SULFONYL CYCLIC DERIVATIVES, AND COMPOSITIONS AND METHODS THEREOF

The invention provides novel sulfonyl cyclic derivatives, and compositions and methods of preparation and use thereof, that are useful in treating various diseases and disorders related to TRPML activities such as lysosome storage diseases, muscular dystrophy, neurodegenerative diseases, oxidative stress or reactive oxygen species (ROS) related diseases, metabolic diseases, metastatic cancer, and ageing.

TECHNICAL FIELD OF THE INVENTION

The invention generally relates to novel compounds and therapeutic uses thereof. More particularly, the invention provides novel sulfonyl cyclic derivatives, 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 lysosome storage diseases, muscular dystrophy, neurodegenerative diseases, reactive oxygen species (ROS) or oxidative stress related diseases, metabolic diseases, metastatic cancer, and ageing.

BACKGROUND OF THE INVENTION

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 reutilization or energy (see, e.g., de Duve 2005 Nat Cell Biol 7(9): 847-9; Parkinson-Lawrence, et al. 2010 Physiology (Bethesda) 25(2): 102-15). Problems in either the degradation step (due to lack of hydrolytic enzymes) or the transport step 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 for common 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 diseases.

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, et al. 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 to be required for the formation of transport vesicles from the 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 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 Ca2+ release channel that regulates lysosomal trafficking

PI(3,5)P2, a low-abundance phosphoinositide, is the primary activator of ML1 and 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)P2 system represents a common signaling pathway essential for late endocytic trafficking.

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 ageing (Xu, et al. 2015 Annu 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 an accessible and direct target of ROS signaling. Given that ROS reportedly regulate ion channels (Bogeski, et al. 2014 Antioxid Redox Signal 21, 859-862), it is possible that lysosomal conductance, particularly through lysosomal Ca2+ channels such as TRPML1, may mediate ROS-regulation of lysosomal function. Indeed, electrophysiological studies revealed that whole-endolysosome TRPML1 currents were directly activated by ROS.

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 ageing (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 ageing, especially photo ageing in the skin.

Transcription factor (TF)EB regulates autophagy and lysosome biogenesis. Overexpression of TFEB has been reportedly induce cellular clearance in a number of lysosome storage diseases, including Pompe Disease, Cystinosis, multiple sulfatase deficiency, as well as common neurodegenerative diseases, including Parkinson's disease and Huntinton's disease (Settembre, et al., 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.

Previously, a potent synthetic agonist for TRPML1 has been reported (Shen, et al. 2012Nat Commun 3, 731). This SF-51-related compound (Mucolipin Synthetic Agonist 1 or ML-SA1) that could induce significant [Ca2+]cyt increases in HEK293 cells stably or transiently expressing ML1-4A. In electrophysiological assays, ML-SA1 robustly activated whole-cell IML1-4A and whole-endolysosome IML1. ML-SA1 also activated whole-cell ITRPML2 and ITRPML3, but not six other related channels. ML-SA1 (10 μM) activation of whole-endolysosome IML1 was comparable to the effect of the endogenous TRPML agonist PI(3,5)P2 (1 μM), and these agonists were synergistic with each other. ML-SA1 activated an endogenous whole-endolysosome TRPML-like current (IML-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-L in wild-type (WT; ML1+/+), 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 TRPML1 is the predominant lysosomal TRPML channel in this cell type. These results suggest that ML-SA1 is a reasonably specific and potent agonist that can be a useful for modulating the functions of TRPMLs.

High concentrations of ML-SA1 (˜10 μM) are 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 (Qiu et al. WO 2022/076383 A1). However, most of these potent agonists are highly hydrophobic molecules that are metabolically labile and have very more solubility, which in turn leads to very poor oral bioavailability and systemic exposure.

There is an urgent need for more potent TRPML activators, in particular, compounds that are useful in treating disorders related to TRPML activities such as lysosome storage diseases, muscular dystrophy, age-related common neurodegenerative diseases, ROS or oxidative stress related diseases, metabolic diseases, metastatic cancer, and ageing.

SUMMARY OF THE INVENTION

The invention is based in part on novel sulfonyl cyclic derivatives, 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.

In one aspect, the invention generally relates to a compound having the structural formula I:

or a pharmaceutically acceptable form or an isotope derivative thereof, wherein

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

In yet another aspect, the invention generally relates to a pharmaceutical composition comprising a compound of structural formula I.

or a pharmaceutically acceptable form or an isotope derivative thereof, wherein

In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

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 pharmaceutical composition comprising a compound disclosed herein.

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 pharmaceutical composition comprising a compound disclosed herein.

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 an effective amount of a TRPML1 agonist or a composition comprising of a TRPML1 agonist.

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 pharmaceutical composition comprising a compound disclosed herein.

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

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.

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

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 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

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

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, “C1-6 alkyl” 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 C5-6 alkyl. 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)—.

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).

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

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 include the 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.

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. 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.

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.

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 and bases. 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, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, 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.

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)4 salts. 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, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt can be chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

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.

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.

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 pH compared to the parent compound, or it can enhance absorption from the digestive tract, or it can enhance drug stability for long-term storage.

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.

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.)

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.

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). Different physical 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, dichloromethane, 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).

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.

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 amelioration of 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.

As used herein, the terms “alk” or “alkyl” refer to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, containing no unsaturation. The expression “lower alkyl” refers to alkyl groups of 1 to 4 carbon atoms (inclusive). 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 C1-6 alkyl group. In some embodiments, “alkyl” can be a C1-3 alkyl group.

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.

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

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.

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.

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—.

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 1 to 3 lower alkyl groups. Exemplary alkynylene groups are —C≡C—, —CH2—C≡C—, —CH(CH3)C≡C— and —C≡C≡CH(C2H5)CH2—.

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

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.

As used herein, the terms “aromatic”, “ar” or “aryl” refer to a radical with 6 to 14 ring atoms (e.g., C6-14 aromatic or C6-14 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.

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

As used herein, the term “heteroaryl” 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 14 π 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 or more 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.

As used herein, the terms “heterocycle”, “heterocyclic” or “heterocyclo” 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.

As used herein, the term “heterocyclyl” refers 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 heterocyclyl 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 heterocyclyl group may be attached at any heteroatom or carbon atom of the ring or ring system.

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.

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

The invention provides novel sulfonyl cyclic derivatives, 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 lysosome storage diseases, muscular dystrophy, neurodegenerative diseases, ROS or oxidative stress related diseases, and damages caused in skin or photoaging.

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, wherein

In certain embodiments of (I), Ring B is a substituted or unsubstituted 6-membered aryl.

In certain embodiments, Ring B is a substituted or unsubstituted phenyl.

In certain embodiments, i is 0 and Ring B is unsubstituted phenyl:

In certain embodiments, Ring B is a substituted or unsubstituted 6-membered heteroaryl.

In certain embodiments, Ring B is a substituted or unsubstituted pyridinyl. In certain embodiments, i is 0 and Ring B is an unsubstituted pyridinyl:

In certain embodiments, Ring B is a substituted or unsubstituted pyrimidinyl, pyrazinyl or pyridazinyl.

In certain embodiments, Ring B is a substituted or unsubstituted 5-membered heteroaryl.

In certain embodiments, Ring B is a substituted or unsubstituted thiophene. In certain embodiments, i is 0 and Ring B is unsubstituted thiophene:

In certain embodiments, Ring B is a substituted or unsubstituted pyrrolyl. In certain embodiments, i is 0 and Ring B is unsubstituted pyrrolyl:

In certain embodiments, Ring B is a substituted or unsubstituted thiazolyl, pyrazolyl, imidazolyl or triazolyl.

In certain embodiments, Ring B is a substituted or unsubstituted bi- or multi-cyclic carbocyclic.

In certain embodiments, Ring B is bicyclo[1.1.1]pentane:

In certain embodiments, Ring B is a substituted or unsubstituted bi- or multi-cyclic heterocyclic.

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

In certain embodiments, R1 is S(O)2CHRR′.

In certain embodiments, R1 is S(O)2C(CH3)RR′.

In certain embodiments, R1 is S(O)2NRR′.

In certain embodiments of R1, R and R′ is independently H, C1-6 alkyl or cycloalkyl.

In certain embodiments of R1, R and R′, together with the nitrogen or carbon atom to which they are attached, form a substituted or unsubstituted 3- to 6-membered carbocycle or heterocycle.

In certain embodiments, R1 is a C1-5 alkyl, C3-7cycloalkyl or heterocyclic, wherein the alkyl, cycloalkyl or heterocyclic is substituted with 0-6 F's.

Non-limiting examples of include:

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

In certain embodiments of (I), X is CH.

In certain embodiments of (I), Y is N.

In certain embodiments of (I), Y is CH.

In certain embodiments of (I), Z is O.

In certain embodiments of (I), Z is NH.

In certain embodiments of (I), X is N, Y is N, and Z is O:

In certain embodiments of (I), Ring A is a 4-membered substituted heterocycle.

In certain embodiments of (I), Ring A is a 5-membered substituted heterocycle.

In certain embodiments of (I), Ring A is a 6-membered substituted heterocycle.

In certain embodiments, Ring A is:

wherein

In certain embodiments, Ring A has a structural formula selected from:

wherein W is NR7, CR7R7′ or O.

In certain embodiments, Ring A has a structural formula selected from:

wherein

In certain embodiments, Ring A is:

In certain embodiments, Ring A is:

In certain embodiments, Ring A is:

In certain embodiments, Ring A is:

In certain embodiments, each of R5 and R6 is CH3 or CH2CH3. In certain embodiments, each of R5 and R6 is CH3.

In certain embodiments, one of R5 and R6 is CH3, CH2CH3, OCH3 or OCH2CH3 and the other is H.

In certain embodiments, one of R5 and R6 is CF3, CFHCH3, CH2CFH2, CF2CH3, CFHCF2H, CH2CF2H, CH2CF3, CFHCFH2 or CF2CF3 and the other is H. In certain embodiments, one of R5 and R6 is CF3 and the other is H.

In certain embodiments, one of R5 and R6 is CH═CH2, CF═CH2, CH═CFH, CH═CF2, CF═CFH or CF═CF2 and the other is H.

In certain embodiments, one of R5 and R6 is C═CH, C≡CF or CN and the other is H.

In certain embodiments, one of R5 and R6 is a substituted or unsubstituted cyclopropyl, cyclobutyl or cyclopentyl ring and the other is H.

In certain embodiments, R5 and R6, together with the carbon atom to which they are attached to, are linked to form a substituted or unsubstituted 3- to 6-membered carbocyclic or heterocyclic ring (e.g., cyclopropyl ring).

In certain embodiments, n is 0 and Ring A is selected from:

In certain embodiments, Ring A is:

wherein

In certain embodiments, U is CH2 and q is 0, 1 or 2.

In certain embodiments, U is O and q is 1.

In certain embodiments, Ring A is:

wherein

In certain embodiments, k is 0.

In certain embodiments, k is 1.

Non-limiting examples of Ring A include:

Additional non-limiting examples of Ring A include:

wherein

In certain embodiments, V is N:

In certain embodiments, j is 1.

In certain embodiments, R8 has the following positioning:

In certain embodiments, R8 is F or Cl.

In certain embodiments, V is CH, optionally substituted with a halo or C1-C3 alkyl.

In certain embodiments, V is C—F or C—Cl:

In certain embodiments, j is 1.

In certain embodiments, R8 has the following positioning:

In certain embodiments, R8 is F or Cl.

In certain embodiments, a compound of the invention has the structure of:

In certain embodiments, a compound of the invention has the structure of:

In certain embodiments, a compound of the invention has the structure of:

In certain embodiments, a compound of the invention has the structure of:

In certain embodiments, a compound of the invention has the structure of:

In certain embodiments, a compound of the invention has the structure of:

In certain embodiments, a compound of the invention has the structure of:

wherein

In certain embodiments, j is 1 and R7 is:

In certain embodiments, R8 is F.

In certain embodiments, R8 is Cl.

In certain embodiments, R10 is CHCH3CH3.

In certain embodiments, R10 is C(CH3)3.

In certain embodiments, R10 is NCH3CH3.

In certain embodiments, m is 0.

In certain embodiments, m is 1.

In certain embodiments, m is 2.

In certain embodiments, R2 has a positioning selected from:

In certain embodiments, R2 is independently a halo.

In certain embodiments, each R2 is independently selected from F and Cl.

Exemplary compounds of the invention include but not limited to:

Exemplary Compounds

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

In yet another aspect, the inventio generally relates to a pharmaceutical composition comprising a compound of structural formula I:

or a pharmaceutically acceptable form or an isotope derivative thereof, wherein

In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

In certain embodiments, the unit dosage form is a tablet or a capsule.

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 pharmaceutical composition comprising a compound disclosed herein.

In certain embodiments, the disease or disorder is mediated by loss-of-function in TRPML1, including ML4 and NPC.

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

In certain embodiments, the disease or disorder is selected from the group consisting of age-related neurodegenerative disease, including Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease, or a related disease or disorder.

