine-1 -carboxylate was consumed completely and one new spot was formed. The reaction mixture was partitioned between 10 mL of HzO and 10 mL of DCM. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under127SUBSTITUTE SHEET (RULE 26)reduced pressure to give the desired 3, 3-difluoro-4-methyl-pyrrolidine (372 mg, crude, TFA) as a white solid.

[0360] Step 3: To a solution of 3, 3-difluoro-4-methyl-pyrrolidine (390 mg, 1.66 mmol, 1 eq, TFA) in THF (10 mL) were added TEA (168 mg, 1.66 mmol, 231 uL, 1 eq) and (lE)-2, 6- dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (689 mg, 1.82 mmol, 1.1 eq) at 0 °C. The mixture was stirred at 15 °C for 1 hour. LC-MS showed 3, 3-difluoro-4-methyl-pyrrolidine was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 10 mL of H2O and 10 mL of EtOAc. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired N-[(E)-[(2, 6-dichlorophenyl)-(3, 3-difluoro-4-methyl-pyrrolidin-l- yl)methylene]amino]-4-methyl-benzenesulfonamide (766 mg, crude) as a black solid. MS (ESI): mass calcd. For C19H19CI2F2N3O2S 461.1, m / z found 462.0 [M+H]+.

[0361] Step 4: To a solution of N-[(E)-[(2, 6-dichlorophenyl)-(3, 3-difluoro-4-methyl- pyrrolidin- 1 -yl) methylene] amino]-4-methyl-benzenesulfonamide (766 mg, 1.66 mmol, 1 eq) in DMF (8 mL) was added K2CO3(1.14 g, 8.28 mmol, 5 eq). The mixture was stirred at 100 °C for 12 hours. LC-MS showed N-[(E)-[(2, 6-dichlorophenyl)-(3, 3-difluoro-4-methyl-pyrrolidin-l-yl) methylene] amino]-4-methyl-benzenesulfonamide was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 10 mL of H2O and 10 mL of EtOAc. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired 4-chloro-3-(3, 3-difluoro-4- methyl-pyrrolidin-l-yl)-l-(p-tolylsulfonyl) indazole (700 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C19H18CIF2N3O2S 425.1, m / z found 426.1 [M+H]+.

[0362] Step 5 : To a solution of 4-chloro-3-(3, 3-difluoro-4-methyl-pyrrolidin-l-yl)-l-(p- tolyl sulfonyl) indazole (700 mg, 1.64 mmol, 1 eq) in MeOH (8 mL) was added K2CO3(1.14 g, 8.22 mmol, 5 eq). The mixture was stirred at 40 °C for 1 hour. LC-MS showed 4-chloro-3-(3, 3- difluoro-4-methyl-pyrrolidin-l-yl)-l-(p-tolylsulfonyl) indazole was consumed completely and the desired mass was detected. The reaction mixture was filtered, and the filter liquor was concentrated under reduced pressure to give a residue. The residue was purified by prTeLp-C (silica gel, petroleum ether / ethyl acetate = 2 / 1) to give the desired 4-chloro-3-(3, 3-difluoro-4- methyl-pyrrolidin-l-yl)-lH-indazole (120 mg, 442 μmol, 26.9% yield) as a white solid. MS (ESI): mass calcd. For C12H12CIF2N3271.1 m / z found 272.1 [M+H]+.128SUBSTITUTE SHEET (RULE 26)

[0363] Step 6: To a solution of 4-chloro-3-(3, 3-difluoro-4-methyl-pyrrolidin-l-yl)-lH- indazole (120 mg, 442 μmol, 1 eq) and 4-(l, l-difluoroethyl)benzenesulfonyl chloride (106 mg, 442μmol , 1 eq) in DCM (2 mL) were added TEA (89.4 mg, 883 μmoll 123 μL, 2 eq) and DMAP (5.40 mg, 44.2 μmol, 0.1 eq). The mixture was stirred at 15 °C for 1 hour. LC-MS showed 4-chloro-3-(3, 3-difluoro-4-methyl-pyrrolidin-l-yl)-lH-indazole was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 10 mL of H2O and 10 mL of EtOAc. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by / wey>-HPLC (TFA condition; column: Phenom enex Luna C18 75 * 30 mm * 3 μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 70%-95% B over 8.0 min to give the desired 4-chloro-l-[4-(l,l-difluoroethyl)phenyl]sulfonyl-3-(3,3-difluoro-4-methyl- pyrrolidin-l-yl)indazole (30 mg, 62.3 μmol, 14.1% yield, 98.80% purity) as a white solid.JH NMR (400 MHz, DMSO-d6) δ 8.08 (d, J= 8.3 Hz, 1H), 7.95 (d, J= 8.4 Hz, 2H), 7.75 (d, J= 8.4 Hz, 2H), 7.65 (t, J= 8.1 Hz, 1H), 7.49 (d, J= 7.5 Hz, 1H), 4.09 (br d, J= 18.0 Hz, 1H), 3.90 - 3.76 (m, 2H), 3.38 (s, 2H), 1.92 (t, J= 19.2 Hz, 3H), 1.08 (d, J= 6.8 Hz, 3H). HPLC: 98.80% (220 nm), 98.82% (215 nm), 98.44% (254 nm). MS (ESI): mass calcd. For C2OHI8C1F4N302S 475.1 m / z found 476.1 [M+H]+.Compound 32: l-[4-(l, 1-Difluoroethyl) phenyl] sulfonyl-3-(3, 3, 4, 4-tetrafluoropyrrolidin-1-yl) indazol-4-amine

[0364] Step 1 : To a solution of 4-nitro-2H-indazole (100 mg, 613 μm,o 1l eq) in DMF (5 mL) was added NIS (152 mg, 674 μmo,l 1.1 eq). The mixture was stirred at 75 °C for 2 hours.129SUBSTITUTE SHEET (RULE 26)TLC indicated 4-nitro-2H-indazole was consumed completely and one new spot was formed. The reaction mixture was diluted with H2O (30 mL) and extracted with MTBE (20 mL X 3). The combined organic phase was washed with brine (20 mL X 3), dried over Na2SO4, filtered, and concentrated in vacuum to give the desired 3-iodo-4-nitro-2H-indazole (200 mg, crude) as a yellow solid.

[0365] Step 2 : To a solution of 3-iodo-4-nitro-lH-indazole (200 mg, 692 μm,ol 1 eq) and tert-butoxycarbonyl tert-butyl carbonate (151 mg, 692 μmoll 159 μL, 1 eq) in DCM (10 mL) were added TEA (140 mg, 1.38 mmol, 192 μL, 2 eq) and DMAP (8.45 mg, 69.2 μm,o 0l .1 eq). The mixture was stirred at 15 °C for 2 hours. TLC indicated 3-iodo-4-nitro-lH-indazole was consumed completely and one new spot was formed. The reaction mixture was concentrated to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / petroleum ether gradient @ 80 mL / min) to give the desired tert-butyl 3-iodo-4-nitro-indazole-l-carboxylate (140 mg, 360 μmoll 52.0% yield) as a yellow solid.

[0366] Step 3 : A mixture of tert-butyl 3 -iodo-4-nitro-indazole-l -carboxylate (100 mg, 257 μmol, 1 eq), 3, 3, 4, 4- tetrafluoropyrrolidine hydrochloride (46.1 mg, 257 μm,ol 1 eq), Pd2(dba)s (23.5 mg, 25.7 μmol, 0.1 eq), CS2CO3(251 mg, 771 μm,o 3l eq) and BINAP (16 mg, 25.7 μm, ol 0.1 eq) in toluene (2 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100 °C for 12 hours under N2atmosphere. TLC indicated 3-iodo-4-nitro-indazole-l- carboxylate was consumed completely and one new spot was formed. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL X 3). The combined organic phase was washed with brine (20 mL X 3), dried over Na2SO4, filtered, and concentrated in vacuum to give the desired tert-butyl 4-nitro-3 -(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)indazole-l -carboxylate (320 mg, crude) as a yellow solid.

[0367] Step 4 : To a solution of tert-butyl 4-nitro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl) indazole- 1 -carboxylate (270 mg, 668 μmoll 1 eq) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 15 °C for 0.5 hour. TLC (silica gel, petroleum ether / ethyl acetate =3 / 1) indicated tert-butyl 4-nitro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl) indazole-1 -carboxylate was consumed completely and one new spot was formed. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL X 3). The combined organic phase was washed with brine (20 mL X 2), dried over Na2SO4, filtered, and concentrated in vacuum to give a residue.130SUBSTITUTE SHEET (RULE 26)The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate =3 / 1) to give the desired 4-nitro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole (30 mg, 98.6 μmoll 14.8% yield) as a yellow solid.

[0368] Step 5: To a solution of 4-nitro-3-(3,3,4,4-tetrafluoropyrrolidin-l-yl)-lH-indazole (25 mg, 82.2 μmol, 1 eq) and 4-(l, 1- difluoroethyl)benzenesulfonyl chloride (29.7 mg, 123 μm,ol 1.5 eq) in DCM (3 mL) were added TEA (25 mg, 246 μmoll 34.3 μL, 3 eq) and DMAP (1.00 mg, 8.22 μmol, 0.1 eq) at 0 °C. The mixture was stirred at 15 °C for 0.5 hour. LC-MS showed 4- nitro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole was consumed completely and the desired mass was detected. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL X 3). The combined organic phase was washed with brine (20 mL X 2), dried over Na2SO4, filtered, and concentrated in vacuum to give the desired l-[4-(l, 1- difhioroethyl)phenyl]sulfonyl-4-nitro-3-(3,3,4,4-tetrafluoropyrrolidin-l-yl)indazole (90 mg, crude) as a brown solid. MS (ESI): mass calcd. For C19H14F6N4O4S 508.06 m / z found 509.2 [M+H]+.

[0369] Step 6: To a solution of l-[4-(l, 1 -difluoroethyl) phenyl] sulfonyl-4-nitro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl) indazole (90 mg, 177 μmol, 1 eq) in EtOH (2 mL) and H2O (0.4 mL) were added Fe (9.89 mg, 177 μmoll 1 eq) and NH4CI (9.47 mg, 177 μm,o 1l eq). The mixture was stirred at 80 °C for 0.5 hour. LC-MS showed l-[4-(l , 1 -difluoroethyl) phenyl] sulfonyl-4-nitro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl) indazole was consumed completely and the desired mass was detected. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL X 3). The combined organic phase was washed with brine (10 mL X 2), dried over Na2SO4, filtered, and concentrated in vacuum to give a residue. The residue was purified by prepH- PLC (TFA condition; column: Phenomenex Luna C18 75 * 30 mm * 3 μm; mobile phase: [H2O (0.1%TFA)-CAN ]; gradient:50%-75% B over 8.0 min) to give the desired 1 - [4-( 1 , 1 -difluoroethyl)phenyl] sulfonyl-3 -(3 ,3 ,4,4-tetrafluoropyrrolidin- 1 -yl)indazol-4-amine (3 mg, 6.17 μmol, 3.49% yield, 98.45% purity) as a light yellow solid.1HNMR (400 MHz, 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% (220 nm), 96.30% (215 nm), 98.45% (254 nm). MS (ESI): mass calcd. For C19H16F6N4O2S 478.09 m / z found 479.2 [M+H]+.131SUBSTITUTE SHEET (RULE 26)Compound 33: l-[4-Chloro-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-indazol-3-yl]-4, 4- difluoro-pyrrolidin-3-ol

[0370] Step 1. To a solution of 5, 5-difluoropyrrolidin-3-ol (250 mg, 1.57 mmol, 1 eq, HC1) in THF (5 mL) was added dropwise TEA (1.59 g, 15.7 mmol, 2.18 mL, 10 eq) at 25 °C. After addition, the mixture was stirred at this temperature for 10 minutes. The solution of (lZ)-2, 6- dichloro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride (888 mg, 2.35 mmol, 1.5 eq) 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 indicated 5, 5-difluoropyrrolidin-3-ol was consumed completely and one new spot was formed. Then it was separated between 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 give the desired N-[(E)-[(2, 6-dichlorophenyl)-(2, 2- difluoro-4-hydroxy-pyrrolidin-l-yl) methylene] amino]-4-methyl-benzenesulfonamide (720 mg, crude) as a yellow solid.