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

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

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 pharmaceutical composition comprising a compound disclosed herein.

In certain embodiments, the effect of aging comprises skin aging.

In certain embodiments, the effect of aging comprises photoaging.

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 an effective amount of a TRPML1 agonist or a composition comprising of a TRPML1 agonist.

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 pharmaceutical composition comprising a compound disclosed herein.

In certain embodiments, administration is via oral administration.

In certain embodiments, administration is via topical administration.

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.

In certain embodiments, the disease or disorder is selected from the group consisting of age-related neurodegenerative disease, including Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease, or a related disease or disorder.

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

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

In certain embodiments, the disease or disorder is skin aging or photoaging.

In certain embodiments, the compound is any of those shown in Table 1.

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 use 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, 3rd Ed., 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.

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).

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

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.

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.

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.

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 (17th ed. 1985).

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.

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.

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 of 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, U.S. Pat. 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. Pat. 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 hydroxypropylmethylcellulose acetate succinate.

In the case of tablets for oral use, carriers that are commonly used include lactose and corn 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.

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.

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.)

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.

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.

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.

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 with these compounds include other kinase inhibitors and/or other chemotherapeutic agents for the treatment of the diseases and disorders discussed above.

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.

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. 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).

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.

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.

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 amount 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, et al., eds. 2000 Pharmacotherapy Handbook, 2nd Edition, 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.

It is expected that some of the second therapeutic agents referenced above will act synergistically with the compounds of this invention. When this occurs, its 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.

The invention also provides a method of treating a subject suffering from or susceptible to a disease or disorder or symptom thereof (e.g., those delineated herein) comprising the step of administering to said subject an effective amount of a compound or a composition of this invention. Some diseases are well known in the art and are also disclosed herein.

In certain embodiments, the methods disclosed herein are suitable for treating diseases or disorders that are mediated by the TRPMLs. In certain embodiments, the methods disclosed herein are suitable for treating disease or disorders that are mediated by loss-of-function in TRPML1, including ML4 and NPC.

In certain embodiments, the disease is one of the lysosomal storage diseases, such as Niemen-Pick C (NPC) disease.

In certain embodiments, the methods disclosed herein are suitable for treating diseases or disorders that are age-related including common neurodegenerative diseases, such as AD, PD, and HD.

In certain embodiments, the methods disclosed herein are suitable for treating type IV Mucolipidosis (ML4), a neurodegenerative LSD caused by human mutations in TRPML1.

In certain embodiments, the methods disclosed herein are suitable for treating certain metabolic diseases such as glycogen storage diseases (GSDs) and nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH).

In certain embodiments, the methods disclosed herein are suitable for treating cancers in which TRPML1 is overexpressed in cancer cells,

In certain embodiments, the methods disclosed herein are suitable for treating a ROS or oxidative stress related disease or disorder.

In certain embodiments, the methods disclosed herein are suitable for treating diseases or disorders due or related to ageing.

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 an 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 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.

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.

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.

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.

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 Marker 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.

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.

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.

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 blister 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.

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.

The following examples are meant to be illustrative of the practice of the invention and not limiting in any way.

EXAMPLES

The structures depicted herein may contain certain —NH—, —NH2 (amino) and —OH (hydroxyl) groups where the corresponding hydrogen atom(s) do not explicitly appear; however, they are to be read as —NH—, —NH2 or —OH as the case may be. In certain structures, a stick bond is drawn and is meant to depict a methyl group.

Results of TFEB Nuclear Translocation Assay

number
activation (nM)
Name

METHODS OF SYNTHESIS

The following examples are given for the purpose of illustrating the invention, but not for limiting the scope or spirit of the invention.

Compounds of the invention, including those specifically disclosed herein above and herein below, may be prepared as described in the following schemes. For example, the compounds of Formula I may be prepared as described in Schemes below, which are known to those of skill in the art for making fragments and combinations thereof.

Step 1: To a solution of 2-bromo-1, 3-dichloro-5-fluoro-benzene (12 g, 49.2 mmol, 0.67 eq) in THF (120 mL) was added dropwise i-PrMgCl—LiCl (1.3 M, 56.5 mL, 1 eq) at 0° C. After addition, the mixture was stirred at this temperature for 0.5 hour, and then CO2 (15 psi) was added dropwise at 0° C. The resulting mixture was stirred at 0° C. for 0.5 hour. TLC (petroleum ether/EtOAc=4/1) indicated 2-bromo-1, 3-dichloro-5-fluoro-benzene was consumed completely and one new spot formed. The crude was added H2O (100 mL) and extracted with EtOAc (150 mL*3). The combined organic layers were washed with brine (100 mL), dried over anhydrous 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˜20% EtOAc/petroleum ether gradient @100 mL/min) to give desired 2, 6-dichloro-4-fluorobenzoic acid (5.3 g, 25.4 mmol, 34.5% yield) as a yellow solid.

Step 2: To a solution of 4-methylbenzenesulfonohydrazide (7.18 g, 38.6 mmol, 1.5 eq) in DCM (90 mL) was added TEA (6.50 g, 64.3 mmol, 8.94 mL, 2.5 eq) at 20° C. After addition, the mixture was stirred at this temperature for 10 minutes, and then 2, 4, 6-trifluorobenzoyl chloride (5 g, 25.7 mmol, 1.0 eq) in DCM (10 mL) was added dropwise at 0° C. The resulting mixture was stirred at 20° C. for 2 hours. LC-MS showed 4-methylbenzenesulfonohydrazide was consumed completely and one main peak with desired mass was detected. The residue was diluted with H2O (100 mL) and extracted with DCM (50 mL*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 flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0˜35% EtOAc/petroleum ether gradient @100 mL/min) to give desired 2, 4, 6-trifluoro-N′-(p-tolylsulfonyl) benzohydrazide (4 g, crude) as a yellow solid. MS (ESI): mass calcd. For C14H11F3N2O3S 344.04 m/z found 345.2 [M+H]+.

Step 3: A mixture of 2, 4, 6-trifluoro-N′-(p-tolylsulfonyl) benzohydrazide (0.7 g, 2.03 mmol, 1 eq) in SOCl2 (6 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80° C. for 1 hour under the atmosphere of nitrogen. TLC (petroleum ether/EtOAc=3/1) indicated 2, 4, 6-trifluoro-N′-(p-tolylsulfonyl) benzohydrazide was consumed completely and two new spots formed. The reaction mixture was concentrated in vacuum to give desired (1Z)-2, 4, 6-trifluoro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride (0.7 g, crude) as a yellow solid.

Step 1: To a solution of 7-(5-chloropyrimidin-2-yl)-4,7-diazaspiro[2.5]octane (251 mg, 963 μmol, 1 eq, HCl) in THF (5 mL) was added dropwise TEA (974 mg, 9.63 mmol, 1.34 mL, 10 eq) at 25° C. After addition, the mixture was stirred at this temperature for 10 minutes, and then (1Z)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (400 mg, 1.06 mmol, 1.1 eq) in THF (2 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 20 minutes. LC-MS showed 7-(5-chloropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octane was consumed completely and one main peak with 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, filtered and concentrated under reduced pressure to give desired N—[(Z)-[[7-(5-chloropyrimidin-2-yl)-4, 7-diazaspiro[2.5]octan-4-yl]-(2,6-dichlorophenyl)methylene]amino]-4-methyl-benzenesulfonamide (520 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C24H23C13N6O2S 564.07, m/z found 565.1 [M+H]+.

Step 2: To a solution of N—[(Z)—[[7-(5-chloropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]-(2, 6-dichlorophenyl) methylene]amino]-4-methyl-benzenesulfonamide (520 mg, 919 μmol, 1 eq) in DMF (10 mL) was added K2CO3 (508 mg, 3.68 mmol, 4 eq). The mixture was stirred at 80° C. for 1 hour. LC-MS showed N—[(Z)—[[7-(5-chloropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]-(2, 6-dichlorophenyl) methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and desired mass was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 4-chloro-3-[7-(5-chloropyrimidin-2-yl)-4,7-diazaspiro[2.5]octan-4-yl]-1-(p-tolylsulfonyl)indazole (500 mg, crude) as a black oil. MS (ESI): mass calcd. For C24H22C12N6O2S 528.09, m/z found 529.1 [M+H]+.

Step 3: To a solution of 4-chloro-3-[7-(5-chloropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (500 mg, 944 μmol, 1 eq) in MeOH (10 mL) was added K2CO3 (652 mg, 4.72 mmol, 5 eq). The mixture was stirred at 70° C. for 1 hour. LC-MS showed 4-chloro-3-[7-(5-chloropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and desired compound was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/Ethyl acetate=1/0 to 1/1) to give desired 4-chloro-3-[7-(5-chloropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]-1H-indazole (150 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C17H16C12N6 374.08, m/z found 375.1 [M+H]+.

Step 1: To a solution of 7-(5-fluoropyrimidin-2-yl)-4,7-diazaspiro[2.5]octane (778 mg, 3.18 mmol, 1.5 eq, HCl) in THF (5 mL) was added dropwise TEA (2.14 g, 21.2 mmol, 2.95 mL, 10 eq) at 25° C. After addition, the mixture was stirred at this temperature for 10 minutes, and then (1Z)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (800 mg, 2.12 mmol, 1 eq) in THF (3 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 20 minutes. LC-MS showed 7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octane was consumed completely and 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 desired N—[(Z)-[(2, 6-dichlorophenyl)-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzene sulfonamide (1.35 g, crude) was obtained as a white solid. MS (ESI): mass calcd. For C24H23Cl2FN6O2S 548.10, m/z found 549.1 [M+H]+.

Step 2: To a solution of N—[(Z)-[(2, 6-dichlorophenyl)-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (1.3 g, 2.37 mmol, 1 eq) in DMF (14 mL) was added K2CO3 (1.63 g, 11.8 mmol, 5 eq). The mixture was stirred at 80° C. for 12 hours. LC-MS showed N—[(Z)-[(2, 6-dichlorophenyl)-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and desired mass was detected. The reaction mixture was partitioned between 20 mL of H2O and 20 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 desired 4-chloro-3-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (1.5 g, crude) as a yellow oil. MS (ESI): mass calcd. For C24H22ClFN6O2S 512.12, m/z found 513.0 [M+H]+.

Step 2: To the solution of (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (3.34 g, 8.85 mmol, 1 eq) in THF (20 mL) was added TEA (8.95 g, 88.5 mmol, 10 eq) at 15° C. and the solution was stirred at 15° C. for 0.5 hour. To the reaction mixture was added 4-azaspiro [2.5]octan-7-one (1.43 g, 8.85 mmol, 1 eq, HCl) at 15° C. and the solution was stirred at 15° C. for 0.5 hour. LCMS showed (1E)-2, 6-dichloro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride was consumed completely and desired mass was detected. The reaction mixture was concentrated to give desired N—[(E)-[(2,6-dichlorophenyl)-(7-oxo-4-azaspiro[2.5]octan-4-yl)methylene]amino]-4-methyl-benzenesulfonamide (4 g, crude) as a yellow solid. MS (ESI): mass calcd. For C21H21N3Cl2SO3 465.07, m/z found 466.1 [M+H]+.

Step 1: To a solution of 2-chloro-5-fluoro-pyrimidine (618 mg, 4.67 mmol, 578 μL, 1 eq) in NMP (10 mL) was added TEA (1.42 g, 14.0 mmol, 1.95 mL, 3 eq) and tert-butyl 2, 2-dimethylpiperazine-1-carboxylate (1 g, 4.67 mmol, 1 eq). The mixture was stirred at 140° C. for 2 hours. LC-MS showed 2-chloro-5-fluoro-pyrimidine was consumed completely and desired mass was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine 20 mL and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/Ethyl acetate=1/0 to 0/1) to give desired tert-butyl 4-(5-fluoropyrimidin-2-yl)-2, 2-dimethyl-piperazine-1-carboxylate (1.4 g, crude) as a colorless oil. MS (ESI): mass calcd. For C15H23FN4O2 310.18, m/z found 255.1[M+H−56]+.

Step 2: To a solution of N—[(E)-[(2, 6-dichlorophenyl)-[4-(5-fluoropyrimidin-2-yl)-2, 2-dimethyl-piperazin-1-yl]methylene]amino]-4-methyl-benzenesulfonamide (1.8 g, 3.26 mmol, 1 eq) in DMF (10 mL) was added K2CO3 (1.80 g, 13.1 mmol, 4 eq). The mixture was stirred at 100° C. for 12 hours. LC-MS showed N—[(E)-[(2, 6-dichlorophenyl)-[4-(5-fluoropyrimidin-2-yl)-2, 2-dimethyl-piperazin-1-yl]methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and desired mass was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine 20 mL and dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 4-chloro-3-[4-(5-fluoropyrimidin-2-yl)-2, 2-dimethyl-piperazin-1-yl]-1-(p-tolylsulfonyl) indazole (1.8 g, crude) as an orange oil. MS (ESI): mass calcd. For C24H24ClFN6O2S 514.14, m/z found 515.2[M+H]+.

Step 3: To a solution of 4-chloro-3-[4-(5-fluoropyrimidin-2-yl)-2, 2-dimethyl-piperazin-1-yl]-1-(p-tolylsulfonyl) indazole (1.8 g, 3.50 mmol, 1 eq) in MeOH (10 mL) was added K2CO3 (2.42 g, 17.5 mmol, 5 eq). The mixture was stirred at 70° C. for 1 hour. LC-MS showed 4-chloro-3-[4-(5-fluoropyrimidin-2-yl)-2, 2-dimethyl-piperazin-1-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and desired compound was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine 20 mL and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/Ethyl acetate=1/0 to 1/1) to give desired 4-chloro-3-[4-(5-fluoropyrimidin-2-yl)-2, 2-dimethyl-piperazin-1-yl]-1H-indazole (350 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C17H18ClFN6 360.13, m/z found 361.1[M+H]+.

Step 3: To a solution of 4, 6-difluoro-3-[7-(5-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (460 mg, 896 μmol, 1 eq) in MeOH (10 mL) was added K2CO3 (619 mg, 4.48 mmol, 5 eq). The mixture was stirred at 75° C. for 0.5 hour. LC-MS showed 4, 6-difluoro-3-[7-(5-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude was added H2O (10 mL), and extracted with EtOAc (45 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 column chromatography (SiO2, petroleum ether/Ethyl acetate=5/1 to 4/1) to give desired 4, 6-difluoro-3-(7-(5-fluoropyridin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl)-1H-indazole (140 mg, 390 μmol, 43.5% yield) as a brown solid. MS (ESI): mass calcd. For C18H16F3N5 359.14, m/z found 360.1 [M+H]+.

Step 3: To a solution of 4, 6-difluoro-3-[7-(5-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (460 mg, 896 μmol, 1 eq) in MeOH (10 mL) was added K2CO3 (619 mg, 4.48 mmol, 5 eq). The mixture was stirred at 75° C. for 0.5 hour. LC-MS showed 4, 6-difluoro-3-[7-(5-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude was added H2O (10 mL), and extracted with EtOAc (45 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 column chromatography (SiO2, petroleum ether/EtOAc=5/1 to 4/1) to give desired 4, 6-difluoro-3-(7-(5-fluoropyridin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl)-1H-indazole (140 mg, 390 μmol, 43.5% yield) as a brown solid. MS (ESI): mass calcd. For C18H16F3N5 359.14, m/z found 360.1 [M+H]+.

Step 3: To a solution of tert-butyl 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-4, 7-diazaspiro [2.5]octane-7-carboxylate (2.8 g, 5.42 mmol, 1 eq) in MeOH (10 mL) was added K2CO3 (3.74 g, 27.1 mmol, 5 eq). The mixture was stirred at 70° C. for 1 hour. LC-MS showed tert-butyl 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-4, 7-diazaspiro [2.5]octane-7-carboxylate was consumed completely and desired compound was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/Ethyl acetate=1/0 to 1/1) to give desired tert-butyl 4-(4-chloro-1H-indazol-3-yl)-4, 7-diazaspiro [2.5]octane-7-carboxylate (550 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C18H23ClN4O2 362.15, m/z found 363.1[M+H]+.

Step 2: To a solution of 2, 6-difluoro-N′-(p-tolylsulfonyl) benzohydrazide (700 mg, 2.15 mmol, 1 eq) in SOCl2 (10 mL). The mixture was stirred at 75° C. for 0.5 hour. TLC indicated 2, 6-difluoro-N′-(p-tolylsulfonyl) benzohydrazide was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to give desired (E)-2, 6-difluoro-N′-tosylbenzohydrazonoyl chloride (700 mg, crude) as a light yellow solid.

Step 1: To a solution of 2-bromo-3-chloro-1, 4-difluoro-benzene (1 g, 4.40 mmol, 1 eq) in THF (10 mL) was added dropwise n-BuLi (2.5 M, 2.64 mL, 1.5 eq) at −70° C. After addition, the mixture was stirred at this temperature for 0.5 hour, and then CO2 (194 mg, 4.40 mmol, 1 eq) (15 psi) was added dropwise at −70° C. The resulting mixture was stirred at −70° C. for 0.5 hour. TLC (petroleum ether/EtOAc=3/1) indicated 2-bromo-3-chloro-1, 4-difluoro-benzene was consumed completely and one new spot formed. The residue was diluted with H2O (100 mL) and extracted with EtOAc (50 mL*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 (SiO2, petroleum ether/EtOAc=3/1) to give desired 2-chloro-3, 6-difluoro-benzoic acid (0.3 g, 1.56 mmol, 40.0% yield) as a yellow solid.

Step 3: To a solution of 4-chloro-3-[7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (225 mg, 412 μmol, 1 eq) in MeOH (4 mL) was added K2CO3 (285 mg, 2.06 mmol, 5 eq). The mixture was stirred at 70° C. for 4 hours. LC-MS showed 4-chloro-3-[7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and one main peak with desired m/z was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (10 mL) and extracted with DCM (30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/EtOAc=3/1) to give desired 4-chloro-3-[7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1H-indazole (200 mg, 510 μmol, 61.9% yield) as a yellow oil. MS (ESI): mass calcd. For C18H16C12FN5 391.08, m/z found 392.1 [M+H]+.

Step 3: To a solution of 3-[7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-4, 7-difluoro-1-(p-tolylsulfonyl) indazole (0.85 g, 1.55 mmol, 1 eq) in MeOH (10 mL) was added K2CO3 (1.07 g, 7.76 mmol, 5 eq) was stirred at 70° C. for 0.5 hour. LC-MS showed a little of 3-[7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-4, 7-difluoro-1-(p-tolylsulfonyl) indazole remained and desired mass was detected. Then it was separated between 5 mL of water and 10 mL of ethyl acetate. The organic phase was separated, washed with 5 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by prep-TLC (SiO2, petroleum ether/ethyl acetate=5/1) to give desired 3-[7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-4, 7-difluoro-1H-indazole (0.1 g, 254 μmol, 16.4% yield) as a yellow solid. MS (ESI): mass calcd. For C18H15ClF3N5 393.10, m/z found 394.2 [M+H]+.

Step 2: To the solution of 4-methylbenzenesulfonohydrazide (5.34 g, 28.7 mmol, 1.1 eq) and TEA (10.55 g, 104 mmol, 14.5 mL, 4 eq) in DCM (40 mL) was added the solution of 4-chloro-2, 6-difluoro-benzoyl chloride (5.5 g, 26.1 mmol, 1 eq) in DCM (10 mL) at 0° C. and the solution was stirred at 20° C. for 2 hours. LC-MS showed 4-methylbenzenesulfonohydrazide was consumed completely and desired mass was detected. The reaction was concentrated to get a residue. The residue was added water (50 mL) and extracted with EtOAc (3*20 mL). The combined organics were 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 desired 4-chloro-2, 6-difluoro-N′-(p-tolylsulfonyl) benzohydrazide (1.54 g, 4.27 mmol, 16.4% yield) as a white solid. MS (ESI): mass calcd. For C14H11ClF2N2O3S 360.04 m/z found 360.9 [M+H]+.

Step 3: The solution of 4-chloro-2, 6-difluoro-N′-(p-tolylsulfonyl) benzohydrazide (660 mg, 1.83 mmol, 1 eq) in SOCl2 (6 mL) was stirred at 75° C. for 1 hour. TLC (SiO2, petroleum ether/EtOAc=3/1) showed 4-chloro-2, 6-difluoro-N′-(p-tolylsulfonyl) benzohydrazide was consumed completely and a new spot with lower priority was detected. The reaction mixture was concentrated in vacuum to give desired (1Z)-4-chloro-2, 6-difluoro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride (690 mg, crude) as an off-white solid.

Step 1: A mixture of 1-(2, 6-dichloro-3-fluoro-phenyl) ethanone (5 g, 24.2 mmol, 3.57 mL, 1 eq) in NaClO (75 mL, 10% purity) was stirred at 70° C. for 12 hours. TLC (SiO2, petroleum ether/EtOAc=4/1) showed a little of tert-butyl 1-(2, 6-dichloro-3-fluoro-phenyl)ethanone remained and a new spot formed. The temperature was cooled to room temperature, and 25 g of dichloromethane was added to extract unreacted materials. The layers were separated. The aqueous phase was neutralized with about 20 g of hydrochloric acid to pH value was 3, cooled, filtered, and dried at 80° C. give desired 2, 6-dichloro-3-fluorobenzoic acid (400 mg, crude) as a white solid.

Step 4: To a solution of 2, 6-dichloro-3-fluoro-N′-(p-tolylsulfonyl) benzohydrazide (150 mg, 398 μmol, 1 eq) and SOCl2 (3 mL) was stirred at 75° C. for 0.5 hour. The reaction was cooled to 60° C. and an additional portion of 2, 6-dichloro-3-fluoro-N′-(p-tolylsulfonyl) benzohydrazide (150 mg, 398 μmol, 1 eq) was added and the reaction heated back to 75° C. for 0.5 hour. LC-MS (the simple was quenched with piperidine) showed 2, 6-dichloro-3-fluoro-N′-(p-tolylsulfonyl) benzohydrazide was consumed completely and desired mass was detected. The reaction mixture was concentrated to give desired (Z)-2, 6-dichloro-3-fluoro-N′-tosylbenzohydrazonoyl chloride (300 mg, crude) as a white solid. MS (ESI): mass calcd. For C14H10C13FN2O2S 393.95, m/z found 444.0 [M+H+50]+.

Step 3: To a solution of 4-chloro-3-[7-(5-chloropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]-6-fluoro-1-(p-tolylsulfonyl) indazole (2 g, 3.65 mmol, 1 eq) in MeOH (20 mL) was added K2CO3 (2.52 g, 18.3 mmol, 5 eq). The mixture was stirred at 70° C. for 0.2 hour. LC-MS showed 4-chloro-3-[7-(5-chloropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]-6-fluoro-1-(p-tolylsulfonyl) indazole was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude was added H2O (40 mL) and extracted with EtOAc (30 mL*3). The combined organic layers were washed with brine (40 mL), dried over anhydrous 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˜35% EtOAc/petroleum ether gradient @100 mL/min) to give desired 4-chloro-3-(7-(5-chloropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl)-6-fluoro-1H-indazole (60 mg, 153 μmol, 4.18% yield) as a yellow oil. MS (ESI): mass calcd. For C17H15C12FN6 392.07, m/z found 393.0 [M+H]+.

Step 1: To a solution of 7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octane (1.20 g, 4.60 mmol, 1 eq, HCl) in THF (10 mL) was added dropwise TEA (1.86 g, 18.4 mmol, 2.56 mL, 4 eq) at 25° C. After addition, the mixture was stirred at this temperature for 10 minutes, and then (1Z)-2, 6-dichloro-4-fluoro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride (2.0 g, 5.05 mmol, 1.1 eq) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 0.5 hour. LC-MS showed 7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octane was consumed completely and one main peak with desired mass was detected. Then it was separated between 20 mL of water and 40 mL of EtOAc. The organic phase was separated, washed with 30 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give desired N—[(Z)-[(2, 6-dichloro-4-fluoro-phenyl)-[7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (2.7 g, crude) as a yellow solid. MS (ESI): mass calcd. For C25H22C12F3N5O2S 583.08 m/z found 584.1 [M+H]+.

Step 3: To a solution of 4-chloro-3-[7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-6-fluoro-1-(p-tolylsulfonyl) indazole (2.6 g, 4.74 mmol, 1 eq) in MeOH (20 mL) was added K2CO3 (3.28 g, 23.7 mmol, 5 eq). The mixture was stirred at 70° C. for 1 hour. LC-MS showed 4-chloro-3-[7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-6-fluoro-1-(p-tolylsulfonyl) indazole was consumed completely and desired compound was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/EtOAc=1/0 to 1/1) to give desired 4-chloro-3-[7-(3,5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-6-fluoro-1H-indazole (800 mg, 2.03 mmol, 42.8% yield) as a yellow oil. MS (ESI): mass calcd. For C18H15ClF3N5 393.10 m/z found 394.2 [M+H]+.

Step 2: A mixture of tert-butyl 7-(5-chlorothiazol-2-yl)-4, 7-diazaspiro [2.5]octane-4-carboxylate (0.5 g, 1.52 mmol, 1 eq) in HCl/EtOAc (4 M, 5 mL, 13.2 eq) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20° C. for 0.5 hour under the atmosphere of nitrogen. LC-MS showed tert-butyl 7-(5-chlorothiazol-2-yl)-4, 7-diazaspiro [2.5]octane-4-carboxylate was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated in vacuum to give desired 2-(3, 8-diazabicyclo [3.2.1]octan-3-yl)-5-chlorothiazole (0.4 g, crude, HCl) as a yellow solid. MS (ESI): mass calcd. For C9H12ClN3S 229.04 m/z found 230.0 [M+H]+.