[0371] Step 2\ To a solution of N-[(E)-[(2, 6-dichlorophenyl)-(3, 3-difluoro-4-hydroxy- pyrrolidin-l-yl) methylene] amino]-4-methyl-benzenesulfonamide (720 mg, 1.55 mmol, 1 eq) in DMF (10 mL) was added K2CO3(1.07 g, 7.75 mmol, 5 eq). The mixture was stirred at 100 °C for 2 hours. TLC indicated N-[(E)-[(2, 6-dichlorophenyl)-(3, 3-difluoro-4-hydroxy-pyrrolidin-l- yl) methylene] amino]-4-methyl-benzenesulfonamide was consumed completely and one new spot was formed. The reaction mixture was added to water (30 mL) and extracted with EtOAc (30 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by132SUBSTITUTE SHEET (RULE 26)column chromatography (silica gel, petroleum ether / ethyl acetate =1 / 0 to 0 / 1) to give the desired l-(4-chloro-lH-indazol-3-yl)-4, 4-difluoro-pyrrolidin-3-ol (400 mg, crude) as a yellow oil.

[0372] Step 3: To a solution of l-(4-chloro-lH-indazol-3-yl)-4,4-difluoro-pyrrolidin-3-ol (200 mg, 731 μmol, 1 eq) in DCM (2 mL) were added imidazole (99.5 mg, 1.46 mmol, 2 eq) and TBSC1 (132 mg, 877 μmol, 108 μL, 1.2 eq) at 0 °C under N2. The mixture was stirred at 20 °C for 0.5 hour. LC-MS showed l-(4-chloro-lH-indazol-3-yl)-4, 4-difluoro-pyrrolidin-3-ol was consumed completely and one main peak with the desired mass was detected. The reaction mixture was added to sat. aq. NaHCO3(30 mL) and extracted with DCM (30 mL X 3). The combined organic layers were washed with brine (20 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired tert-butyl-[l-(4-chloro-lH-indazol-3-yl)- 4,4-difluoro-pyrrolidin-3-yl]oxy-dimethyl-silane (180 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C17H24Cl2N3 Si 387.13 m / z found 388.1 [M+H]+.

[0373] Step 4. To a solution of tert-butyl-[l-(4-chloro-lH-indazol-3-yl)-4, 4-difluoro- pyrrolidin-3-yl] oxy-dimethyl-silane (100 mg, 258 μmoll 1 eq) and 4-(l, 1 -difluoroethyl) benzenesulfonyl chloride (93.1 mg, 387 μmoll 1.5 eq) in DCM (1 mL) were added TEA (78.3 mg, 773 μmol, 108 μL, 3 eq) and DMAP (3.15 mg, 25. 8 μmoll 0.1 eq). The mixture was stirred at 20 °C for 0.5 hour. LC-MS showed tert-butyl-[l-(4-chloro-lH-indazol-3-yl)-4, 4-difluoro- pyrrolidin-3-yl] oxy-dimethyl-silane was consumed completely and one main peak with the desired mass was detected. The reaction mixture was concentrated to give the desired tert-butyl- [l-[4-chloro-l-[4-(l, 1 -difluoroethyl) phenyl] sulfonyl-indazol-3-yl]-4, 4-difluoro-pyrrolidin-3- yl] oxy-dimethyl-silane (150 mg, crude) as a white solid. MS (ESI): mass calcd. For C25H3oClF4N303SSi 591.14 m / z found 592.2 [M+H]+.

[0374] Step 5: To a solution of tert-butyl-[l-[4-chloro-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-indazol-3-yl]-4, 4-difluoro-pyrrolidin-3-yl] oxy-dimethyl-silane (80 mg, 135 μm,ol 1 eq) in THF (1 mL) was added TBAF (70.7 mg, 270 μmoll 2 eq). The mixture was stirred at 20 °C for 0.5 hour. LC-MS showed tert-butyl-[l-[4-chloro-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-indazol-3-yl]-4, 4-difluoro-pyrrolidin-3-yl] oxy-dimethyl-silane was consumed completely and one main peak with the desired mass was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna Cl 8 75 * 30 mm * 3 μm; mobile phase:133SUBSTITUTE SHEET (RULE 26)[H2O(0.1%TFA)-ACN]; gradient: 55%-80% B over 8.0 min) to give the desired 1 -[4-chl oro-1 - [4-(l, 1 -difluoroethyl) phenyl] sulfonyl-indazol-3-yl]-4, 4-difluoro-pyrrolidin-3-ol (1.1 mg, 2.28 μmol, 1.69% yield, 98.90% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 8.3 Hz, 1H), 7.98 (d, J= 8.3 Hz, 2H), 7.78 (d, J= 8.3 Hz, 2H), 7.71 - 7.64 (m, 1H), 7.52 (d, J= 7.7 Hz, 1H), 6.33 - 6.04 (m, 1H), 4.40 - 4.29 (m, 1H), 4.14 - 3.74 (m, 4H), 1.95 (t, J= 19.1 Hz, 3H). HPLC: 98.90% (220 nm), 98.83% (215 nm), 100.00% (254 nm). MS (ESI): mass calcd. For C19H16CIF4N3O3S 477.05 m / z found 478.0 [M+H]+.Compound 34: 4-Chloro-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-3-[(4R)-3, 3-difluoro-4- methyl-pyrrolidin-l-yl] indazoleCompound 35: 4-Chloro-l-[4-(l,l-difluoroethyl)phenyl]sulfonyl-3-[(4S)-3,3-difluoro-4- methyl-pyrrolidin-l-yl]indazole

[0375] Step 1. 4-Chloro-l-[4-(l,l-difluoroethyl)phenyl]sulfonyl-3-(3,3-difluoro-4-methyl- pyrrolidin-l-yl)indazole (20 mg, 62.3 μmol μmol, 1 eq) was separated by chiral SFC (column: Phenomenex Luna CN 100 * 30 mm * 5 μm; mobile phase: [Heptane-EtOH]; gradient: 20%- 50% B over 10.0 min) to give two isomers. The structures were assigned arbitrarily. 4-Chloro-l- [4-(l, 1-difluoroethyl) phenyl] sulfonyl-3-[(4R)-3, 3-difluoro-4-methyl-pyrrolidin-l-yl] indazole (7 mg, 14.7 μmol, 34.9% yield, 98.98% purity, Rt = 4.948 minutes; E.E. by chiral HPLC (%) = 100.0%) was isolated as a white solid. 1H NMR (400 MHz, DMSO-cL) δ 8.08 (d, J= 8.4 Hz, 1H), 7.95 (d, J= 8.4 Hz, 2H), 7.75 (d, J= 8.5 Hz, 2H), 7.64 (t, J= 8.1 Hz, 1H), 7.48 (d, J= 7.6 Hz, 1H), 4.09 (br d, J= 17.9 Hz, 1H), 3.89 - 3.77 (m, 2H), 3.38 (s, 1H), 2.78 - 2.61 (m, 1H), 1.92 (t, J= 19.1 Hz, 3H), 1.08 (d, J= 6.9 Hz, 3H). HPLC: 98.98% (220 nm), 99.47% (215 nm), 99.10% (254 nm). MS (ESI): mass calcd. For C20H18CIF4N3O2S 475.1 m / z found 476.1 [M+H]+.

[0376] 4-Chloro-l-[4-(l,l-difluoroethyl)phenyl]sulfonyl-3-[(4S)-3,3-difluoro-4-methyl- pyrrolidin-l-yl]indazole (8 mg, 16.61 μmol, 39.5% yield, 98.79% purity, Rt = 5.261 minutes; E.E. by chiral HPLC (%) = 97.88%) was isolated as a white solid.1H NMR (400 MHz, DMSO-134SUBSTITUTE SHEET (RULE 26)d6) 5 8.08 (d, J= 8.4 Hz, 1H), 7.95 (d, J= 8.3 Hz, 2H), 7.75 (d, J= 8.4 Hz, 2H), 7.64 (t, J= 8.1 Hz, 1H), 7.48 (d, ,7= 7.8 Hz, 1H), 4.09 (td, J= 11.6, 17.9 Hz, 1H), 3.90 - 3.77 (m, 2H), 3.41 - 3.36 (m, 1H), 2.75 - 2.65 (m, 1H), 1.92 (t, J= 19.1 Hz, 3H), 1.08 (d, .7= 6.8 Hz, 3H). HPLC: 98.79% (220 nm), 98.92% (215 nm), 99.06% (254 nm). MS (ESI): mass calcd. For C20H18CIF4N3O2S 475.1 m / z found 476.1 [M+H]+.Compound 36: 4-Chloro-l-[4-(l,l-difluoroethyl)phenyl]sulfonyl-3-[(3R,4R)-3-fluoro-4- methyl-pyrrolidin-l-yl]indazoleCompound 37: 4-Chloro-l-[4-(l,l-difluoroethyl)phenyl]sulfonyl-3-[(3S,4S)-3-fluoro-4- methyl-pyrrolidin-l-yl]indazoleCompound 38: 4-Chloro-l-[4-(l,l-difluoroethyl)phenyl]sulfonyl-3-[(3R,4S)-3-fluoro-4- methyl-pyrrolidin-l-yl]indazoleCompound 39: 4-Chloro-l-[4-(l, l-difluoroethyl)phenyl]sulfonyl-3-[(3S,4R)-3-fluoro-4- methyl-pyrrolidin-l-yl]indazole

[0377] Step 1: 4-Chloro-l-[4-(l, 1 -difluoroethyl) phenyl] sulfonyl-3-(3-fluoro-4-methyl- pyrrolidin- 1 -yl) indazole (20 mg, 43.68 μmoll 1 eq) was separated by chiral SFC (column: Daicel ChiralPak IG (250 * 30 mm, 10 μm); mobile phase: [Heptane-IPA]; B%:20%, isocratic elution mode) to give four isomers. The structures were assigned arbitrarily. 4-Chl oro-1 -[4-(l , 1 - difluoroethyl)phenyl]sulfonyl-3-[(3R,4R)-3-fluoro-4-methyl-pyrrolidin-l-yl]indazole (2.2 mg, 4.55μmol , 10.4% yield, 94.67% purity, Rt = 3.919 minutes; E.E. by chiral HPLC (%) = 100.00%) was isolated as a colorless oil. 1H NMR (400 MHz, DMSO-fik) δ 8.12 (s, 1H), 7.95 (d, J= 8.4 Hz, 2H), 7.77 (d, J= 8.6 Hz, 2H), 7.66 (t, J= 8.1 Hz, 1H), 7.50 (d, J= 7.6 Hz, 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= 19.1 Hz, 3H), 1.32 (br d, J= 6.8 Hz, 3H). HPLC: 94.67% (220 nm), 95.53% (215 nm), 86.92% (254 nm). MS (ESI): mass calcd. For C20H19CIF3N3O2S 457.08 m / z found 458.0 [M+H] .