Step 1: To the solution of 5-chloro-2-(4, 7-diazaspiro [2.5]octan-7-yl)thiazole (808 mg, 3.04 mmol, 1.2 eq, HCl) and K2CO3 (1.40 g, 10.1 mmol, 1.41 mL, 4 eq) in NMP (3 mL) was added the solution of (1Z)-2, 6-dichloro-4-fluoro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride (1 g, 2.53 mmol, 1 eq) in NMP (3 mL) at 20° C. and the solution was stirred at 20° C. for 1 hour. LCMS showed 5-chloro-2-(4, 7-diazaspiro [2.5]octan-7-yl) thiazole remained and one main peak with desired mass was detected. The reaction mixture was stirred at 70° C. for 11 hours. LCMS showed tert-butyl 7-(5-chlorothiazol-2-yl)-4, 7-diazaspiro [2.5]octane-4-carboxylate was consumed completely and one main peak with desired mass was detected. The reaction was added water (20 mL) and extracted with MTBE (2*20 mL). The combined organics were washed with brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to get a residue. The residue was purified by column chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0˜10% EtOAc/petroleum ether gradient @60 mL/min) to give desired 5-chloro-2-(4-(4-chloro-6-fluoro-1-tosyl-1H-indazol-3-yl)-4, 7-diazaspiro [2.5]octan-7-yl) thiazole (200 mg, 362 μmol, 14.3% yield) as a yellow oil. MS (ESI): mass calcd. For C23H20C12FN5O2S2 551.04, m/z found 552.1 [M+H]+.

Step 1: To a solution of 7-(5-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octane (400 mg, 1.64 mmol, 1 eq, HCl) in THF (10 mL) was added dropwise TEA (1.66 g, 16.4 mmol, 2.28 mL, 10 eq) at 25° C. After addition, the mixture was stirred at this temperature for 10 minutes, and then (1Z)-2, 6-dichloro-4-fluoro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (714 mg, 1.81 mmol, 1.1 eq) in THF (5 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 0.5 hour. LC-MS showed 7-(5-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octane was consumed completely and one main peak with desired mass was detected. Then it was separated between 20 mL of water and 40 mL of EtOAc. The organic phase was separated, washed with 30 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give desired N—[(Z)-[(2, 6-dichloro-4-fluoro-phenyl)-[7-(5-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (930 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C25H23C12F2N5O2S 565.09, m/z found 566.2 [M+H]+.

Step 3: To a solution of 4-chloro-6-fluoro-3-[7-(5-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (870 mg, 1.64 mmol, 1 eq) in MeOH (20 mL) was added K2CO3 (1.13 g, 8.21 mmol, 5 eq). The mixture was stirred at 70° C. for 1 hour. LC-MS showed 4-chloro-6-fluoro-3-[7-(5-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and desired compound was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/EtOAc=1/0 to 1/1) to give desired 4-chloro-6-fluoro-3-[7-(5-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1H-indazole (490 mg, 1.30 mmol, 79.4% yield) as a yellow oil. MS (ESI): mass calcd. For C18H16ClF2N5 375.11, m/z found 376.1 [M+H]+.

Step 2: To a solution of tert-butyl 4-(5-chloropyrimidin-2-yl)-2-cyclopropyl-piperazine-1-carboxylate (670 mg, 1.98 mmol, 1 eq) in HCl/EtOAc (4M, 7 mL). The mixture was stirred at 25° C. for 0.5 hour. LC-MS showed tert-butyl 4-(5-chloropyrimidin-2-yl)-2-cyclopropyl-piperazine-1-carboxylate was consumed completely and desired mass was detected. The reaction mixture was filtered and the filter liquor was concentrated under reduced pressure to give desired 5-chloro-2-(3-cyclopropylpiperazin-1-yl) pyrimidine (540 mg, crude) as a white solid. MS (ESI): mass calcd. For C11H15ClN4 238.10, m/z found 239.1 [M+H]+.

Step 3: To a solution of 4-chloro-3-[7-(5-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (750 mg, 1.46 mmol, 1 eq) in MeOH (10 mL) was added K2CO3 (1.01 g, 7.32 mmol, 5 eq). The mixture was stirred at 80° C. for 0.5 hour. LC-MS showed 4-chloro-3-[7-(5-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude was added H2O (20 mL), and extracted with EtOAc (45 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 column prep-TLC (SiO2, petroleum ether/ethyl acetate=2/1) to give desired 4-chloro-3-(7-(5-fluoropyridin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl)-1H-indazole (110 mg, 307 μmol, 21.0% yield) as a yellow oil. MS (ESI): mass calcd. For C18H17ClFN5 357.12, m/z found 358.1 [M+H]+.

Step 1: To a solution of 7-(3,5-difluoro-2-pyridyl)-4,7-diazaspiro[2.5]octane (252 mg, 964 μmol, 1 eq, HCl) in THF (5 mL) was added dropwise TEA (975 mg, 9.64 mmol, 1.34 mL, 10 eq) at 25° C. After addition, the mixture was stirred at this temperature for 10 minutes, and then (1Z)-2,6-dichloro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride (400 mg, 1.06 mmol, 1.1 eq) in THF (3 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 20 minutes. LC-MS showed 7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octane was consumed completely and 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 desired N—[(Z)-[(2,6-dichlorophenyl)-[7-(3,5-difluoro-2-pyridyl)-4,7-diazaspiro[2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (700 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C25H23C12F2N5O2S 565.09, m/z found 566.1 [M+H]+.

Step 2: To a solution of N—[(Z)-[(2, 6-dichlorophenyl)-[7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (700 mg, 1.24 mmol, 1 eq) in DMF (8 mL) was added K2CO3 (854 mg, 6.18 mmol, 5 eq). The mixture was stirred at 80° C. for 12 hours. LC-MS showed N—[(Z)-[(2,6-dichlorophenyl)-[7-(3,5-difluoro-2-pyridyl)-4,7-diazaspiro[2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and desired mass was detected. The reaction mixture was partitioned between 20 mL of H2O and 20 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 desired 4-chloro-3-[7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl)indazole (700 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C25H22ClF2N5O2S 529.12, m/z found 530.1 [M+H]+.

Step 3: To a solution of 4-chloro-3-[7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (700 mg, 1.32 mmol, 1 eq) in MeOH (6 mL) was added K2CO3 (913 mg, 6.60 mmol, 5 eq). The mixture was stirred at 70° C. for 1 hour. LC-MS showed 4-chloro-3-[7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and desired mass was detected. The reaction mixture was filtered and the filter liquor was concentrated under reduced pressure to give a residue. 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 (SiO2, petroleum ether/ethyl acetate=2/1) to give desired 4-chloro-3-[7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1H-indazole (150 mg, 399 μmol, 30.2% yield) as a yellow oil. MS (ESI): mass calcd. For C18H16ClF2N5 375.11, m/z found 376.1 [M+H]+.

Step 3: To a solution of 3-[7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-4, 6-difluoro-1-(p-tolylsulfonyl) indazole (1.2 g, 2.26 mmol, 1 eq) in MeOH (10 mL) was added K2CO3 (1.56 g, 11.3 mmol, 5 eq). The mixture was stirred at 75° C. for 0.5 hour. LC-MS showed 3-[7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-4, 6-difluoro-1-(p-tolylsulfonyl) indazole was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude was added H2O (10 mL), and extracted with EtOAc (45 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 column chromatography (SiO2, petroleum ether/ethyl acetate=5/1 to 4/1) to give desired 3-(7-(3, 5-difluoropyridin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl)-4, 6-difluoro-1H-indazole (450 mg, 1.19 mmol, 52.8% yield) as a brown solid. MS (ESI): mass calcd. For C18H15F4N5 377.13, m/z found 378.1 [M+H]+.

Step 1: To a solution of tert-butyl 2-cyclopropylpiperazine-1-carboxylate (526 mg, 2.32 mmol, 1.1 eq) and 2-chloro-5-fluoro-pyrimidine (280 mg, 2.11 mmol, 1 eq) in NMP (6 mL) was added TEA (641 mg, 6.34 mmol, 3 eq). The mixture was stirred at 140° C. for 12 hours. LC-MS showed 2-chloro-5-fluoro-pyrimidine was consumed completely and 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 crude product. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 3/1) to give desired tert-butyl 2-cyclopropyl-4-(5-fluoropyrimidin-2-yl)piperazine-1-carboxylate (600 mg, 1.86 mmol, 88.1% yield) as a yellow solid. MS (ESI): mass calcd. For C16H23N4FO2 322.18, m/z found 267.1 [M+H−56]+.

Step 1: To a solution of (1Z)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (408 mg, 1.08 mmol, 1.2 eq) and 2-(3-cyclopropylpiperazin-1-yl)-5-fluoro-pyrimidine (200 mg, 900 μmol, 1 eq) in THF (6 mL) was added TEA (910 mg, 9.00 mmol, 1.25 mL, 10 eq). The mixture was stirred at 20° C. for 1 hour. LC-MS showed (1Z)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride was consumed completely and 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 desired N—[(Z)-[[2-cyclopropyl-4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]-(2,6-dichlorophenyl)methylene]amino]-4-methyl-benzenesulfonamide (510 mg, crude) as a white solid. MS (ESI): mass calcd. For C25H25C12N6SO2F 562.11, m/z found 563.2 [M+H]+.

Step 2: To a solution of N—[(Z)-[[2-cyclopropyl-4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]-(2,6-dichlorophenyl)methylene]amino]-4-methyl-benzenesulfonamide (510 mg, 905 μmol, 1 eq) in DMF (6 mL) was added K2CO3 (1.25 g, 9.05 mmol, 10 eq). The mixture was stirred at 100° C. for 12 hours. LC-MS showed N—[(Z)-[[2-cyclopropyl-4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]-(2,6-dichlorophenyl)methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and desired mass was detected. The reaction mixture was partitioned between 50 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 desired 4-chloro-3-[2-cyclopropyl-4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]-1-(p-tolylsulfonyl)indazole (490 mg, crude) as a black oil. MS (ESI): mass calcd. For C25H24N6FClSO2 526.14, m/z found 527.2 [M+H]+.

Step 3: To a solution of 4-chloro-3-[2-cyclopropyl-4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]-1-(p-tolylsulfonyl)indazole (490 mg, 930 μmol, 1 eq) in MeOH (5 mL) was added K2CO3 (643 mg, 4.65 mmol, 5 eq). The mixture was stirred at 80° C. for 1 hour. LC-MS showed 4-chloro-3-[2-cyclopropyl-4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]-1-(p-tolylsulfonyl)indazole was consumed completely and 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 (SiO2, petroleum ether:ethyl acetate=2:1) to give desired 4-chloro-3-[2-cyclopropyl-4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]-1H-indazole (25 mg, 67.1 μmol, 7.21% yield) as a white solid. MS (ESI): mass calcd. For C18H18ClN6F 372.13, m/z found 373.1 [M+H]+.

Step 1: To a solution of (1Z)-2,6-dichloro-4-fluoro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (367 mg, 928 μmol, 1.2 eq) and 2-(3-cyclopropylpiperazin-1-yl)-5-fluoro-pyrimidine (200 mg, 773 μmol, 1 eq, HCl) in THF (6 mL) was added TEA (782 mg, 7.73 mmol, 1.08 mL, 10 eq). The mixture was stirred at 20° C. for 1 hour. LC-MS showed (1Z)-2,6-dichloro-4-fluoro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride was consumed completely and 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 desired N—[(Z)-[[2-cyclopropyl-4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]-(2,6-dichloro-4-fluoro-phenyl)methylene]amino]-4-methyl-benzenesulfonamide (450 mg, crude) as a white solid. MS (ESI): mass calcd. For C25H24C12N6SO2F2 580.1, m/z found 581.2 [M+H]+.

Step 2: To a solution of N—[(Z)-[[2-cyclopropyl-4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]-(2,6-dichloro-4-fluoro-phenyl)methylene]amino]-4-methyl-benzenesulfonamide (450 mg, 774 μmol, 1 eq) in DMF (6 mL) was added K2CO3 (1.07 g, 7.74 mmol, 10 eq). The mixture was stirred at 100° C. for 12 hours. LC-MS showed N—[(Z)-[[2-cyclopropyl-4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]-(2,6-dichloro-4-fluoro-phenyl)methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and desired mass was detected. The reaction mixture was partitioned between 50 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 desired 4-chloro-3-[2-cyclopropyl-4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]-6-fluoro-1-(p-tolylsulfonyl)indazole (440 mg, crude) as a black oil. MS (ESI): mass calcd. For C25H23F2ClN6SO2 544.13, m/z found 545.1 [M+H]+.

Step 3: To a solution of 4-chloro-3-[2-cyclopropyl-4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]-6-fluoro-1-(p-tolylsulfonyl)indazole (440 mg, 807 μmol, 1 eq) in MeOH (5 mL) was added K2CO3 (558 mg, 4.04 mmol, 5 eq). The mixture was stirred at 80° C. for 1 hour. LC-MS showed 4-chloro-3-[2-cyclopropyl-4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]-6-fluoro-1-(p-tolylsulfonyl)indazole was consumed completely and 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 (SiO2, petroleum ether:ethyl acetate=2:1) to give desired 4-chloro-3-[2-cyclopropyl-4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]-6-fluoro-1H-indazole (17 mg, 43.5 μmol, 5.39% yield) as a white solid. MS (ESI): mass calcd. For C18H17ClN6F2 390.12, m/z found 391.1 [M+H]+.

Step 1: To a solution of tert-butyl 4-oxo-2-(trifluoromethyl) piperidine-1-carboxylate (1.14 g, 4.27 mmol, 1 eq) in EtOH (12 mL) was added NaBH4 (323 mg, 8.53 mmol, 2 eq) at 0° C. The mixture was stirred at 20° C. for 12 hours. TLC (petroleum ether/ethyl acetate=3/1) indicated tert-butyl 4-oxo-2-(trifluoromethyl) piperidine-1-carboxylate was consumed completely and one new spot was formed. The reaction was clean according to TLC. The residue was diluted with HCl (1N, 8 mL) and the resulting mixture was allowed to return to room temperature. The MeOH was evaporated in vacuo. The reaction mixture was added to water (20 mL), extracted with DCM (10 mL*3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give desired tert-butyl 4-hydroxy-2-(trifluoromethyl)piperidine-1-carboxylate (1.2 g, crude) as a white solid.

Step 2: A mixture of tert-butyl 4-hydroxy-2-(trifluoromethyl) piperidine-1-carboxylate (1.2 g, 4.46 mmol, 1.0 eq) in HCl/EtOAc (4M, 20 mL) was stirred at 20° C. for 0.5 hour. TLC (petroleum ether/ethyl acetate=3/1) indicated tert-butyl 4-hydroxy-2-(trifluoromethyl) piperidine-1-carboxylate was consumed completely and one new spot was formed. The reaction was clean according to TLC. The reaction mixture was concentrated to give desired 2-(trifluoromethyl) piperidin-4-ol (1.1 g, crude, HCl) as a yellow solid.

Step 3: To a solution of 2-(trifluoromethyl) piperidin-4-ol (220 mg, 1.07 mmol, 1 eq, HCl) in THF (3 mL) was added dropwise TEA (1.08 g, 10.7 mmol, 1.49 mL, 10 eq) at 25° C. After addition, the mixture was stirred at this temperature for 10 mins, and then (1Z)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (445 mg, 1.18 mmol, 1.1 eq) in THF (3 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 20 mins. LC-MS showed (1Z)-2, 6-dichloro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride was consumed completely and one main peak with 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, filtered and concentrated under reduced pressure to give desired N—[(E)-[(2,6-dichlorophenyl)-[4-hydroxy-2-(trifluoromethyl)-1-piperidyl]methylene]amino]-4-methyl-benzenesulfonamide (600 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C20H20C12F3N3O3S 509.06, mass found 510.0 [M+H]+.

Step 4: To a solution of N—[(E)-[(2, 6-dichlorophenyl)-[4-hydroxy-2-(trifluoromethyl)-1-piperidyl]methylene]amino]-4-methyl-benzenesulfonamide (550 mg, 1.08 mmol, 1 eq) in DMF (2 mL) was added K2CO3 (596 mg, 4.31 mmol, 4 eq). The mixture was stirred at 100° C. for 2 hours. LC-MS showed N—[(E)-[(2, 6-dichlorophenyl)-[4-hydroxy-2-(trifluoromethyl)-1-piperidyl]methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and desired mass was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine 20 mL and dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 1-[4-chloro-1-(p-tolylsulfonyl)indazol-3-yl]-2-(trifluoromethyl)piperidin-4-ol (510 mg, crude) as an orange oil. MS (ESI): mass calcd. For C20H19ClF3N3O3S 473.08, mass found 473.9 [M+H]+.

Step 5: To a solution of 1-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-2-(trifluoromethyl) piperidin-4-ol (510 mg, 1.08 mmol, 1 eq) in DCM (10 mL) was added DMP (685 mg, 1.61 mmol, 1.5 eq). The mixture was stirred at 25° C. for 1 hour. LC-MS showed 1-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-2-(trifluoromethyl) piperidin-4-ol was consumed completely and desired mass was detected. The reaction mixture was added to sat.aq.NaHCO3 (20 mL), extracted with DCM (10 mL*3). The combined organic layers were washed with brine 20 mL and 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 desired 1-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-2-(trifluoromethyl) piperidin-4-one (110 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C20H17ClF3N3O3S 471.06, mass found 472.0 [M+H]+.

Step 1: To a solution of (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (446 mg, 1.18 mmol, 1.5 eq) and tert-butyl 3-(trifluoromethyl)piperazine-1-carboxylate (200 mg, 787 μmol, 1 eq) in THF (7 mL) was added TEA (398 mg, 3.93 mmol, 547 μL, 5 eq) at 0° C. The mixture was stirred at 25° C. for 1 hour. LC-MS showed tert-butyl 3-(trifluoromethyl) piperazine-1-carboxylate was consumed completely and 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 desired tert-butyl 4-[(E)-C-(2,6-dichlorophenyl)-N-(p-tolylsulfonylamino)carbonimidoyl]-3-(trifluoromethyl)piperazine-1-carboxylate (640 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C24H27Cl2F3N4O4S 594.1 mass found 595.1 [M+H]+

Step 2: To a solution of tert-butyl 4-[(E)-C-(2, 6-dichlorophenyl)-N-(p-tolylsulfonylamino) carbonimidoyl]-3-(trifluoromethyl) piperazine-1-carboxylate (640 mg, 1.07 mmol, 1 eq) in DMF (8 mL) was added K2CO3 (743 mg, 5.37 mmol, 5 eq). The mixture was stirred at 100° C. for 12 hours. LC-MS showed tert-butyl 4-[(E)-C-(2, 6-dichlorophenyl)-N-(p-tolylsulfonylamino) carbonimidoyl]-3-(trifluoromethyl) piperazine-1-carboxylate was consumed completely and 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 desired tert-butyl 4-[4-chloro-1-(p-tolylsulfonyl)indazol-3-yl]-3-(trifluoromethyl)piperazine-1-carboxylate (600 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C24H26ClF3N4O4S 558.1 mass found 559.1 [M+H]+.

Step 3: To a solution of tert-butyl 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-3-(trifluoromethyl) piperazine-1-carboxylate (600 mg, 1.07 mmol, 1 eq) in MeOH (7 mL) was added K2CO3 (742 mg, 5.37 mmol, 5 eq). The mixture was stirred at 40° C. for 1 hour. LC-MS showed tert-butyl 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-3-(trifluoromethyl) piperazine-1-carboxylate was consumed completely and 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 crude product. The residue was purified by prep-TLC (Silica gel, petroleum ether/ethyl acetate=3/1) to give desired tert-butyl 4-(4-chloro-1H-indazol-3-yl)-3-(trifluoromethyl) piperazine-1-carboxylate (130 mg, 321 μmol, 29.9% yield) as a yellow solid. MS (ESI): mass calcd. For C17H20ClF3N4O2 404.1, mass found 405.1 [M+H]+.

Step 1: To a solution of (1E)-2, 6-dichloro-3-fluoro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride (1.14 g, 2.88 mmol, 1.5 eq) and 7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octane (400 mg, 1.92 mmol, 1 eq) in THF (5 mL) was added TEA (1.94 g, 19.2 mmol, 2.67 mL, 10 eq) at 0° C. The mixture was stirred at 25° C. for 12 hours. LC-MS showed 7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octane was consumed completely and one main peak with desired mass was detected. The reaction mixture was added to water (20 mL) and extracted with EtOAc (20 mL*3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give desired N—[(E)-[(2, 6-dichloro-3-fluoro-phenyl)-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (1.17 g, crude) as a white solid. MS (ESI): mass calcd. For C24H22N6F2SO2Cl2 566.09, mass found 567.1[M+H]+.

Step 2: To a solution of N—[(E)-[(2, 6-dichloro-3-fluoro-phenyl)-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (1 g, 1.76 mmol, 1 eq) in DMF (10 mL) was added K2CO3 (974 mg, 7.05 mmol, 4 eq). The mixture was stirred at 100° C. for 3 hours. LC-MS showed N—[(E)-[(2, 6-dichloro-3-fluoro-phenyl)-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and desired mass was detected. The reaction mixture was added to water (30 mL) and extracted with MTBE (30 mL*3). The combined organic layers were washed with brine (30 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 4-chloro-7-fluoro-3-[7-(5-fluoropyrimidin-2-yl)-4,7-diazaspiro[2.5]octan-4-yl]-1-(p-tolylsulfonyl)indazole (2.5 g, crude) as a white solid. MS (ESI): mass calcd. For C24H21ClF2N6SO2 530.11, mass found 531.2[M+H]+.

Step 3: To a solution of 4-chloro-7-fluoro-3-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (2.5 g, 4.71 mmol, 1 eq) in MeOH (5 mL) was added K2CO3 (3.25 g, 23.5 mmol, 5 eq). The mixture was stirred at 40° C. for 1 hour. LC-MS showed 4-chloro-7-fluoro-3-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and one main peak with desired mass was detected. The reaction mixture was added to water (30 mL), extracted with EtOAc (30 mL*3). The combined organic layers were washed with brine (30 mL) and 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 desired 4-chloro-7-fluoro-3-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]-1H-indazole (230 mg, 610 μmol, 13% yield) as a white solid. MS (ESI): mass calcd. For C17H15ClF2N6 376.1, mass found 377.0[M+H]+.

Step 1: To a solution of (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (446 mg, 1.18 mmol, 1.5 eq) and tert-butyl 3-(trifluoromethyl)piperazine-1-carboxylate (200 mg, 787 μmol, 1 eq) in THF (7 mL) was added TEA (398 mg, 3.93 mmol, 547 μL, 5 eq) at 0° C. The mixture was stirred at 25° C. for 1 hour. LC-MS showed tert-butyl 3-(trifluoromethyl) piperazine-1-carboxylate was consumed completely and 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 desired tert-butyl 4-[(E)-C-(2,6-dichlorophenyl)-N-(p-tolylsulfonylamino)carbonimidoyl]-3-(trifluoromethyl)piperazine-1-carboxylate (640 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C24H27Cl2F3N4O4S 594.1 mass found 595.1 [M+H]+

Step 2: To a solution of tert-butyl 4-[(E)-C-(2, 6-dichlorophenyl)-N-(p-tolylsulfonylamino) carbonimidoyl]-3-(trifluoromethyl) piperazine-1-carboxylate (640 mg, 1.07 mmol, 1 eq) in DMF (8 mL) was added K2CO3 (743 mg, 5.37 mmol, 5 eq). The mixture was stirred at 100° C. for 12 hours. LC-MS showed tert-butyl 4-[(E)-C-(2, 6-dichlorophenyl)-N-(p-tolylsulfonylamino) carbonimidoyl]-3-(trifluoromethyl) piperazine-1-carboxylate was consumed completely and 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 desired tert-butyl 4-[4-chloro-1-(p-tolylsulfonyl)indazol-3-yl]-3-(trifluoromethyl)piperazine-1-carboxylate (600 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C24H26ClF3N4O4S 558.1 mass found 559.1 [M+H]+.

Step 3: To a solution of tert-butyl 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-3-(trifluoromethyl) piperazine-1-carboxylate (600 mg, 1.07 mmol, 1 eq) in MeOH (7 mL) was added K2CO3 (742 mg, 5.37 mmol, 5 eq). The mixture was stirred at 40° C. for 1 hour. LC-MS showed tert-butyl 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-3-(trifluoromethyl) piperazine-1-carboxylate was consumed completely and 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 crude product. The residue was purified by prep-TLC (Silica gel, petroleum ether/ethyl acetate=3/1) to give desired tert-butyl 4-(4-chloro-1H-indazol-3-yl)-3-(trifluoromethyl) piperazine-1-carboxylate (130 mg, 321 μmol, 29.9% yield) as a yellow solid. MS (ESI): mass calcd. For C17H20ClF3N4O2 404.1, mass found 405.1 [M+H]+.

Step 1: To a solution of 4-chloro-1H-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-1H-indazole was consumed completely and desired mass was detected. The crude was added H2O (50 mL), and extracted with MTBE (50 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 4-chloro-3-iodo-1H-indazole (8 g, crude) as a yellow solid. MS (ESI): mass calcd. For C7H4ClIN2 277.91 m/z found 278.8 [M+H]+.

Step 3: To a solution of 3-(5-azaspiro [2.5]octan-5-yl)-4-chloro-1-(p-tolylsulfonyl) indazole (1.4 g, 3.37 mmol, 1 eq) in MeOH (5 mL) was added K2CO3 (2.33 g, 16.8 mmol, 5 eq). The mixture was stirred at 70° C. for 2 hours. LC-MS showed 3-(5-azaspiro [2.5]octan-5-yl)-4-chloro-1-(p-tolylsulfonyl) indazole remained and desired compound was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (30 mL). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/EtOAc=3/1) to give desired 3-(5-azaspiro [2.5]octan-5-yl)-4-chloro-1H-indazole (330 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C14H16ClN3 261.10, m/z found 262.1 [M+H]+.