[0378] 4-Chloro-l-[4-(l,l-difluoroethyl)phenyl]sulfonyl-3-[(3S,4S)-3-fluoro-4-methyl- pyrrolidin-l-yl]indazole (1.0 mg, 2.13 μmol, 4.87% yield, 97.38% purity, Rt = 4.352 minutes;SUBSTITUTE SHEET (RULE 26)E.E. by chiral HPLC (%) = 93.52%) was isolated as a colorless oil. 1H NMR (400 MHz, DMSO- de) 8 8.10 (d, J= 8.8 Hz, 1H), 7.94 (d, J= 8.3 Hz, 2H), 7.76 (d, J= 8.4 Hz, 2H), 7.67 - 7.60 (m, 1H), 7.51 - 7.45 (m, 1H), 5.25 - 5.07 (m, 1H), 3.94 (d, J= 5.6 Hz, 1H), 3.64 - 3.46 (m, 3H), 2.41 - 2.29 (m, 1H), 1.94 (t, J= 19.2 Hz, 3H), 1.13 (d, J= 6.7 Hz, 3H). HPLC: 97.38% (220 nm), 92.54% (215 nm), 97.31% (254 nm). MS (ESI): mass calcd. For C20H19CIF3N3O2S 457.08 m / z found 458.0 [M+H]+.

[0379] 4-Chloro-l-[4-(l,l-difluoroethyl)phenyl]sulfonyl-3-[(3R,4S)-3-fluoro-4-methyl- pyrrolidin-l-yl]indazole (1.0 mg, 2.10 μmol, 4.82% yield, 96.33% purity, Rt = 4.561 minutes; E.E. by chiral HPLC (%) = 44.52%) was isolated as a colorless oil. 1H NMR (400 MHz, DMSO- de) 8 8.12 (s, 1H), 7.95 (br d, J= 7.8 Hz, 2H), 7.80 - 7.73 (m, 2H), 7.70 - 7.61 (m, 1H), 7.50 (dd, J= 3.9, 7.7 Hz, 1H), 5.19 - 4.92 (m, 1H), 4.26 (dd, J = 2.2, 5.3 Hz, 1H), 3.95 (d, J= 5.5 Hz, 4H), 1.94 (dt, J= 2.3, 19.2 Hz, 3H), 1.33 (br d, J= 7.0 Hz, 3H). HPLC: 96.33% (220 nm), 97.27% (215 nm), 73.24% (254 nm). MS (ESI): mass calcd. For C20H19CIF3N3O2S 457.08 m / z found 458.0 [M+H]+.

[0380] 4-Chloro-l-[4-(l,l-difluoroethyl)phenyl]sulfonyl-3-[(3S,4R)-3-fluoro-4-methyl- pyrrolidin-l-yl]indazole (1.2 mg, 2.54 μmol, 5.83% yield, 97.10% purity, Rt = 6.393 minutes; E.E. by chiral HPLC (%) = 100.0%) was isolated as a colorless oil. ' H NMR (400 MHz, DMSO- dd) 8 8.12 (s, 1H), 7.95 (d, J= 8.4 Hz, 2H), 7.77 (d, J= 8.4 Hz, 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= 6.7 Hz, 3H). HPLC: 97.10% (220 nm), 98.03% (215 nm), 81.97% (254 nm).MS (ESI): mass calcd. For C20H19CIF3N3O2S 457.08 m / z found 458.0 [M+H]+.Compound 40: 4-Chloro-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-3-(3, 3, 4- trifluoropyrrolidin-l-yl) indazole136SUBSTITUTE SHEET (RULE 26)

[0381] Step 1. To a solution of 5, 5-difluoropyrrolidin-3-ol (250 mg, 1.57 mmol, 1 eq, HC1) in THF (5 mL) was added dropwise TEA (1.59 g, 15.7 mmol, 2.18 mL, 10 eq) at 25 °C. After addition, the mixture was stirred at this temperature for 10 minutes. (lZ)-2, 6-dichloro-N-(p- tolyl sulfonyl) benzohydrazonoyl chloride (888 mg, 2.35 mmol, 1.5 eq) 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 indicated 5, 5-difluoropyrrolidin-3-ol was consumed completely and one new spot was formed. Then it was separated between 20 mL of water and 40 mL of ethyl acetate. The organic phase was separated, washed with 30 mL of brine, dried over IsfeSCL, filtered, and concentrated under reduced pressure to give the desired N-[(E)-[(2, 6-dichlorophenyl)-(2, 2-difluoro-4-hydroxy- pyrrolidin- 1 -yl) methylene] amino]-4-methyl-benzenesulfonamide (720 mg, crude) as a yellow solid.

[0382] Step 1. To a solution of N-[(E)-[(2, 6-dichlorophenyl)-(3, 3-difluoro-4-hydroxy- pyrrolidin- 1 -yl) methylene] amino]-4-methyl-benzenesulfonamide (720 mg, 1.55 mmol, 1 eq) in DMF (10 mL) was added K2CO3(1.07 g, 7.75 mmol, 5 eq). The mixture was stirred at 100 °C for 2 hours. TLC indicated N-[(E)-[(2, 6-dichlorophenyl)-(3, 3-difluoro-4-hydroxy-pyrrolidin-l- yl) methylene] amino]-4-methyl-benzenesulfonamide was consumed completely and one new spot was formed. The reaction mixture was added to water (30 mL) and extracted with EtOAc (30 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by p / xyi-HPLC (TFA condition; column: Phenomenex Luna C18 75 * 30 mm * 3 μm; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 35%-60% B over 8.0 min) to give the desired 1 - [4-chl oro-1 - (p-tolyl sulfonyl) indazol-3-yl]-4, 4-difluoro-pyrrolidin-3-ol (60 mg, crude) as a yellow oil.137SUBSTITUTE SHEET (RULE 26)

[0383] Step 3 : Two reactions were carried out in parallel. To a solution of l-[4-chloro-l-(p- tolyl sulfonyl) indazol-3-yl]-4, 4-difluoro-pyrrolidin-3-ol (30 mg, 70.1 μm,o 1l eq) in toluene (1 mL) was added DAST (22.6 mg, 140 μmoll 18.5 μL, 2 eq) at 0 °C. The mixture was stirred at 50 °C for 12 hours. Two reactions were carried out in parallel. LC-MS showed 1 -[4-chl oro-l-(p- tolyl sulfonyl) indazol-3-yl]-4, 4-difluoro-pyrrolidin-3-ol remained. Several new peaks were shown on LC-MS and the desired compound was detected. Two reactions were combined for workup. The reaction mixture was added to water (30 mL) and extracted with EtOAc (30 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, fdtered, and concentrated under reduced pressure to give the desired 4-chloro-l-(p-tolylsulfonyl)-3- (3,3,4-trifluoropyrrolidin-l-yl)indazole (60 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C18H15CIF3N3O2S 429.05 m / z found 430.2 [M+H]+.

[0384] Step 4. To a solution of 4-chloro-l-(p-tolylsulfonyl)-3-(3, 3, 4-trifluoropyrrolidin-l- yl) indazole (60 mg, 140 μmol, 1 eq) in MeOH (1 mL) was added K2CO3(57.9 mg, 419 μm, o 3l eq). The mixture was stirred at 70 °C for 1 hour. LC-MS showed 4-chl oro-1 -(p-tolyl sulfonyl)-3- (3, 3, 4-trifluoropyrrolidin-l-yl) indazole remained. Several new peaks were shown on LC-MS and the desired compound was detected. The reaction mixture was added to water (30 mL) and extracted with EtOAc (30 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by / ?rcp-TLC (silica gel, petroleum ether I ethyl acetate = 1 / 1) to give the desired 4-chl oro-3 -(3, 3, 4-trifluoropyrrolidin-l-yl)-lH-indazole (20 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C11H9CIF3N3275.04 m / z found 276.0 [M+H]+.

[0385] Step 5\ To a solution of 4-chloro-3-(3,3,4-trifluoropyrrolidin-l-yl)-lH-indazole (20 mg, 72.6 μmol, 1 eq) and 4-(l,l-difluoroethyl)benzenesulfonyl chloride (26.2 mg, 109 μmoll 1.5 eq) in DCM (1 mL) were added TEA (22.0 mg, 218 μmoll 30.3 μL, 3 eq) and DMAP (886 μg, 7.26μmol , 0.1 eq). The mixture was stirred at 20 °C for 0.5 hour. LC-MS showed 4-chloro-3-(3, 3, 4-trifluoropyrrolidin-l-yl)-lH-indazole was consumed completely and one main peak with the desired mass was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by prepH-PLC (TFA condition; column: Phenomenex Luna C18 75 * 30 mm * 3 μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 50%-75% B over 8.0 min) to give the desired 4-chloro-l-[4-(l,l-difluoroethyl)phenyl]sulfonyl-3-(3,3,4- trifluoropyrrolidin-l-yl)indazole (1 mg, 2.04 μmol, 2.81% yield, 97.79% purity) as a pink solid.138SUBSTITUTE SHEET (RULE 26)1H NMR (400 MHz, DMSO-4) δ 8.10 (d, J = 8.5 Hz, 1H), 7.98 (br d, J= 8.3 Hz, 2H), 7.76 (br d, J= 8.3 Hz, 2H), 7.67 (t, J= 8.1 Hz, 1H), 7.51 (d, J= 7.8 Hz, 1H), 5.59 - 5.32 (m, 1H), 4.28 - 3.94 (m, 3H), 3.91 - 3.78 (m, 1H), 1.93 (t, J= 19.1 Hz, 3H). HPLC: 97.79% (220 nm), 96.44% (215 nm), 96.90% (254 nm). MS (ESI): mass calcd. For C19H15CIF5N3O2S 479.05 m / z found 480.0 [M+H]+.Compound 41: (3S)-l-[4-chloro-l-[4-(l,l-difluoroethyl)phenyl]sulfonyl-indazol-3-yl]-4,4- difluoro-pyrrolidin-3-olCompound 42: (3R)-l-[4-chloro-l-[4-(l,l-difluoroethyl)phenyl]sulfonyl-indazol-3-yl]-4,4- difluoro-pyrrolidin-3-ol

[0386] Step 1: \ -[4 -Chloro-l-[4-(l,l-difluoroethyl)phenyl]sulfonyl-indazol-3-yl]-4,4- difluoro-pyrrolidin-3-ol (60 mg, 126 μmol, 1 eq) was separated by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [Heptane-IPA]; B%: 20%, isocratic elution mode) to give two isomers. The structures were assigned arbitrarily. (3 S)-l -[4- chloro-l-[4-(l, 1 -difluoroethyl) phenyl] sulfonyl-indazol-3-yl]-4, 4-difluoro-pyrrolidin-3-ol (5.8 mg, 11.94 μmol, 9.51% yield, 98.41% purity, Rt = 4.278 minutes; E.E. by chiral HPLC (%) = 100.0%) was isolated as a white solid. Tl NMR (400 MHz, DMSO-d6) δ 8.14 (d, J= 8.5 Hz, 1H), 8.01 (d, J= 8.4 Hz, 2H), 7.81 (d, J= 8.4 Hz, 2H), 7.70 (t, J= 8.1 Hz, 1H), 7.54 (d, J= 7.8 Hz, 1H), 6.17 (d, J= 5.1 Hz, 1H), 4.42 - 4.32 (m, 1H), 4.14 - 3.91 (m, 3H), 3.51 - 3.45 (m, 1H), 1.98 (t, J= 19.1 Hz, 3H). HPLC: 98.41% (220 nm), 98.26% (215 nm), 98.10% (254 nm). MS (ESI): mass calcd. For C19H16CIF4N3O3S 477.05 m / z found 478.0 [M+H]+.