Step 3: To a solution of 2, 4-dichloro-N′-(p-tolylsulfonyl) pyridine-3-carbohydrazide (500 mg, 1.39 mmol, 1 eq) in SOCl2 (5 mL). The mixture was stirred at 80° C. for 1 hour. LC-MS showed 2, 4-dichloro-N′-(p-tolylsulfonyl) pyridine-3-carbohydrazide was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove SOCl2 to give desired (3Z)-2, 4-dichloro-N-(p-tolylsulfonyl) pyridine-3-carbohydrazonoyl chloride (500 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C13H10C13N3O2S 377.0, m/z found 427.0 [M+49+H]+.

Step 4: To a solution of 7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octane (250 mg, 899 μmol, 1 eq, HCl) in THF (2 mL) was added TEA (273 mg, 2.70 mmol, 375 μL, 3 eq) at 0° C. Then (3Z)-2, 4-dichloro-N-(p-tolylsulfonyl) pyridine-3-carbohydrazonoyl chloride (408 mg, 1.08 mmol, 1.2 eq) in THF (4 mL) was added to the above mixture dropwise at 0° C. The mixture was stirred at 20° C. for 12 hours. LC-MS showed 7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octane was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (100 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous 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˜30% EtOAc/petroleum ether gradient @60 mL/min) to give desired N—[(Z)—[[7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-(2, 4-dichloro-3-pyridyl) methylene]amino]-4-methyl-benzenesulfonamide (200 mg, 343 μmol, 38.1% yield) as a white solid which was confirmed by LC-MS. MS (ESI): mass calcd. For C24H22C13FN6O2S 582.1, m/z found 583.1 [M+H]+.

Step 1: To a solution of 4-azaspiro [2.5]octan-7-one (1.35 g, 8.34 mmol, 1.1 eq, HCl) in THF (10 mL) was added TEA (767 mg, 7.58 mmol, 1.06 mL, 1 eq). The mixture was stirred at 0° C. for 10 mins. Then (1E)-2,6-dichloro-4-fluoro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (3 g, 7.58 mmol, 1 eq) was added to the mixture. The mixture was stirred at 20° C. for 12 hours. LC-MS showed (1E)-2, 6-dichloro-4-fluoro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (150 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give desired N—[(E)-[(2, 6-dichloro-4-fluoro-phenyl)-(7-oxo-4-azaspiro [2.5]octan-4-yl)methylene]amino]-4-methyl-benzenesulfonamide (3.7 g, crude) as a yellow solid. MS (ESI): mass calcd. For C21H20C12FN3O3S 483.1 m/z found 484.0 [M+H]+.

Step 2: To a solution of N—[(E)-[(2, 6-dichloro-4-fluoro-phenyl)-(7-oxo-4-azaspiro [2.5]octan-4-yl) methylene]amino]-4-methyl-benzenesulfonamide (3.7 g, 7.64 mmol, 1 eq) in DMF (30 mL) was added K2CO3 (10.6 g, 76.4 mmol, 10 eq). The mixture was stirred at 100° C. for 3 hours. LCMS showed N—[(E)-[(2, 6-dichloro-4-fluoro-phenyl)-(7-oxo-4-azaspiro [2.5]octan-4-yl) methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with H2O (50 mL) and extracted with MTBE (300 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0˜35% EtOAc/petroleum ether gradient @70 mL/min) to give desired 4-[4-chloro-6-fluoro-1-(p-tolylsulfonyl)indazol-3-yl]-4-azaspiro[2.5]octan-7-one (860 mg, 1.92 mmol, 25.1% yield) as a yellow solid which was confirmed by LC-MS. MS (ESI): mass calcd. For C14H13ClFN3O 447.1 m/z found 448.1 [M+H]+.

Step 1: A mixture of 2-methylpropane-2-thiol (332 mg, 3.68 mmol, 414 μL, 1.2 eq), 2-bromothiophene (500 mg, 3.07 mmol, 298 μL, 1 eq), DIEA (793 mg, 6.13 mmol, 1.07 mL, 2 eq), Xantphos (177 mg, 307 umol, 0.1 eq) and Pd(dppf)C12 (56.1 mg, 76.7 μmol, 0.025 eq) in Tol. (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110° C. for 12 hours under the atmosphere nitrogen. TLC indicated 2-methylpropane-2-thiol was consumed completely and one new spot was formed. The reaction mixture was concentrated under reduced pressure to remove toluene. The reaction mixture was added to water (30 mL), extracted with EtOAc (30 mL*3). The combined organic layers were washed with brine (20 mL) and 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˜10% ethyl acetate/petroleum ether gradient @40 mL/min) to give desired 2-tert-butylsulfanylthiophene (250 mg, crude) as a yellow oil.

Step 2: To the solution of 2-tert-butylsulfanylthiophene (150 mg, 871 μmol, 1 eq) in DMF (5 mL) was added NBS (155 mg, 871 μmol, 1.0 eq) at 20° C. and the solution was stirred at 20° C. for 0.5 hour. TLC showed 2-tert-butylsulfanylthiophene was consumed completely and a new spot with lower polarity. The reaction was poured into water (10 mL) and extracted with MTBE (3*5 mL). The combined organics were 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/petroleum ether gradient @40 mL/min) to give desired 2-bromo-5-tert-butylsulfanyl-thiophene (178 mg, 709 μmol, 81.4% yield) as a yellow oil.

Step 3: To the solution of 2-bromo-5-tert-butylsulfanyl-thiophene (178 mg, 709 μmol, 1 eq) in DCM (10 mL) was added m-CPBA (1.44 g, 7.09 mmol, 85% purity, 10 eq) at 20° C. and the solution was stirred at 20° C. for 12 hours. TLC showed 2-bromo-5-tert-butylsulfanyl-thiophene was consumed completely and a new spot with larger polarity. The reaction was poured into water (10 mL) and extracted with MTBE (3*5 mL). The combined organics were washed with 1N NaOH (2*10 mL), dried over Na2SO4 and concentrated to get to give desired 2-bromo-5-tert-butylsulfonyl-thiophene (213 mg, crude) as a yellow solid.

Step 5: To the solution of 2-benzylsulfanyl-5-tert-butylsulfonyl-thiophene (210 mg, 643 μmol, 1 eq) in AcOH (4 mL) and H2O (0.5 mL) was added NCS (344 mg, 2.57 mmol, 4 eq) in portions at 20° C. and the solution was stirred at 20° C. for 2 hours. TLC showed 2-benzylsulfanyl-5-tert-butylsulfonyl-thiophene was consumed completely and a main new spot. The reaction was poured into water (10 mL) and extracted with MTBE (3*5 mL). The combined organics were washed with 1N NaOH (2*10 mL), dried over Na2SO4 and concentrated to get a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-25% ethyl acetate/Petroleum ether gradient @60 mL/min) to give desired 5-tert-butylsulfonylthiophene-2-sulfonyl chloride (130 mg, 429 μmol, 66.75% yield) as a white solid.

Step 2: To a solution of 2-bromo-5-isopropylsulfanyl-thiophene (17 g, 71.7 mmol, 1 eq) in DCM (300 mL) was added m-CPBA (50.9 g, 251 mmol, 85% purity, 3.5 eq) at 0° C. The mixture was stirred at 20° C. for 1 hour. TLC (petroleum ether/Ethyl acetate=3/1) indicated 2-bromo-5-isopropylsulfanyl-thiophene was consumed completely and one new spot formed. The reaction was clean according to TLC. Then it was partitioned between 300 mL of sat. Na2SO3 and 100 mL of DCM. The organic phase was separated, washed with 300 mL of sat. Na2SO3, 30 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether/Ethyl acetate=1/0 to 0/1) to give desired 2-bromo-5-isopropylsulfonyl-thiophene (21 g, crude) as a yellow solid.

Step 3: A mixture of phenylmethanethiol (6.09 g, 49.0 mmol, 5.75 mL, 1.1 eq), 2-bromo-5-isopropylsulfonyl-thiophene (12 g, 44.6 mmol, 1 eq), DIEA (11.5 g, 89.2 mmol, 15.5 mL, 2 eq), Xantphos (2.58 g, 4.46 mmol, 0.1 eq) and Pd(dppf)C12 (815 mg, 1.11 mmol, 0.025 eq) in Tol. (100 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110° C. for 12 hours under the atmosphere of nitrogen. TLC (petroleum ether/Ethyl acetate=3/1) indicated 2-bromo-5-isopropylsulfonyl-thiophene was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was concentrated under reduced pressure to remove Tol. The reaction mixture was added to water (500 mL), extracted with EtOAc (300 mL*3). The combined organic layers were washed with brine 300 mL and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/Ethyl acetate=1/0 to 1/1) to give desired 2-benzylsulfanyl-5-isopropylsulfonyl-thiophene (10.8 g, crude) as an orange oil.

Step 4: To a solution of 2-benzylsulfanyl-5-isopropylsulfonyl-thiophene (10.8 g, 34.6 mmol, 1 eq) in AcOH (80 mL) and H2O (20 mL) was added NCS (13.9 g, 104 mmol, 3 eq). The mixture was stirred at 20° C. for 12 hours. TLC (petroleum ether/Ethyl acetate=3/1) showed 2-benzylsulfanyl-5-isopropylsulfonyl-thiophene was consumed completely and one major new spot with larger polarity was detected. The reaction mixture was diluted with water 50 mL and extracted with EtOAc 450 mL (50 mL*3). The combined organic layers were washed with brine 50 mL, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give desired 5-isopropylsulfonylthiophene-2-sulfonyl chloride (7.8 g, crude) as a yellow oil.

Step 1: A mixture of 4-bromobenzenethiol (10 g, 52.9 mmol, 1 eq), 2-bromopropane (13.0 g, 106 mmol, 9.93 mL, 2 eq), K2CO3 (25.6 g, 185 mmol, 3.5 eq) in acetone (100 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 40° C. for 12 hours under the atmosphere of nitrogen. TLC (petroleum ether/Ethyl acetate=5/1) indicated 4-bromobenzenethiol was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was added to water (200 mL), extracted with EtOAc (100 mL*3). The combined organic layers were washed with brine 200 mL and dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 1-bromo-4-isopropylsulfanyl-benzene (12 g, 51.9 mmol, 98.2% yield) as a brown oil.

Step 2: To a solution of 1-bromo-4-isopropylsulfanyl-benzene (1 g, 4.33 mmol, 1 eq) in DCM (10 mL) was added m-CPBA (2.63 g, 13.0 mmol, 85% purity, 3 eq) at 0° C. The mixture was stirred at 20° C. for 1 hour. TLC (petroleum ether/Ethyl acetate=4/1) indicated 1-bromo-4-isopropylsulfanyl-benzene was consumed completely and one new spot formed. The reaction was clean according to TLC. Then it was partitioned between 30 mL of sat. Na2SO3 and 100 mL of DCM. The organic phase was separated, washed with 30 mL of sat. Na2SO3, 30 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether/Ethyl acetate=1/0 to 0/1) to give desired 1-bromo-4-isopropylsulfonyl-benzene (1 g, crude) as a white solid.

Step 4: To the solution of 1-benzylsulfanyl-4-isopropylsulfonyl-benzene (1.24 g, 4.05 mmol, 1 eq) in AcOH (24 mL) and H2O (2.4 mL) was added NCS (2.16 g, 16.2 mmol, 4 eq) at 20° C. and the solution was stirred at 20° C. for 12 hours. TLC (petroleum ether/Ethyl acetate=2/1) showed 1-benzylsulfanyl-4-isopropylsulfonyl-benzene was consumed completely and a new spot. The reaction was quenched slowly with saturated NaHCO3 solution (200 mL) and extracted with MTBE (2*30 mL). The combined organics were 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 desired 4-isopropylsulfonylbenzenesulfonyl chloride (0.78 g, 2.76 mmol, 68.2% yield) as a white solid.

Step 2: To the solution of 1-bromo-4-cyclopropylsulfanyl-benzene (600 mg, 2.62 mmol, 1 eq) in DCM (20 mL) was added m-CPBA (2.66 g, 13.1 mmol, 85% purity, 5 eq) at 0° C. by portions and stirred at 20° C. for 1 hour. The mixture was stirred at 20° C. for 1 hour. TLC showed 1-bromo-4-cyclopropylsulfanyl-benzene was consumed completely and desired spot. The reaction was filtered and the filtrate was washed with 1N NaOH (20 mL) and dry the organic layer with sodium sulfate. The mixture was filtered and the filtrate was concentrated to give desired 1-bromo-4-cyclopropylsulfonyl-benzene (600 mg, crude) as a yellow oil.

Step 4: To the solution of 1-benzylsulfanyl-4-cyclopropylsulfonyl-benzene (600 mg, 1.97 mmol, 1 eq) in AcOH (5 mL) and H2O (0.5 mL) was added NCS (1.05 g, 7.88 mmol, 4 eq) at 20° C. and the solution was stirred at 20° C. for 2 hours. TLC showed 1-benzylsulfanyl-4-cyclopropylsulfonyl-benzene was consumed completely and a new spot. The reaction was quenched slowly with saturated NaHCO3 solution (10 mL) and extracted with MTBE (2*10 mL). The combined organics were concentrated to get a residue. The combined organics were concentrated to get 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 ether gradient @60 mL/min) to give desired 4-cyclopropylsulfonylbenzenesulfonyl chloride (331 mg, crude) as a white solid.

Step 1: To a solution of 1-bromo-4-isopropylsulfonyl-benzene (3 g, 11.4 mmol, 1 eq) in THF (30 mL) was added NaHMDS (1 M, 13.7 mL, 1.2 eq) at −78° C. under N2. The mixture was stirred at 0° C. for 30 minutes. NFSI (5.46 g, 17.3 mmol, 1.52 eq) was added to the mixture at −78° C. The mixture was stirred at −78° C. for 30 minutes. TLC (petroleum ether/EtOAc=5/1) indicated 1-bromo-4-isopropylsulfonyl-benzene was consumed completely and one major new spot with lower polarity was detected. The reaction mixture was with H2O (20 mL) and extracted with EtOAc (90 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0˜10% EtOAc/petroleum ether gradient @60 mL/min) to give desired 1-bromo-4-(1-fluoro-1-methyl-ethyl)sulfonyl-benzene (750 mg, 2.67 mmol, 23.40% yield) as a yellow oil. MS (ESI): mass calcd. For C9H10BrFO2S 279.96, m/z found 204.8 [M−74+H]+.

Step 2: A mixture of 1-bromo-4-(1-fluoro-1-methyl-ethyl)sulfonyl-benzene (750 mg, 2.67 mmol, 1 eq), phenylmethanethiol (364 mg, 2.93 mmol, 344 μL, 1.1 eq), DIEA (690 mg, 5.34 mmol, 929 μL, 2 eq), Pd(dppf)C12 (48.8 mg, 66.7 μmol, 0.025 eq) and Xantphos (154 mg, 267 μmol, 0.1 eq) in Tol. (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110° C. for 12 hours under the atmosphere of nitrogen. TLC (petroleum ether/EtOAc=3/1) indicated 1-bromo-4-(1-fluoro-1-methyl-ethyl)sulfonyl-benzene was consumed completely and three new spots formed. The reaction mixture was concentrated under reduced pressure to remove Tol. The reaction mixture was added to water (10 mL), extracted with EtOAc (30 mL). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/EtOAc=3/1) to give desired 1-benzylsulfanyl-4-(1-fluoro-1-methyl-ethyl)sulfonyl-benzene (830 mg, 2.56 mmol, 95.9% yield) as a yellow oil.

Step 3: To a solution of 1-benzylsulfanyl-4-(1-fluoro-1-methyl-ethyl)sulfonyl-benzene (830 mg, 2.56 mmol, 1 eq) in AcOH (6 mL) and H2O (1.5 mL) was added NCS (1.02 g, 7.67 mmol, 3 eq) at 0° C. The mixture was stirred at 20° C. for 12 hours. TLC (petroleum ether/EtOAc=3/1) indicated 1-benzylsulfanyl-4-(1-fluoro-1-methyl-ethyl)sulfonyl-benzene was consumed completely and three new spots formed. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (10 mL). The combined organic layers were washed with brine (6 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether/EtOAc=3/1) to give 4-(1-fluoro-1-methyl-ethyl)sulfonylbenzenesulfonyl chloride (440 mg, 1.46 mmol, 57.19% yield) as a white solid.

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 had completely dissolved and then cooled to 25° C. A solution of 1-(4-fluorophenyl) ethanone (8 g, 57.9 mmol, 7.02 mL, 1 eq) in EtOH (20 mL) was then added dropwise and the mixture was heated to 100° C. for 7 hours. TLC (petroleum ether/EtOAc=5/1) indicated 1-(4-fluorophenyl) ethanone was consumed completely and one new spot formed. The crude was added H2O (100 mL), and extracted with EtOAc (100 mL*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/EtOAc=5/1) to give desired 1-(4-benzylsulfanylphenyl) ethanone (14 g, crude) as a brown oil.

Step 2: To a solution of 1-(4-benzylsulfanylphenyl) ethanone (12 g, 49.5 mmol, 1 eq) in DAST (120 mL). The mixture was stirred at 70° C. for 1 hour. TLC (petroleum ether/EtOAc=5/1) indicated 1-(4-benzylsulfanylphenyl) ethanone was consumed completely two new spots formed. Then it was partitioned between water (200 mL) and EtOAc (150 mL*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 desired 1-benzylsulfanyl-4-(1, 1-difluoroethyl) benzene (2.5 g, 9.46 mmol, 19.1% yield) as a white solid.

Step 3: To a solution of 1-benzylsulfanyl-4-(1, 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 1-benzylsulfanyl-4-(1, 1-difluoroethyl) benzene was consumed completely and desired mass was detected (The sample was 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 desired 4-(1, 1-difluoroethyl) benzenesulfonyl chloride (1.33 g, 5.53 mmol, 58.4% yield) as a yellow oil. MS (ESI): mass calcd. For C8H7F2SO2Cl 239.98, mass found 290.1[M+49+H]+.

Step 1: To a solution of 4-bromobenzenethiol (2.0 g, 10.6 mmol, 1 eq) in DCM (10 mL) was added KOH (17.8 g, 63.5 mmol, 20% purity, 6 eq) with vigorous stirring. Then a solution of [bromo (difluoro) methyl]-trimethyl-silane (4.30 g, 21.2 mmol, 2 eq) in DCM (10 mL) was added into the mixture at 0° C. The mixture was stirred at 0° C. for 30 min. TLC (petroleum ether/Ethyl acetate=1/0) indicated 4-bromobenzenethiol remained and one new spot formed. The reaction was clean according to TLC. The reaction mixture was added to water (50 mL), extracted with EtOAc (30 mL*3). The combined organic layers were washed with brine 20 mL and dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 1-bromo-4-(difluoromethylsulfanyl)benzene (2.7 g, crude) as a colourless oil.

Step 2: To a solution of 1-bromo-4-(difluoromethylsulfanyl) benzene (2.7 g, 11.3 mmol, 1 eq) in DCM (30 mL) was added m-CPBA (6.88 g, 33.9 mmol, 85% purity, 3 eq) at 0° C. The mixture was stirred at 20° C. for 1 hour. TLC (petroleum ether/Ethyl acetate=5/1) indicated 1-bromo-4-(difluoromethylsulfanyl) benzene was consumed completely and one new spot formed. The reaction was clean according to TLC. Then it was partitioned between 30 mL of sat. Na2SO3 and 100 mL of DCM. The organic phase was separated, washed with 30 mL of sat. NaHCO3, 30 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether/Ethyl acetate=1/0 to 10/1) to give desired 1-bromo-4-(difluoromethylsulfonyl) benzene (2 g, crude) as a yellow oil.

Step 4: To a solution of 1-benzylsulfanyl-4-(difluoromethylsulfonyl) benzene (50 mg, 159 μmol, 1 eq) in HCl (1 mL, 10% purity) was gradually introduced C12 (5.00 g, 70.5 mmol, 443 eq) (15 psi) at −10° C. for 0.5 hour, and a white solid gradually precipitated; After the chlorine gas is stopped, the excess chlorine gas is purged with nitrogen at −10° C. for 0.5 hour. LC-MS showed 1-benzylsulfanyl-4-(difluoromethylsulfonyl) benzene was consumed completely and desired mass was detected. The crude was added NaHSO3 (10 mL), and extracted with EtOAc 30 mL (10 mL*3). The combined organic layers were washed with brine 10 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 4-(difluoromethylsulfonyl)benzenesulfonyl chloride (100 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C7H5ClF2O4S 289.93, m/z found 300.0 [M+H+9]+.

Step 1: To a solution of pyrrole (500 mg, 7.45 mmol, 517 μL, 1 eq) in THF (20 mL) was added hexamethyldisiliconyl potassium amino (KHMDS) (1 M, 7.45 mL, 1 eq) slowly at 0° C. under N2. The reaction mixture was stirred at 0° C. for 30 mins under N2. Then to the reaction mixture was added propane-2-sulfonyl chloride (1.06 g, 7.45 mmol, 830 μL, 1 eq) slowly at 0° C. under N2. The reaction mixture was warmed to 30° C. and stirred at 30° C. for 16 hours under N2. LC-MS showed pyrrole was consumed completely and desired mass was detected. The reaction mixture was partitioned between 100 mL of H2O and 100 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 desired 1-isopropylsulfonylpyrrole (900 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C7H11NO2S 173.05, m/z found 174.0 [M+H]+.

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 1 hour. TLC indicated methyl 3-[methoxy (methyl) carbamoyl]bicycle [1.1.1]pentane-1-carboxylate was consumed completely and one new spot formed. The reaction mixture was quenched by addition saturated aqueous NH4Cl (50 mL) at 0° C. slowly under N2 and stirred at 25° C. for 15 mins. THF was removed under vacuum. The resulting solution was diluted with water (30 mL), extracted with EtOAc (30 mL*3). The combined organic phase was washed with brine (30 mL*2), dried over Na2SO4, filtered and concentrated in vacuum. 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 desired methyl 3-acetylbicyclo[1.1.1]pentane-1-carboxylate (700 mg, 4.16 mmol, 49.30% yield) as a light yellow solid.

Step 4: To a solution of methyl 3-(1, 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-(1, 1-difluoroethyl) bicycle [1.1.1]pentane-1-carboxylate was consumed completely and one new spot formed. The pH value of the reaction mixture was adjust to 3˜4 with 1N HCl, then the reaction mixture was partitioned between H2O (30 mL) and EtOAc (20 mL*3). The organic phase was separated, washed with brine (15 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 3-(1,1-difluoroethyl) bicycle [1.1.1]pentane-1-carboxylic acid (300 mg, crude) as a white solid.

Step 7: The solution of (2-thioxo-1-pyridyl) 3-(1, 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 the solution was irradiated with a 2000 W halogen lamp under argon atmosphere at 20° C. for 2 hours. LCMS showed (2-thioxo-1-pyridyl) 3-(1, 1-difluoroethyl) bicycle [1.1.1]pentane-1-carboxylate was consumed completely and desired mass was detected. 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/petroleum ether gradient @80 mL/min) to give desired 2-[[3-(1, 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]+.

Step 9: To the solution of NaH (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 solution was stirred at 0° C. for 1 hour. To the solution was added 2-[[3-(1, 1-difluoroethyl)-1-bicyclo [1.1.1]pentanyl]sulfonyl]pyridine (100 mg, 366 μmol, 1 eq) and the solution was stirred at 20° C. for 11 hours. TLC showed 2-[[3-(1, 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 desired [3-(1, 1-difluoroethyl)-1-bicyclo [1.1.1]pentanyl]sulfinyloxysodium (40 mg, crude) as a white solid.

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

Step 3: The mixture of (2-thioxo-1-pyridyl) 3-(trifluoromethyl) bicycle [1.1.1]pentane-1-carboxylate (2 g, 6.91 mmol, 1 eq) in Tol. (50 mL) was degassed and purged with Ar for 3 times, and then was added 2-(2-pyridyldisulfanyl)pyridine (3.81 g, 17.3 mmol, 2.5 eq) at 0° C., and then the mixture was stirred at 25° C. for 2 hours under argon atmosphere under 1000 w lamp. LCMS showed (2-thioxo-1-pyridyl) 3-(trifluoromethyl) bicycle [1.1.1]pentane-1-carboxylate was consumed completely and desired mass was detected. The reaction was concentrated to get a residue. The residue was added water (30 mL) and extracted with EtOAc (3*50 mL). The residue was purified by column chromatography (SiO2, petroleum ether/Ethyl acetate=97/3 to 90:10) to give 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]+.

Step 5: The mixture of NaH (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, and the mixture was stirred at 0° C. for 1 hour, and then the mixture was added 2-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]sulfonyl]pyridine (1.1 g, 3.97 mmol, 1 eq) at 0° C., and then the mixture was stirred at 25° C. for 11 hours under Ar atmosphere. TLC (petroleum ether/Ethyl acetate=3/1) indicated 2-[[3-(trifluoromethyl)-1-bicyclo [1.1.1]pentanyl]sulfonyl]pyridine was consumed completely and one new spot 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 desired [3-(trifluoromethyl)-1-bicyclo [1.1.1]pentanyl]sulfinyloxysodium (500 mg, 2.25 mmol, 56.7% yield) as a white solid.