[0387] (3R)-l-[4-chloro-l-[4-(l, 1 -difluoroethyl) phenyl] sulfonyl-indazol-3-yl]-4, 4- difluoro-pyrrolidin-3-ol (4.5 mg, 9.24 μmol, 7.36% yield, 98.09% purity, Rt = 4.825 minutes; E.E. by chiral HPLC (%) = 91.20%) was isolated as a white solid.rH NMR (400 MHz, DMSO- d6) δ 8.09 (d, J= 8.4 Hz, 1H), 7.96 (d, J= 8.4 Hz, 2H), 7.76 (d, J= 8.5 Hz, 2H), 7.65 (t, J= 8.1 Hz, 1H), 7.49 (d, J= 7.8 Hz, 1H), 6.12 (d, J= 5.1 Hz, 1H), 4.37 - 4.27 (m, 1H), 4.06 - 3.86 (m,139SUBSTITUTE SHEET (RULE 26)3H), 3.43 (ddd, 2.1, 4.2, 11.3 Hz, 1H), 1.93 (t, 19.1 Hz, 3H). HPLC: 98.09% (220 nm),98.26% (215 nm), 97.30% (254 nm). MS (ESI): mass calcd. For C19H16CIF4N3O3S 477.05 m / z found 478.0 [M+H]+.Compound 43: 4-Chloro-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-3-[(4R)-3, 3, 4- trifluoropyrrolidin-l-yl] indazoleCompound 44: 4-Chloro-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-3-[(4S)-3, 3, 4- trifluoropyrrolidin-l-yl] indazole

[0388] Step 1: 4-Chloro-l-((4-(l, 1-difluoroethyl) phenyl) sulfonyl)-3-(3, 3, 4- trifluoropyrrolidin-l-yl)-lH-indazole (20 mg) was separated by SFC (column: Daicel ChiralPak IG (250 * 30 mm, 10 μm); mobile phase: [Heptane-EtOH]; B%:20%, isocratic elution mode) to give two isomers. The structures were assigned arbitrarily. 4-Chloro-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-3-[(4R)-3, 3, 4-trifluoropyrrolidin-l-yl] indazole (1.0 mg, 1.89 μm,o 4l .52% yield, 90.85% purity, Rt = 2.851 minutes; E.E. by chiral HPLC (%) = 100.00%) was isolated as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J= 8.4 Hz, 1H), 7.98 (d, J= 8.4 Hz, 2H), 7.76 (d, J= 8.5 Hz, 2H), 7.67 (t, J= 8.1 Hz, 1H), 7.51 (d, J= 7.6 Hz, 1H), 5.59 - 5.37 (m, 1H), 4.25 - 3.99 (m, 3H), 3.92 - 3.76 (m, 1H), 1.93 (t, J= 19.1 Hz, 3H). HPLC: 90.85% (220 nm), 91.20% (210 nm), 88.67% (254 nm). MS (ESI): mass calcd. For C19H15CIF5N3O2S 479.05, m / z found 480.0 [M+H]+.

[0389] 4-Chloro-l-[4-(l, 1-difluoroethyl) phenyl] sulfonyl-3-[(4S)-3, 3, 4- trifluoropyrrolidin-l-yl] indazole (1.2 mg, 2.41 μmoll 5.76% yield, 96.33% purity, Rt = 3.172 minutes; E.E. by chiral HPLC (%) = 100.00%) was isolated as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J= 8.5 Hz, 1H), 7.98 (d, J= 8.4 Hz, 2H), 7.76 (d, J= 8.5 Hz, 2H), 7.67 (t, J= 8.1 Hz, 1H), 7.51 (d, J= 7.6 Hz, 1H), 5.63 - 5.37 (m, 1H), 4.25 - 4.00 (m, 3H), 3.91 - 3.79 (m, 1H), 1.93 (t, J= 19.1 Hz, 3H). HPLC: 96.33% (220 nm), 96.57% (210 nm), 94.05% (254 nm). MS (ESI): mass calcd. For C19H15C1F5N3O2S 479.05, m / z found 480.0 [M+H]+. 140SUBSTITUTE SHEET (RULE 26)Compound 45: 4-Chloro-l-[[6-(l, l-difluoroethyl)-3-pyridyl] sulfonyl]-3-(3, 3, 4, 4- tetrafluoropyrrolidin-l-yl) indazole

[0390] Step 1 To a solution of l-(5-bromo-2-pyridyl) ethanone (1 g, 5.00 mmol, 1 eq) in toluene (10 mL) was added DAST (4.03 g, 25.0 mmol, 3.30 mL, 5 eq) at 0 °C. The mixture was stirred at 80 °C for 1 hour. TLC indicated l-(5-bromo-2-pyridyl) ethanone was consumed completely one new spot was formed. The reaction was quenched with ice-water (10 g) and extracted with EtOAc (2 X 10 mL). The combined organics were concentrated to get a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 5 / 1) to give the desired 5-bromo-2-(l, 1 -difluoroethyl) pyridine (330 mg, 1.49 mmol, 29.7% yield) as a yellow oil. MS (ESI): mass calcd. For C7H6Br 221.0, m / z found 222.0 [M+H]+.

[0391] Step 2'. A mixture of 5-bromo-2-(l, l-difluoroethyl)pyridine (330 mg, 1.49 mmol, 1 eq), phenylmethanethiol (277 mg, 2.23 mmol, 262 μL, 1.5 eq), DIEA (384 mg, 2.97 mmol, 518 μL, 2 eq), Xantphos (86.0 mg, 149 μmol, 0.1 eq) and Pd2(dba)3(136 mg, 149 μm,o 0l.1 eq) in dioxane (5 mL) was degassed and purged with N2for 3 times. The mixture was stirred at 100 °C for 12 hours under N2atmosphere. LC-MS showed 5-bromo-2-(l, 1 -difluoroethyl) pyridine was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 10 mL of H2O and 10 mL of EtOAc. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 5 / 1) to give the desired 5-benzylsulfanyl-2-(l, 1 -difluoroethyl) pyridine (230 mg, 867 μm,ol 141SUBSTITUTE SHEET (RULE 26)58.3% yield) as a yellow oil. MS (ESI): mass calcd. For C14H13F2NS 265.1, m / z found 266.1 [M+H]+.

[0392] Step 3. To a solution of 5-benzylsulfanyl- 2-(l, 1 -difluoroethyl) pyridine (230 mg, 867μmol , 1 eq) in AcOH (0.8 mL) and H2O (0.2 mL) was added NCS (463 mg, 3.47 mmol, 4 eq). The mixture was stirred at 15 °C for 1 hour. LC-MS showed 5-benzylsulfanyl-2-(l, 1- difluoroethyl) pyridine was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 10 mL of H2O and 10 mL of EtOAc. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by prep-TLC (silica gel, petroleum ether / ethyl acetate = 5 / 1) to give the desired 6-(l, 1 -difluoroethyl) pyridine-3- sulfonyl chloride (80 mg, 331 μmol, 38.2% yield) as a white solid. MS (ESI): mass calcd. For C7H6CIF2NO2S 241.0, m / z found 242.0 [M+H]+.

[0393] Step 4: To a solution of 4-chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole (20 mg, 68.1 μmol, 1 eq) and 6-(l, 1-difluoroethyl) pyridine-3 -sulfonyl chloride (32.9 mg, 136 μmol, 2 eq) in pyridine (1 mL) was added DMAP (83 μg, 6.81 μmoll 0.1 eq). The mixture was stirred at 15 °C for 1 hour. LC-MS showed 4-chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH- indazole was consumed completely and the desired mass was detected. The reaction mixture was filtered, and the filter liquor was concentrated under reduced pressure to give a residue. The residue was purified by pre-HPLC (TFA condition; Method: column: Phenomenex Luna Cl 8 75 * 30 mm * 3 μm; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 50%-80% B over 8.0 min) to give the desired 4-chloro-l-[[6-(l,l-difhioroethyl)-3-pyridyl]sulfonyl]-3-(3, 3, 4, 4- tetrafluoropyrrolidin-l-yl)indazole (4.3 mg, 8.48 μmol, 12.5% yield, 98.38% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J= 1.3 Hz, 1H), 8.48 (dd, J= 2.1, 8.4 Hz, 1H), 8.12 (d, J= 8.4 Hz, 1H), 7.89 (d, J= 8.4 Hz, 1H), 7.70 (t, J= 8.1 Hz, 1H), 7.54 (d, J= 7.8 Hz, 1H), 4.24 (br t, J= 12.3 Hz, 4H), 1.95 (t, J= 19.3 Hz, 3H). HPLC: 98.38% (220 nm), 98.29% (215 nm), 98.79% (254 nm). MS (ESI): mass calcd. For C18H13CIF6N4O2S 498.0 m / z found 499.0 [M+H]+.Compound 46: 5-Chloro-l-((4-(l,l-difluoroethyl)phenyl)sulfonyl)-3-(3, 3,4,4- tetrafluoropyrrolidin-l-yl)imidazo[l,5-a]pyridine 142SUBSTITUTE SHEET (RULE 26)

[0394] Step 1 : To a solution of 4-(l, 1 -difluoroethyl) benzenesulfonyl chloride (1 g, 4.16 mmol, 1 eq) in H2O (10 mL) were added NaHCO3(698 mg, 8.31 mmol, 2 eq) and TsfeSCh (1.05 g, 8.31 mmol, 2 eq). The mixture was stirred at 80 °C for 2 hours. TLC indicated 4-(l, 1- difluoroethyl) benzenesulfonyl chloride was consumed completely and one new spot was formed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was added MeOH (20 mL). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the desired [4-(l, 1 -difluoroethyl) phenyl] sulfinyloxysodium (1 g, crude) as a white solid.

[0395] Step 2: To a solution of 3, 3, 4, 4-tetrafluoropyrrolidine (3 g, 16.7 mmol, 1 eq, HC1) in DCM (30 mL) were added NaHCCL (7.02 g, 83.6 mmol, 5 eq) and bis (trichloromethyl) carbonate (2.38 g, 8.02 mmol, 0.48 eq) at 0 °C. The mixture was stirred at 15 °C for 1 hour. The reaction was filtered, and the filtrate was concentrated to give the desired 3, 3, 4, 4- tetrafluoropyrrolidine-1 -carbonyl chloride (3.3 g, crude) as a white oil.

[0396] Step 3: To a solution of (6-chloro-2-pyridyl) methanamine (1.83 g, 12.8 mmol, 0.8 eq) in DCM (35 mL) were added DIEA (10.4 g, 80.3 mmol, 14.0 mL, 5 eq) and 3, 3, 4, 4- tetrafluoropyrrolidine-1 -carbonyl chloride (3.3 g, 16.1 mmol, 1 eq) at 0 °C. The mixture was stirred at 15 °C for 1 hour. LCMS showed (6-chloro-2-pyridyl) methanamine was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 30 mL of FEO 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 give a residue. The 143SUBSTITUTE SHEET (RULE 26)residue was purified by purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-50% ethyl acetate I petroleum ether gradient @60 mL / min) to give the desired N-[(6-chloro-2-pyridyl) methyl]-3, 3, 4, 4-tetrafluoro-pyrrolidine-l -carboxamide (2.74 g, 8.79 mmol, 54.8% yield) as a yellow solid. MS (ESI): mass calcd. For C11H10CIN3F4O 311.04 m / z found 312.0 [M+H]+.

[0397] Step 4: To a solution of N-[(6-chloro-2-pyridyl)methyl]-3, 3, 4, 4-tetrafluoro- pyrrolidine-l -carboxamide (2.74 g, 8.79 mmol, 1 eq) in DCM (30 mL) were added trifluoromethylsulfonyl trifluoromethanesulfonate (2.98 g, 10.6 mmol, 1.74 mL, 1.2 eq) and 2- methoxypyridine (1.06 g, 9.67 mmol, 1.01 mL, 1.1 eq) at 0 °C. The mixture was stirred at 35 °C for 1 hour. LCMS showed N-[(6-chloro-2-pyridyl) methyl]-3, 3, 4, 4-tetrafluoro-pyrrolidine-l - carboxamide was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 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 give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0 - 15 % ethyl acetate / petroleum ether gradient @60 mL / min) to give the desired 5-chloro-3-(3,3,4,4-tetrafluoropyrrolidin-l-yl)imidazo[l,5- a]pyridine (2.55 g, 8.68 mmol, 98.8% yield) as a yellow solid. MS (ESI): mass calcd. For C11H8N3CIF4293.03 m / z found 294.0 [M+H]+.

[0398] Step 5: To the mixture ofNIS (613 mg, 2.72 mmol, 1.0 eq) in THF (10 mL) was added 5-chloro-3-(3,3,4,4-tetrafluoropyrrolidin-l-yl)imidazo[l,5-a]pyridine (800 mg, 2.72 mmol, 1 eq) at -78 °C. The mixture was stirred at 20 °C for 0.5 hour. TLC indicated 5-chloro-3- (3,3,4,4-tetrafluoropyrrolidin-l-yl)imidazo[l,5-a]pyridine was consumed completely and a new spot with lower polarity was detected. The reaction was quenched with saturated NH4CI solution (10 mL) and extracted with MTBE (2 X 20 mL). The combined organics were dried over Na2SO4and concentrated to get a residue. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0-10% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give the desired 5-chloro-l-iodo-3-(3, 3,4,4- tetrafluoropyrrolidin-l-yl)imidazo[l,5-a]pyridine (230 mg, 548 μmol, 20.1% yield) as a yellow solid.

[0399] Step 6: A mixture of 5-chloro-l-iodo-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl) imidazo [1, 5-a] pyridine (50 mg, 119 μmoll 1 eq), [4-(l, 1 -difluoroethyl) phenyl] sulfmyloxysodium 144SUBSTITUTE SHEET (RULE 26)(81.6 mg, 358 μmol, 3 eq), Cui (90.8 mg, 477 μmoll 4 eq) in DMSO (3 mL) under N2atmosphere. The mixture was stirred at 110 °C for 12 hours. LCMS showed 5-chloro-l-iodo-3- (3,3,4,4-tetrafluoropyrrolidin-l-yl)imidazo[l,5-a]pyridine was consumed completely and the desired mass was detected. The reaction was poured into water (15 mL) and extracted with MTBE (2 X 10 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75 * 30 mm * 3 μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 40%-60% B over 8.0 minutes) to give the desired 5-chloro-l- [4-(l,l-difluoroethyl)phenyl]sulfonyl-3-(3,3,4,4-tetrafluoropyrrolidin-l-yl)imidazo[l,5- a]pyridine (13.4 mg, 26.9 μmol, 22.5% yield, 99.75% purity) as a white solid. 1H NMR (DMSO- d6) 5 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% (220 nm), 99.72% (215 nm), 99.67% (254 nm). MS (ESI): mass calcd. For C19H14SN3CIF6O2497.04 m / z found 498.0 [M+H]+.Compound 47: l-((4-(l, 1-Difluoroethyl) phenyl) sulfonyl)-3-(3, 3, 4, 4- tetrafluoropyrrolidin-l-yl)-lH-indazol-4-ol

[0400] Step 1. To the solution of lH-indazol-4-ol (1 g, 7.46 mmol, 1 eq) in DMF (10 mL) were added imidazole (761 mg, 11.2 mmol, 1.5 eq) and TBSC1 (1.69 g, 11.2 mmol, 1.38 mL, 1.5 145SUBSTITUTE SHEET (RULE 26)eq) at 0 °C and the reaction mixture was stirred at 20 °C for 2 hours. TLC (silica gel, petroleum ether I EtOAc = 1 / 1) showed lH-indazol-4-ol was consumed completely and a new spot was formed. The reaction mixture was poured into water (120 mL) and stirred at 20 °C for 0.5 hour. The mixture was filtered, and the cake was dried over reduce pressure to give the desired tert- butyl-(lH-indazol-4-yloxy)-dimethyl-silane (1.85 g, crude) as a black oil.

[0401] Step 2'. To the solution of tert-butyl-(lH-indazol-4-yloxy)-dimethyl-silane (1.85 g, 7.45 mmol, 1 eq) in DCM (20 mL) was added NIS (1.84 g, 8.19 mmol, 1.1 eq) at 0 °C and the solution was stirred at 20 °C for 2 hours. LC-MS showed tert-butyl-(lH-indazol-4-yloxy)- dimethyl-silane was consumed completely and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give the desired tert-butyl-[(3-iodo-lH- indazol-4-yl) oxy]-dimethyl-silane (2.79 g, crude) as a black oil. MS (ESI): mass calcd. For Ci3Hi9IN2OSi 374.03 m / z found 375.0 [M+H]+.

[0402] Step 3 : To the solution of tert-butyl-[(3-iodo-lH-indazol-4-yl)oxy]-dimethyl-silane (2.75 g, 7.35 mmol, 1 eq) and TsOH.H2O (140 mg, 735 μmoll 0.1 eq) in DCM (30 mL) was added 3,4-dihydro-2H-pyran (927 mg, 11.0 mmol, 1.01 mL, 1.5 eq) at 0 °C. The solution was stirred at 20 °C for 1 hour. LC-MS showed tert-butyl-[(3-iodo-lH-indazol-4-yl) oxy]-dimethyl- silane was consumed completely and the desired mass was detected. The reaction was poured into water (30 mL) and extracted with MTBE (2 X 30 mL). The combined organics were dried over anhydrous sodium sulfate and concentrated to get a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-50% ethyl acetate / petroleum ether gradient @ 80 mL / min) to give the desired tert-butyl-(3- iodo-l-tetrahydropyran-2-yl-indazol-4-yl) oxy-dimethyl-silane (980 mg, 2.14 mmol, 29.1% yield) as a colorless oil. MS (ESI): mass calcd. For CigFEylbWhSi 458.09 m / z found 459.0 [M+H]+.

[0403] Step 4. To the solution of tert-butyl-(3 -iodo- l-tetrahydropyran-2-yl-indazol -4-yl) oxy-dimethyl-silane (780 mg, 1.70 mmol, 1 eq) in THF (8 mL) was added TBAF (1 M, 2.04 mL, 1.2 eq) at 20 °C. The mixture was stirred at 20 °C for 12 hours. TLC (silica gel, petroleum ether / EtOAc = 3 / 1) showed tert-butyl-(3-iodo-l-tetrahydropyran-2-yl-indazol-4-yl) oxy-dimethyl- silane was consumed completely and a new spot was formed. The reaction was concentrated to get a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-50% ethyl acetate I petroleum ether gradient @ 146SUBSTITUTE SHEET (RULE 26)100 mL / min) to give the desired 3-iodo-l-tetrahydropyran-2-yl-indazol-4-ol (0.8 g, crude) as a black oil.

[0404] Step 5: To the mixture of 3-iodo-l-tetrahydropyran-2-yl-indazol-4-ol (0.8 g, 2.32 mmol, 1 eq) and K2CO3(964 mg, 6.97 mmol, 3 eq) in ACN (10 mL) was added benzyl bromide (477 mg, 2.79 mmol, 331 μL, 1.2 eq) at 0 °C and the solution was stirred at 20 °C for 12 hours. LC-MS showed 3-iodo-l-tetrahydropyran-2-yl-indazol-4-ol was consumed completely and the desired mass was detected. The reaction was concentrated to get a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-10% ethyl acetate I petroleum ether gradient @ 50 mL / min) to give the desired 4- benzyloxy-3-iodo-l-tetrahydropyran-2-yl-indazole (600 mg, crude) as a colorless oil. MS (ESI): mass calcd. For C19H19IN2O2434.05 m / z found 435.0 [M+H]+.

[0405] Step 6. A mixture of 4-benzyloxy-3-iodo-l-tetrahydropyran-2-yl-indazole (450 mg, 1.04 mmol, 1 eq), 3, 3, 4, 4- tetrafluoropyrrolidine (186 mg, 1.04 mmol, 1 eq, HC1), CS2CO3(675 mg, 2.07 mmol, 2 eq), SPhos Pd G3 (80.9 mg, 104 μmoll 0.1 eq) in dioxane (5 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100 °C for 12 hours under N2atmosphere. LC-MS showed 4-benzyloxy-3-iodo-l-tetrahydropyran-2-yl-indazole was consumed completely and the desired mass was detected. The crude was added H2O (20 mL) and extracted with EtOAc (15 mL X 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by p / rp-TLC (silica gel, petroleum ether / EtOAc = 3 / 1) to give the desired 4-benzyloxy-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-l-tetrahydropyran-2-yl-indazole (0.4 g, 890 μmol, 85.9% yield) as a brown oil. MS (ESI): mass calcd. For C23H23F4N3O2449.17 m / z found 450.3 [M+H]+.

[0406] Step 7: To a solution of 4-benzyloxy-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-l- tetrahydropyran-2-yl-indazole (0.4 g, 890 μmol, 1 eq) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at 20 °C for 0.5 hour. LC-MS showed 4-benzyloxy-3-(3, 3, 4, 4- tetrafluoropyrrolidin-l-yl)-l-tetrahydropyran-2-yl-indazole was consumed completely and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / EtOAc = 2 / 1) to give the desired 4-benzyloxy-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole (0.2 g, 147SUBSTITUTE SHEET (RULE 26)crude, TFA) as a brown solid. MS (ESI): mass calcd. For C18H15F4N3O 365.12 m / z found 366.2 [M+H]+.

[0407] Step 8. To a solution of 4-benzyloxy-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH- indazole (0.2 g, 417 μmol, 1 eq, TFA) and 4-(l, l-difluoroethyl)benzenesulfonyl chloride (100 mg, 417 μmol, 1 eq) in DCM (1 mL) were added TEA (127 mg, 1.25 mmol, 174 μL, 3 eq) and DMAP (5.10 mg, 41.7 μmol, 0.1 eq). The mixture was stirred at 20 °C for 1 hour. TLC (silica gel, petroleum ether / EtOAc=3 / l) showed 4-benzyloxy-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)- IH-indazole was consumed completely and a new spot was formed. The crude was added H2O (20 mL) and extracted with EtOAc (15 mL X 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / EtOAc = 3 / 1) to give the desired 4-benzyloxy-l-[4-(l,l-difluoroethyl)phenyl]sulfonyl-3-(3,3,4,4- tetrafluoropyrrolidin-l-yl)indazole (0.2 g, 351 μmol, 84.2% yield) as a brown oil.

[0408] Step 9. To a solution of 4-benzyloxy-l-[4-(l,l-difluoroethyl)phenyl]sulfonyl-3- (3,3,4,4-tetrafluoropyrrolidin-l-yl)indazole (0.2 g, 351 μmol, 1 eq) and 4-benzyloxy-l-[4-(l,l- difluoroethyl)phenyl]sulfonyl-3-(3,3,4,4-tetrafluoropyrrolidin-l- yl)indazole (0.2 g, 351 μmoll 1 eq) in MeOH (5 mL) and HC1 (0.1 mL) was added Pd / C (37.4 mg, 35.1 μm,o 1l0% purity, 0.1 eq). The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 Psi) at 15 °C for 0.5 hour. LC-MS showed 4-benzyloxy-l-[4-(l,l- difluoroethyl)phenyl]sulfonyl-3-(3,3,4,4-tetrafluoropyrrolidin-l-yl)indazole was consumed completely and the desired mass was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (silica gel, petroleum ether / EtOAc = 2 / 1) to give the desired 1 -[4-( 1 , 1 -difluoroethyl) phenyl] sulfonyl-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl) indazol-4-ol (5.2 mg, 10.7 μm,o 3l .06% yield, 98.97% purity) as a white solid. 1HNMR (400 MHz, DMSO<fc) δ 11.25 (s, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.79 (d, J= 8.5 Hz, 2H), 7.58 - 7.47 (m, 2H), 6.80 (dd, J= 0.8, 7.6 Hz, 1H), 4.40 - 4.25 (m, 4H), 1.98 (t, J= 19.1 Hz, 3H). HPLC: 94.85% (220 nm), 93.11% (215 nm), 98.97% (254 nm). MS (ESI): mass calcd. For C19H15F6N3O3S 479.07 m / z found 480.1 [M+H]+.Compound 48: l-[4-(l, 1-Difluoroethyl) phenyl] sulfonyl-4-methoxy-3-(3, 3, 4, 4- tetrafluoropyrrolidin-l-yl) indazole 148SUBSTITUTE SHEET (RULE 26)

[0409] Step 1 To a solution of l-[4-(l, 1 -difluoroethyl) phenyl] sulfonyl-3-(3, 3, 4, 4- tetrafluoropyrrolidin-l-yl) indazol-4-ol (10 mg, 20.9 μmol, 1 eq) in ACN (0.5 mL) were added K2CO3(14.4 mg, 104 μmol, 5 eq) and Mel (14.8 mg, 104 μmoll 6.49 μL, 5 eq). The mixture was stirred at 20 °C for 1 hour. LC-MS showed l-[4-(l, 1 -difluoroethyl) phenyl] sulfonyl-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl) indazol-4-ol was consumed completely and one main peak with the desired mass was detected. The reaction mixture was added to HC1 (1 mL, IM) and extracted with EtOAc (3 mL X 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 75 * 30 mm * 3 μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 55%-90% B over 8.0 min) to give the desired l-[4-(l, 1 -difluoroethyl) phenyl] sulfonyl-4-methoxy-3-(3, 3, 4, 4-tetrafluoropyrrolidin- l-yl) indazole (5 mg, 10.0 μmol, 48.0% yield, 98.85% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (br d, J= 8.1 Hz, 2H), 7.73 (br d, J= 8.3 Hz, 2H), 7.66 - 7.56 (m, 2H), 6.93 (br d, J= 7.4 Hz, 1H), 4.20 (br t, J= 12.2 Hz, 4H), 3.91 (s, 3H), 1.92 (br t, J= 19.1 Hz, 3H). HPLC: 98.85% (220 nm), 99.10% (215 nm), 99.33% (254 nm). MS (ESI): mass calcd. For C20H17F6N3O3S 493.09 m / z found 494.1 [M+H]+.Compound 49: 4-Chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-l-[4-(l, 1, 2-trifluoroethyl) phenyl] sulfonyl-indazole 149SUBSTITUTE SHEET (RULE 26)

[0410] Step 1 : To a mixture of 2-bromo-l-(4-bromophenyl) ethanone (3 g, 10.8 mmol, 1 eq) was added 3HF.TEA (19.8 g, 128 mmol, 20 mL, 11.4 eq). The mixture was stirred at 120 °C for 2 hours. TLC indicated 2-bromo-l-(4-bromophenyl) ethanone was consumed completely and one new spot was formed. The reaction mixture was added to ice water (20 mL) and extracted with EtOAc (10 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / EtOAc = 1 / 0 to 5 / 1) to give the desired l-(4-bromophenyl)-2-fluoro-ethanone (1.8 g, crude) as a white solid.

[0411] Step 2'. A mixture of phenylmethanethiol (504 mg, 4.05 mmol, 475 μL, 1.1 eq), l-(4- bromophenyl)-2-fluoro-ethanone(800 mg, 3.69 mmol, 1 eq), DIEA (953 mg, 7.37 mmol, 1.28 mL, 2 eq), Xantphos (213 mg, 369 μmoll 0.1 eq) and Pd2(dba)s (84.4 mg, 92.2 μm,o 0l.025 eq) in dioxane (10 mL) was degassed and purged with N2for 3 times. The mixture was stirred at 100 °C for 3 hours under N2atmosphere. TLC indicated phenylmethanethiol was consumed completely and one new spot was formed. The reaction mixture was added to water (20 mL) and extracted with EtOAc (20 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / EtOAc = 1 / 0 to 1 / 1) to give the desired l-(4-benzylsulfanylphenyl)-2-fluoro-ethanone (840 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C15H13FOS 260.1, m / z found 261.1 [M+H]+.

[0412] Step 3: To a solution of l-(4-benzylsulfanylphenyl)-2-fluoro-ethanone (300 mg, 1.15 mmol, 1 eq) in DCM (3 mL) was added DAST (929 mg, 5.76 mmol, 761 μL, 5 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. TLC (silica gel, petroleum ether / EtOAc = 5 / 1)150SUBSTITUTE SHEET (RULE 26)indicated l-(4-benzylsμLfanylphenyl)-2-fluoro-ethanone was consumed completely and one new spot was formed. The reaction mixture was added to water (20 mL) and extracted with EtOAc (10 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / EtOAc = 1 / 0 to 1 / 1) to give the desired 1- benzylsulfanyl-4-(l, 1, 2-trifluoroethyl) benzene (160 mg, crude) as a colourless oil. MS (ESI): mass calcd. For C15H13F3S 282.1, m / z found 283.1 [M+H]+.

[0413] Step 4. To a solution of l-benzylsulfanyl-4-(l, 1, 2-trifluoroethyl) benzene (50 mg, 177 μmol, 1 eq) in AcOH (2 mL) and H2O (0.4 mL) was added NCS (71.0 mg, 531 μm,o 3l eq). The mixture was stirred at 20 °C for 1 hour. LC-MS (the sample quenched with piperidine) showed l-benzylsulfanyl-4-(l, 1, 2-trifluoroethyl) benzene was consumed completely and the desired compound was detected. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL X 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether / EtOAc= 5 / 1) to give the desired 4-(l, 1, 2-trifluoroethyl) benzenesulfonyl chloride (30 mg, crude) as a colourless oil. MS (ESI): mass calcd. For C8H6CIF3O2S 258.0, m / z found 308.0 [M+H+49]+.

[0414] Step 5: To a solution of 4-chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole (8 mg, 27.2 μmol, 1 eq) and 4-(l, 1, 2-trifluoroethyl)benzenesulfonyl chloride (7.05 mg, 27.2 μmol, 1 eq) in DCM (1 mL) were added TEA (2.76 mg, 27.2 μmoll 3.79 μL, 1 eq) and DMAP (3.33 mg, 27.2 μmol, 1 eq). The mixture was stirred at 15 °C for 1 hour. LC-MS showed 4- chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 5 mL of H2O and 10 mL of EtOAc. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 75 * 30 mm * 3 μm; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 55%-75% B over 8.0 min) to give the desired 4-chloro-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-l-[4-(l, 1, 2-trifluoroethyl)phenyl] sulfonyl-indazole (2 mg, 3.62 μmol, 13.3% yield, 93.36% purity) as a little yellow solid.JH NMR (400 MHz, DMSO-d6) δ 8.12 - 8.02 (m, 3H), 7.80 (d, J= 8.5 Hz, 2H), 7.68 (t, J = 8.1 Hz, 1H), 7.52 (d, J= 7.6 Hz, 1H), 5.06 - 4.83 (m, 2H), 4.23 (br t, J= 12.2 Hz, 4H). HPLC: 93.36%151SUBSTITUTE SHEET (RULE 26)(220 nm), 92.65% (215 nm), 92.83% (254 nm). MS (ESI): mass calcd. For C19H13CIF7N3O2S 515.0, m / z found 516.0 [M+H]+.Compound 50: l-[4-(l, 1-Difluoroethyl) phenyl] sulfonyl-4-methyl-3-(3, 3, 4, 4- tetrafluoropyrrolidin-l-yl) indazole

[0415] Step 1: To a solution of 4-methyl-lH-indazole (3 g, 22.7 mmol, 1 eq) in DCM (30 mL) was added NIS (5.62 g, 25.0 mmol, 1.1 eq) at 0 °C. The mixture was stirred at 20 °C for 12 hours. LC-MS showed 4-m ethyl- IH-indazole remained and the desired mass was detected. The reaction mixture was concentrated to give the desired 3-iodo-4-methyl-lH-indazole (5.8 g, crude) as a yellow solid. MS (ESI): mass calcd. For C8H7IN2258.0, m / z found 259.0 [M+H]+.

[0416] Step 2: To a solution of 3-iodo-4-methyl-lH-indazole (5.8 g, 22.5 mmol, 1 eq) in DCM (60 mL) were added TsOH.H2O (428 mg, 2.25 mmol, 0.1 eq) and 3, 4-dihydro-2H-pyran (2.84 g, 33.7 mmol, 3.08 mL, 1.5 eq) at 0 °C. The mixture was stirred at 20 °C for 1 hour. LC- MS showed 3-iodo-4-methyl-lH-indazole was consumed completely and the desired mass was detected. The reaction mixture was added to water (20 mL) and extracted with EtOAc (10 mL X 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired 3-iodo-4-methyl-l-tetrahydropyran- 3-yl-indazole (7.6 g, crude) as a yellow solid. MS (ESI): mass calcd. For C14H13F2NS 265.1, m / z found 266.1 [M+H]+.152SUBSTITUTE SHEET (RULE 26)

[0417] Step 3 : A mixture of 3-iodo-4-methyl-l-tetrahydropyran-3-yl-indazole (300 mg, 876 μmol, 1 eq), 3, 3, 4, 4-tetrafluoropyrrolidine (157 mg, 877 μmoll 1 eq, HC1), CS2CO3(571 mg, 1.75 mmol, 2 eq), BINAP (54.6 mg, 87.7 μmoll 0.1 eq) and Pd2(dba)3(80.3 mg, 87. 7 μm,o 0l.1 eq) in toluene (2 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100 °C for 12 hours under N2atmosphere. LC-MS showed 3-iodo-4-methyl-l- tetrahydropyran-3-yl-indazole was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 10 mL of H2O and 10 mL of EtOAc. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by prep-TLC (silica gel, petroleum ether / EtOAc = 4 / 1) to give the desired 4-methyl-3-(3, 3, 4, 4- tetrafluoropyrrolidin-l-yl)-l-tetrahydropyran-3-yl-indazole (150 mg, 420 μmol, 47.9% yield) as a yellow solid. MS (ESI): mass calcd. For C17H19F4N3O 357.1, m / z found 358.1 [M+H]+.

[0418] Step 4. To a solution of 4-methyl-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-l- tetrahydropyran-3-yl-indazole (150 mg, 420 μmol, 1 eq) in DCM (2 mL) was added TFA (239 mg, 2.10 mmol, 156 pl, 5 eq). The mixture was stirred at 15 °C for 1 hour. LC-MS showed 4- methyl-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-l-tetrahydropyran-3-yl-indazole was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 10 mL of H2O and 10 mL of EtOAc. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by prep-TLC (silica gel, petroleum ether / EtOAc = 2 / 1) to give the desired 4-methyl-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole (80 mg, 293 μmoll 69.8 % yield) as a white solid. MS (ESI): mass calcd. For C12H11F4N3273.1, m / z found 274.1 [M+H]".

[0419] Step 5: To a solution of 4-methyl-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole (38 mg, 139 μmol, 1 eq) and 4-(l, l-difluoroethyl)benzenesulfonyl chloride (50.2 mg, 209 μmoll 1.5 eq) in DCM (1 mL) were added TEA (28.2 mg, 278 μmoll 38.7 μl, 2 eq) and DMAP (1.70 mg, 13.9 μmol, 0.1 eq). The mixture was stirred at 15 °C for 1 hour. LC-MS showed 4-methyl-3- (3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 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 give the crude product. The residue was purified by p / cyi-HPLC (TFA condition; column: Phenomenex Luna C18 75 * 30mm * 3μm;153SUBSTITUTE SHEET (RULE 26)mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 50%-80% B over 8.0 min) to give the desired 1 - [4-( 1 , 1 -difluoroethyl)phenyl] sulfonyl-4-methyl-3 -(3, 3, 4, 4-tetrafluoropyrrolidin- 1 -yl)indazole (12.9 mg, 24.9 μmol, 17.9% yield, 92.20% purity) as a little yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.00 - 7.88 (m, 3H), 7.73 (d, J= 8.5 Hz, 2H), 7.59 - 7.52 (m, 1H), 7.21 (d, J= 7.3 Hz, 1H), 4.19 - 4.04 (m, 4H), 2.61 - 2.54 (m, 3H), 1.91 (t, J= 19.1 Hz, 3H). HPLC: 92.20% (220 nm), 91.74% (215 nm), 89.46% (254 nm). MS (ESI): mass calcd. For C20H17F6N3O2S 477.1, m / z found 478.1 [M+H]+.Compound 51: l-[4-(l, 1-Difluoroethyl) phenyl] sulfonyl-4-(fluoromethyl)-3-(3, 3, 4, 4- tetrafluoropyrrolidin-l-yl) indazole

[0420] Step 1. To a solution of lH-indazole-4-carbaldehyde (2 g, 13.7 mmol, 1 eq) in EtOH (20 mL) was added NaBH4 (1.04 g, 27.4 mmol, 2 eq) at 0 °C. The mixture was stirred at 15 °C for 1 hour. LC-MS showed lH-indazole-4-carbaldehyde was consumed completely and the desired mass was detected. To the reaction mixture was added 1 N HC1 dropwise to pH = 1, and then concentrated under reduced pressure to give a residue. To the residue was added sat. aq. NaHCO3, to pH = 6, and then extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (20mL), dried over Na2SO4, filtered, and concentrated under reduced pressurefiltered, to give the desired lH-indazol-4-ylmethanol (3.3 g, crude) as a white solid. MS (ESI): mass calcd. For CTITN2O 148.1, m / z found 149.1 [M+H]+.154SUBSTITUTE SHEET (RULE 26)

[0421] Step 2: To a solution of lH-indazol-4-ylmethanol (3.3 g, 22.3 mmol, 1 eq) in DCM (35 mL) were added TBSC1 (4.03 g, 26.7 mmol, 3.29 mL, 1.2 eq) and imidazole (3.03 g, 44.6 mmol, 2 eq) at 0 °C. The mixture was stirred at 15 °C for 0.5 hour. LC-MS showed IH-indazol- 4-ylmethanol was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 50 mL of H2O and 50 mL of DCM. The organic phase was separated, washed with 10 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired tert-butyl-(lH-indazol-4-ylmethoxy)-dimethyl-silane (4.48 g, crude) as a yellow oil. MS (ESI): mass calcd. For CuFfolSLOSi 262.2, m / z found 263.2 [M+H]+.

[0422] Step 3 : To a solution of tert-butyl-(lH-indazol-4-ylmethoxy)-dimethyl-silane (4.48 g, 17.1 mmol, 1 eq) in DMF (45 mL) were added h (6.50 g, 25.6 mmol, 5.16 mL, 1.5 eq) and K2CO3(4.72 g, 34.1 mmol, 2 eq). The mixture was stirred at 15 °C for 12 hours. LC-MS showed tert-butyl-(lH-indazol-4-ylmethoxy)-dimethyl-silane was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 10 mL of H2O and 10 mL of EtOAc. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired tert-butyl-[(3-iodo-lH- indazol-4-yl) methoxy]-dimethyl-silane (6.6 g, crude) as a yellow oil. MS (ESI): mass calcd. For Ci4H2iIN2OSi 388.0, m / z found 389.0 [M+H]+.

[0423] Step 4. To the solution of tert-butyl-[(3-iodo-lH-indazol-4-yl) methoxy]-dimethyl- silane (6.6 g, 17.0 mmol, 1 eq) and TsOH.H2O (323 mg, 1.70 mmol, 0.1 eq) in DCM (70 mL) was added 3, 4-dihydro-2H-pyran (2.14 g, 25.5 mmol, 2.33 mL, 1.5 eq) at 0 °C. The reaction mixture was stirred at 20 °C for 12 hours. LC-MS showed tert-butyl-[(3-iodo-lH-indazol-4-yl) methoxy]-dimethyl-silane was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 20 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 give the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-22% EtOAc / petroleum ether gradient @ 60 mL / min) to give the desired (3-iodo-l-tetrahydropyran-2- yl-indazol-4-yl) methanol (1.92 g, 5.36 mmol, 31.5% yield) as a yellow solid. MS (ESI): mass calcd. For Ci3Hi5IN2O2358.0, m / z found 359.0 [M+H]+.

[0424] Step 5: To a solution of (3-iodo-l-tetrahydropyran-2-yl-indazol-4-yl) methanol (1.92 g, 5.36 mmol, 1 eq) in DCM (20 mL) was added DAST (4.32 g, 26.8 mmol, 3.54 mL, 5 eq). The155SUBSTITUTE SHEET (RULE 26)mixture was stirred at 15 °C for 12 hours. LC-MS showed (3-iodo-l-tetrahydropyran-2-yl- indazol-4-yl) methanol was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 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 give the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 32 g SepaFlash® Silica Flash Column, Eluent of 0—10% EtOAc / petroleum ether gradient @ 40 mL / min). ) to give the desired 4-(fluoromethyl)-3-iodo-l- tetrahydropyran-2-yl-indazole (730 mg, 2.03 mmol, 37.8% yield) as a light yellow solid. MS (ESI): mass calcd. For C13H14FIN2O 360.0, m / z found 361.0 [M+H]+.

[0425] Step 6. Three reactions were carried out in parallel. A mixture of 4-(fluoromethyl)-3- iodo-l-tetrahydropyran-2-yl-indazole (240 mg, 666 μmol, 1 eq), 3, 3, 4, 4-tetrafluoropyrrolidine (144 mg, 800 μmol, 1.2 eq, HC1), Xantphos Pd G4 (64.1 mg, 66.6 μm,o 0l.10 eq), CS2CO3(434 mg, 1.33 mmol, 2 eq) in dioxane (5 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100 °C for 12 hours under N2atmosphere. LC-MS showed 4- (fluoromethyl)-3-iodo-l-tetrahydropyran-2-yl-indazole was consumed completely and the desired mass was detected. Three reactions were combined. The reaction mixture was partitioned between 30 mL of H2O and 40 mL of EtOAc. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by prep-TLC (silica gel, petroleum ether / EtOAc = 3 / 1) to give the desired 4-(fluoromethyl)-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-l-tetrahydropyran-2- yl-indazole (180 mg, 480 μmol, 24.0% yield) as a black solid. MS (ESI): mass calcd. For Ci7Hi8F5N3O 375.1, m / z found 376.1 [M+H]+.

[0426] Step 7: To a solution of 4-(fluoromethyl)-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-l- tetrahydropyran-2-yl-indazole (130 mg, 346 μmol, 1 eq) in DCM (2 mL) was added TFA (3.07 g, 26.9 mmol, 2.00 mL, 77.7 eq). The mixture was stirred at 15 °C for 1 hour. LC-MS showed 4- (fluoromethyl)-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-l-tetrahydropyran-2-yl-indazole was consumed completely and the desired mass was detected. The reaction mixture was partitioned betweenlO 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 give the crude product. The residue was purified by prep-TLC (silica gel, petroleum ether / EtOAc = 1 / 1) to give the desired 4-(fluoromethyl)-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole (80 mg,156SUBSTITUTE SHEET (RULE 26)275μmol , 79.3% yield) as a yellow solid. MS (ESI): mass calcd. For C17H18F5N3O 291.1, m / z found 292.1 [M+H]+.

[0427] Step 8: To a solution of 4-(fluoromethyl)-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH- indazole (40 mg, 137 μmol, 1 eq) and 4-(l, 1 -difluoroethyl) benzenesulfonyl chloride (49.6 mg, 206μmol , 1.5 eq) in DCM (1 mL) were added TEA (27.8 mg, 275 μmoll 38.2 μL, 2 eq) and DMAP (1.68 mg, 13.7 μmol, 0.1 eq). The mixture was stirred at 15 °C for 0.5 hour. LC-MS showed 4-(fluoromethyl)-3-(3, 3, 4, 4-tetrafluoropyrrolidin-l-yl)-lH-indazole was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 10 mL of FEO 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 give the crude product. The residue was purified by prep-HPLC (TFA condition; column: Phenom enex Luna C18 75 * 30mm * 3 μm; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 70%-90% B over 8.0 min) to give the desired l-[4-(l, 1 -difluoroethyl) phenyl] sulfonyl-4-(fluoromethyl)-3-(3, 3, 4, 4- tetrafluoropyrrolidin-l-yl)indazole (2 mg, 3.59 μmol, 2.61% yield, 88.87% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J= 8.8 Hz, 1H), 8.00 (d, J= 8.5 Hz, 2H), 7.78 - 7.71 (m, 3H), 7.52 (br d, J= 7.1 Hz, 1H), 5.81 - 5.65 (m, 2H), 4.20 - 4,05 (m, 4H), 1.92 (t, J= 19.1 Hz, 3H). HPLC: 88.87% (220 nm), 89.36% (215 nm), 98.82% (254 nm). MS (ESI): mass calcd. For C20H16F7N3O2S 495.1, m / z found 496.1 [M+H]+.Compound 52: l-[4-(l, 1-Difluoroethyl) phenyl] sulfonyl-4-(difluoromethyl)-3-(3, 3, 4, 4- tetrafluoropyrrolidin-l-yl) indazole157SUBSTITUTE SHEET (RULE 26)

[0428] Step 1. To a solution of lH-indazole-4-carbaldehyde (3 g, 20.5 mmol, 1 eq) in DCM (30 mL) was added NIS (5.08 g, 22.6 mmol, 1.1 eq) at 0 °C. The mixture was stirred at 20 °C for 12 hours. LC-MS showed lH-indazole-4-carbaldehyde remained and the desired mass was detected. The reaction mixture was concentrated to give the desired 3-iodo-lH-indazole-4- carbaldehyde (5.58 g, crude) as a yellow solid. MS (ESI): mass calcd. For C8H5IN2O 271.9, m / z found 273.0 [M+H]+.

[0429] Step 2\ To a solution of 3-iodo-lH-indazole-4-carbaldehyde (4.5 g, 16.5 mmol, 1 eq) in THF (45 mL) were added TEA (5.02 g, 49.6 mmol, 6.91 mL, 3 eq), DMAP (202 mg, 1.65 mmol, 0.1 eq) and tert-butoxycarbonyl tert-butyl carbonate (4.33 g, 19.9 mmol, 4.56 mL, 1.2 eq). The mixture was stirred at 15 °C for 12 hours. LC-MS showed 3-iodo-lH-indazole-4- carbaldehyde was consumed completely and the desired mass was detected. The reaction mixture was partitioned between 200 mL of H2O and 130 mL of EtOAc. The organic phase was separated, washed with 50 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / petroleum ether gradient @ 60 mL / min) to give the desired tert-butyl 4-formyl-3 -iodo- indazole- 1 -carboxylate (1.96 g, 5.27 mmol, 31.8% yield) as a white solid. MS (ESI): mass calcd. For C13H13IN2O3372.0, m / z found 373.0 [M+H]+.

[0430] Step 3. To a solution of tert-butyl 4-formyl-3 -iodo-indazole- 1 -carboxylate (1 g, 2.69 mmol, 1 eq) in DCM (1 mL) was added DAST (2.17 g, 13.4 mmol, 1.78 mL, 5 eq) at 0 °C. The mixture was stirred at 15 °C for 1 hour. LC-MS showed tert-butyl 4-formyl-3 -iodo-indazole- 1- carboxylate was consumed completely and the desired mass was detected. The reaction mixture was partitioned between...

Claims

What is claimed:CLAIMS1. A compound having the structure of formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 9-membered carbocycle or heterocycle substituted with 1-8 F’s;Ring B is a substituted or unsubstituted phenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, or thiophene, or a substituted or unsubstituted bi- or multi-cyclic carbocyclic or heterocyclic ring system;P is CH, N or CR2;Q is CH, N or CR2;U is C or N;V is C or N;W is CH, N, C(=O), C(=S) or CRW1RW2, wherein each of RW1and RW2is independently H or C1-6alkyl;X is C orN;Y is C, CRYor N, wherein RYis H, F or C1-6alkyl;R1is selected from the group consisting of F, CHF2, -CF3, -CH2CF3, CF2CH3, CF2CH2F, CF2CHF2, -CF(CH3)2, -OCF3and -OCH(CH3)2; each R2is independently selected from the group consisting of halogen, unsubstituted or substituted C1-6alkyl and C1-6alkoxy, OH, CN, NRR , N(R)C(=O)RR , C(=O)R, and C(=O)NRR ; each R3is independently selected from the group consisting of halogen, CN, CF3, C1-5alkyl, C3-7cycloalkyl and heterocyclic;each of R and R is independently H, or C1-6alkyl or cycloalkyl, optionally, R and R , together with the nitrogen or carbon atom to which they are attached, form a 3- to 6- membered ring, each optionally substituted with 0-3 substituents independently selected from the group consisting of C1-3alkyl, halogen, OH, OC1-3alkyl, and CN; m is 0, 1, 2, 3 or 4; n is 1, 2, 3, 4, 5, 6, 7 or 8; and z is 0, 1 or 2.

2. The compound of claim 1, wherein Ring B is a substituted or unsubstituted phenyl.

3. The compound of claim 1, wherein / is 0 and Ring B is unsubstituted phenyl:

4. The compound of claim 1, wherein z is 0 and Ring B is a substituted phenyl:wherein R3is a halogen.

5. The compound of claim 4, wherein R3is F.

6. The compound of claim 1, wherein Ring B is an unsubstituted pyridinyl:

7. The compound of claim 1, wherein Ring B is a substituted or unsubstituted thiophene.

8. The compound of claim 7, wherein z is 0 and Ring B is unsubstituted thiophene:

9. The compound of claim 1, wherein Ring B is a substituted or unsubstituted pyrrole.

10. The compound of claim 9, wherein z is 0 and Ring B is unsubstituted pyrrole:

11. The compound of claim 1, wherein Ring B is bicyclo[l. l.l]pentane:

12. The compound of claim 1, wherein Ring B is selected from:

13. The compound of any one of claims 1-12, wherein X is N.

14. The compound of claim 13, wherein P is CH, Q is CH, U is C and V is C:

15. The compound of claim 14, wherein W is N:

16. The compound of claim 14, wherein W is CH:

17. The compound of any one of claims 1-12, wherein X is C.

18. The compound of claim 17, wherein P is CH, Q is CH, U is N, V is C and W is N:

19. The compound of any one of claims 1-18, wherein Y is N.

20. The compound of any one of claims 1-18, wherein Y is C.

21. The compound of any one of claims 1-18, wherein Y is CH.

22. The compound of any one of claims 1-21, wherein Ring A is a 4-membered carbocyclic or heterocycle substituted with one or more F’s.

23. The compound of any one of claims 1-21, wherein Ring A is a 5-membered carbocyclic or heterocycle substituted with one or more F’s.

24. The compound of any one of claims 1-21, wherein Ring A is a 6-membered carbocyclic or heterocycle substituted with one or more F’s.

25. The compound of any one of claims 1-21, wherein Ring A is a heterobicycle substituted with one or more F’s.

26. The compound of any one of claims 22-25, wherein Ring A is substituted with two or more F’s.

27. The compound of any one of claims 1-21, wherein Ring A has a structural formula selected from:

28. The compound of any one of claims 1-21, wherein Ring A has a structural formula selected from:

29. The compound of any one of claims 1-21, wherein Ring A has a structural formula selected from:

30. The compound of any one of claims 1-21, wherein Ring A is:wherein each R4is independently D, OH, CN, or C1-2alkyl optionally substituted with 0-3 F’s, or two R4’s along with the carbon atom they are bound to form a 3- or 4-membered carbocyclic or heterocyclic ring, or two R4’s along with the carbon atoms they are bound to atom for a 3- to 7-membered carbocyclic or heterocyclic ring n is 1, 2, 3, 4, 5 or 6; and j is 0, 1, 2, 3 or 4.

31. The compound of claim 30, wherein j is 0.

32. The compound of claim 30, wherein / is 1 or 2.

33. The compound of any one of claims 1-32, wherein R1is CHF2.

34. The compound of any one of claims 1-32, wherein R1is CF2CH3.

35. The compound of any one of claims 1-32, wherein R1is CF2CH2F.

36. The compound of any one of claims 1-32, wherein R1is CF2CHF2.

37. The compound of any one of claims 1-32, wherein R1is F.

38. The compound of claim 1, having the structural formula:

39. The compound of claim 1, having the structural formula:

40. The compound of claim 1, having the structural formula:

41. The compound of claim 1, having the structural formula:

42. The compound of claim 1 or 30, having the structural formula:wherein each R4is independently C1-2alkyl optionally substituted with 0-3 F’s, or two R4’s along with the carbon atom they are bound to form a 3 - or 4-membered carbocyclic or heterocyclic, or two R4’s along with the carbon atoms they are bound to atom for a 3- to 6-membered carbocyclic or heterocyclic ring; n is 1, 2, 3, 4, 5 or 6; and j is 0, 1, 2, 3 or 4.

43. The compound of claim 1 or 30, having the structural formula:wherein each R4is independently C1-2alkyl optionally substituted with 0-3 F’s, or two R4’s along with the carbon atom they are bound to form a 3 - or 4-membered carbocyclic or heterocyclic, or two R4’s along with the carbon atoms they are bound to atom for a 3- to 6-membered carbocyclic or heterocyclic ring; n is 1, 2, 3, 4, 5 or 6; and j is 0, 1, 2, 3 or 4.

44. The compound of claim 42 or 43, wherein each R4is independently D, OH, CN, or C1-2alkyl optionally substituted with 0-3 F’s.

45. The compound of claim 42 or 43, wherein two R4’s along with the carbon atom they arebound to form a 3- or 4-membered carbocyclic or heterocyclic ring.

46. The compound of claim 42 or 43, wherein two R4’s along with the carbon atoms they are bound to atom for a 3- to 7-membered carbocyclic or heterocyclic ring.

47. The compound of 46, wherein j ' is 0.

48. The compound of 46, wherein j is 1 or 2.

49. The compound of claim 44, wherein j is 1 and R4is bound to a carbon atom adjacent to the N atom.

50. The compound of claim 49, wherein R4is CF3.

51. The compound of claim 44, wherein / is 2 and both R4’s are bound to a carbon atom adjacent to the N atom of Ring A.

52. The compound of claim 51, wherein one or both of the two R4’s is a C1.3 alkyl, optionally substituted with 1-5 F’s.

53. The compound of claim 45, wherein j is 2 and the two R4’s, along with the carbon atom they are bound to, form a cyclopropyl group.

54. The compound of claim 46, wherein j is 2 and the two R4’s along with the carbon atoms they are bound to atom for a 5- to 7-membered carbocyclic or heterocyclic ring.

55. The compound of any one of claims 38-54, wherein n is an integer selected from 1-4.

56. The compound of claim 55, wherein n is 1.

57. The compound of claim 55, wherein n is 2.

58. The compound of claim 55, wherein n is 3 or 4.

59. The compound of any one of claims 38-58, wherein R1is CF2CH3.

60. The compound of any one of claims 38-58, wherein R1is CF2CH2F.

61. The compound of any one of claims 38-58, wherein R1is CF2CHF2.

62. The compound of any one of claims 38-58, wherein R1is CHF2.

63. The compound of any one of claims 38-58, wherein R1is F.

64. The compound of any one of claims 1-63, wherein m is 1.

65. The compound of claim 64, wherein R2has a positioning selected from:

66. The compound of claim 64, wherein R2has a positioning of:

67. The compound of any of claims 64-66, wherein R2is a halogen.

68. The compound of claim 67, wherein R2is Cl.

69. The compound of any of claims 64-66, wherein R2is amino, OH, Ci alkyl or alkoxy, optionally substituted with 0-3 F’s.

70. A compound selected from Table 1.

71. The compound of any of claims 1-70, having one or more deuterium atoms in place of one or more hydrogen atoms.

72. The compound of claim 71, having one deuterium atom in place of one hydrogen atom.

73. A pharmaceutical composition comprising a compound of any of claims 1-72.

74. A unit dosage form comprising a pharmaceutical composition of claim 73.

75. The unit dosage form of claim 74, being a tablet.

76. The unit dosage form of claim 74, being a capsule.

77. A method for treating or reducing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-72.

78. The method of claim 77, wherein the disease or disorder is mediated by loss-of-function in TRPML1.

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

80. The method of claim 77, wherein the disease or disorder is a lysosome storage disease, or a related disease or disorder.

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

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

83. The method of claim 77, wherein the disease or disorder is a neuronal ceroid lipofuscinoses (NCLs) or Batten disease, or a related disease or disorder.

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

85. The method of claim 77, wherein the disease or disorder is Charcot- Mari s-Tooth disease (CMT), or a related disease or disorder.

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

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

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

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

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

91. The method of 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 effect of aging comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-72.

93. The method of claim 77, wherein the effect of aging comprises skin aging.

94. The method of claim 77, wherein the effect of aging comprises photoaging.

95. A method for treating or reducing oxidative stress or reactive oxygen species (ROS) related diseases or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-72.

96. A method for treating or reducing oxidative stress or reactive oxygen species (ROS) related diseases or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-72.

97. The method of any one of claims 77-96, wherein administration is via oral administration.

98. The method of any one of claims 77-96, wherein administration is via topical administration.

99. Use of a compound of any of claims 1 -72, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.

100. The use of claim 99, wherein the disease or disorder is mediated by loss-of-function in TRPML1.

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

102. The use of claim 99, wherein the disease or disorder is a lysosome storage disease, or a related disease or disorder.

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

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

105. The use of claim 99, wherein the disease or disorder is a neuronal ceroid lipofuscinoses (NCLs) or Batten diseases, or a related disease or disorder.

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

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

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

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

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

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

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

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

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

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

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