Step 2: The mixture of sodium; 1-oxidopyridin-1-ium-2-thiolate (4.34 g, 29.1 mmol, 3.55 mL, 1.2 eq) in Tol. (50 mL) was degassed and purged with Ar for 3 times, and then was added 3-fluorobicyclo [1.1.1]pentane-1-carbonyl chloride (3.6 g, 24.2 mmol, 1 eq) at −10° C., and then the mixture was stirred at 0° C. for 1 hour under Ar atmosphere keep in dark place. LCMS showed sodium; 1-oxidopyridin-1-ium-2-thiolate was consumed completely and desired mass was detected. The reaction mixture was concentrated to give desired (2-thioxo-1-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]+.

Step 3: The mixture of (2-thioxo-1-pyridyl) 3-fluorobicyclo [1.1.1]pentane-1-carboxylate (3.6 g, 15.1 mmol, 1 eq) in Tol. (100 mL) was degassed and purged with Ar for 3 times, and then was added 2-(2-pyridyldisulfanyl)pyridine (8.29 g, 37.6 mmol, 2.5 eq) at 0° C., and then the mixture was stirred at 25° C. for 2 hours under argon atmosphere under 1000 w lamp. LCMS showed (2-thioxo-1-pyridyl) 3-fluorobicyclo [1.1.1]pentane-1-carboxylate was consumed completely and desired mass was detected. The reaction was concentrated to get a residue. The residue was added water (30 mL) and extracted with EtOAc (3*50 mL). The residue was purified by column chromatography (SiO2, petroleum ether/Ethyl acetate=93/7 to 90/10). The reaction mixture was concentrated to give desired 2-[(3-fluoro-1-bicyclo [1.1.1]pentanyl) sulfanyl]pyridine (600 mg, 3.07 mmol, 20.4% yield) as a yellow solid. MS (ESI): mass calcd. For C10H10FNS 195.05 m/z found 196.2 [M+H]+.

Step 5: The mixture of NaH (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, and the mixture was stirred at 0° C. for 1 hour, and then the mixture was added 2-[(3-fluoro-1-bicyclo [1.1.1]pentanyl) sulfonyl]pyridine (500 mg, 2.20 mmol, 1 eq) at 0° C., and then the mixture was stirred at 25° C. for 11 hours under Ar atmosphere. TLC (petroleum ether/Ethyl acetate=3/1) indicated 2-[(3-fluoro-1-bicyclo [1.1.1]pentanyl) sulfonyl]pyridine was consumed completely and one new spot 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 concentrated under reduced pressure to give a residue. The reaction mixture was concentrated to give desired (3-fluoro-1-bicyclo [1.1.1]pentanyl) sulfinyloxysodium (340 mg, 1.97 mmol, 89.8% yield) as a white solid.

Step 3: To a solution of 5-benzylsulfanyl-2-(1, 1-difluoroethyl) pyridine (130 mg, 490 μmol, 1 eq) in AcOH (0.8 mL) and H2O (0.2 mL) was added NCS (262 mg, 1.96 mmol, 4 eq) at 0° C. The mixture was stirred at 15° C. for 1 hour. LC-MS showed 5-benzylsulfanyl-2-(1, 1-difluoroethyl) pyridine was consumed completely and desired mass was detected. TLC indicated 5-benzylsulfanyl-2-(1, 1-difluoroethyl) pyridine was consumed completely one new spot formed. 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 (SiO2, petroleum ether/EtOAc=5/1) to give desired 6-(1, 1-difluoroethyl) pyridine-3-sulfonyl chloride (44 mg, 182 μmol, 37.2% yield) as a white solid. MS (ESI): mass calcd. For C7H6ClF2NO2S 241.0, m/z found 564.1 [M+H]+.

Step 1: To a solution of 2, 4-dibromothiazole (2.48 g, 10.2 mmol, 1 eq) in EtOH (30 mL) was added isopropylsulfanylsodium (1 g, 10.2 mmol, 2.95 mL, 1 eq). The mixture was stirred at 30° C. for 1 hour. LC-MS showed 2, 4-dibromothiazole was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was purified by prep-TLC (SiO2, petroleum ether/EtOAc=10/1) to give desired 4-bromo-2-isopropylsulfanyl-thiazole (1.46 g, 6.13 mmol, 60.2% yield) as a white solid. MS (ESI): mass calcd. For C6H8BrNS2 236.93, m/z found 238.0 [M+H]+.

Step 2: To a solution of 4-bromo-2-isopropylsulfanyl-thiazole (1.46 g, 6.13 mmol, 1 eq) in DCM (25 mL) was added m-CPBA (7.47 g, 36.8 mmol, 85% purity, 6 eq) at 0° C. The mixture was stirred at 20° C. for 0.5 hour. LC-MS showed 4-bromo-2-isopropylsulfanyl-thiazole was consumed completely and one main peak with desired mass was detected. Then it was partitioned between 150 mL of sat. Na2SO3 and 300 mL of DCM. The organic phase was separated, washed with 150 mL of sat. NaHCO3, 15 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 4-bromo-2-isopropylsulfonyl-thiazole (2.4 g, crude) as a white solid. MS (ESI): mass calcd. For C6H8BrNO2S2 268.92, m/z found 270.0 [M+H]+.

Step 4: To a solution of 4-benzylsulfanyl-2-isopropylsulfonyl-thiazole (300 mg, 957 μmol, 1 eq) in AcOH (8 mL) and H2O (2 mL) was added NCS (383 mg, 2.87 mmol, 3 eq) at 0° C. The mixture was stirred at 20° C. for 12 hours. TLC (petroleum ether/EtOAc=2/1) indicated 4-benzylsulfanyl-2-isopropylsulfonyl-thiazole was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was diluted with water (15 mL) and extracted with EtOAc (30 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/EtOAc=2/1) to give desired 2-isopropylsulfonylthiazole-4-sulfonyl chloride (210 mg, 725 μmol, 75.7% yield) as a yellow oil.

Step 1: To a solution of pyrrole (2 g, 29.8 mmol, 2.07 mL, 1 eq) in THF (20 mL) was added KHMDS (1 M, 29.8 mL, 1 eq) slowly at 0° C. under N2. The reaction mixture was stirred at 0° C. for 30 mins under N2. Then to the reaction mixture was added N, N-dimethylsulfamoyl chloride (4.28 g, 29.8 mmol, 3.19 mL, 1 eq) slowly at 0° C. under N2. The reaction mixture was warmed to 30° C. and stirred at 30° C. for 12 hours under N2. LC-MS showed pyrrole was consumed completely and desired mass was detected. The reaction mixture was partitioned between 200 mL of H2O and 200 mL of EtOAc. The organic phase was separated, washed with 100 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give desired N, N-dimethylpyrrole-1-sulfonamide (5.4 g, crude) as a yellow oil. MS (ESI): mass calcd. For C6H10N2O2S 174.05, m/z found 175.0 [M+H]+.

Step 2: To a solution of N, N-dimethylpyrrole-1-sulfonamide (2.5 g, 14.4 mmol, 1 eq) in ACN (40 mL) was added HSO3Cl (3.34 g, 28.7 mmol, 1.91 mL, 2 eq) slowly at 0° C. The mixture was stirred at 80° C. for 2 hours. TLC (SiO2, petroleum ether/EtOAc=3/1) indicated N, N-dimethylpyrrole-1-sulfonamide was consumed completely and one new spot formed. The reaction mixture was quenched by addition water (100 mL) at 0° C., and then diluted with water (100 mL) and extracted with EtOAc (100 mL). 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 column chromatography (SiO2, petroleum ether/Ethyl acetate=1/0 to 1/1) to give desired 1-(dimethylsulfamoyl) pyrrole-3-sulfonyl chloride (160 mg, crude) as a yellow oil.

Step 2: To the solution of 2, 3, 4, 5-tetradeuterio-1-isopropylsulfonyl-pyrrole (500 mg, 2.82 mmol, 1 eq) in ACN (10 mL) was added HSO3Cl (1.64 g, 14.1 mmol, 5 eq) and the solution was stirred at 80° C. for 1 hour. The reaction was poured into water (20 mL) and extracted with MTBE (2*10 mL). The combined organics were concentrated to get a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0˜20% Ethylacetate/petroleum ether gradient @50 mL/min) to give desired 2, 4, 5-trideuterio-1-isopropylsulfonyl-pyrrole-3-sulfonyl chloride (173 mg, 630 μmol, 22.32% yield) as a white solid.

Step 2: To the solution of 1-tert-butylsulfonylpyrrole (4.2 g, 22.4 mmol, 1 eq) in ACN (100 mL) was added HSO3Cl (13.1 g, 112 mmol, 7.47 mL, 5 eq) at 0° C. and the solution was stirred at 20° C. for 12 hours. TLC (SiO2, petroleum ether/Ethyl acetate=2/1) showed 1-tert-butylsulfonylpyrrole was consumed completely and a new spot. The reaction was added into water (10 mL) and extracted with MTBE (3*10 mL). The organics were 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% Ethylacetate/petroleum ether gradient @80 mL/min) to give desired 1-tert-butylsulfonylpyrrole-3-sulfonyl chloride (580 mg, crude) as a white solid.

Step 1: To a solution of pyrrole (2 g, 29.8 mmol, 2.07 mL, 1 eq) in THF (20 mL) was added KHMDS (1 M, 29.8 mL, 1 eq) slowly at 0° C. under N2. The reaction mixture was stirred at 0° C. for 30 mins under N2. Then to the reaction mixture was added cyclopropanesulfonyl chloride (4.19 g, 29.8 mmol, 3.32 mL, 1 eq) slowly at 0° C. under N2. The reaction mixture was warmed to 30° C. and stirred at 30° C. for 12 hours under N2. LC-MS showed pyrrole was consumed completely and desired mass was detected. The reaction mixture was partitioned between H2O (100 mL) and EtOAc (100 mL). The organic phase was separated, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0˜5% EtOAc/petroleum ether gradient @100 mL/min) to give desired 1-cyclopropylsulfonylpyrrole (2.2 g, 12.9 mmol, 43.1% yield) as a yellow oil. MS (ESI): mass calcd. For C7H9NO2S 171.04, m/z found 172.1 [M+H]+.

Step 2: To a solution of 1-cyclopropylsulfonylpyrrole (2.2 g, 12.9 mmol, 1 eq) in ACN (25 mL) was added HSO3Cl (2.99 g, 25.7 mmol, 1.71 mL, 2 eq) slowly at 0° C. The mixture was stirred at 25° C. for 12 hours. TLC (petroleum ether/EtOAc=3/1) indicated 1-cyclopropylsulfonylpyrrole was consumed completely and one new spot formed. The reaction mixture was quenched by addition water (30 mL) at 0° C., and then diluted with water (50 mL) and extracted with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 1-cyclopropylsulfonylpyrrole-3-sulfonyl chloride (680 mg, crude) as a black oil.

Step 1: To a solution of 3-bromo-1H-pyrazole (2 g, 13.6 mmol, 1 eq) in THF (10 mL) was added KHMDS (1 M, 13.6 mL, 1 eq) slowly at 0° C. under N2. The mixture was stirred at 0° C. for 30 mins under N2 atmosphere. Then the reaction mixture was added propane-2-sulfonyl chloride (1.94 g, 13.6 mmol, 1.52 mL, 1 eq) slowly at 0° C. under N2. The mixture was warmed to 30° C. and stirred at 30° C. for 12 hours. LC-MS showed 3-bromo-1H-pyrazole was consumed completely and desired mass was detected. The reaction mixture was quenched by addition NH4Cl solvent (40 mL) at 0° C., and then diluted with H2O (20 mL) and extracted with EtOAc (40 mL). The combined organic layers were dried over anhydrous 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˜1% DCM/MeOH @40 mL/min) to give desired 3-bromo-1-isopropylsulfonyl-pyrazole (2.95 g, 11.7 mmol, 85.7% yield) as a yellow oil. MS (ESI): mass calcd. For C6H9BrN2O2S 251.96 m/z found 252.9 [M+H]+.

Step 3: To a solution of 3-benzylsulfanyl-1-isopropylsulfonyl-pyrazole (2.0 g, 6.75 mmol, 1 eq) in AcOH (20 mL) and H2O (5 mL) was added NCS (2.70 g, 20.2 mmol, 3 eq) at 0° C. The mixture was stirred at 20° C. for 12 hours. TLC (petroleum ether/Ethyl acetate=2/1) indicated 4-benzylsulfanyl-2-isopropylsulfonyl-thiazole was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was diluted with H2O (10 mL) and extracted with EtOAc (20 mL). The combined organic layers were washed with saline (20 mL), dried over anhydrous 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˜23% EtOAc/petroleum ether gradient @120 mL/min) to give desired 1-isopropylsulfonylpyrazole-3-sulfonyl chloride (900 mg, 3.30 mmol, 48.9% yield) as a white solid.

Step 1: To a solution of propane-2-sulfonyl chloride (1.50 g, 10.5 mmol, 1.17 mL, 1 eq) in THF (20 mL) was added KHMDS (1 M, 10.5 mL, 1 eq) slowly at 0° C. under N2. The mixture was stirred at 0° C. for 30 mins under N2. Then to the reaction mixture was added 2, 5-dimethyl-1H-pyrrole (1 g, 10.5 mmol, 1.07 mL, 1 eq) slowly at 0° C. under N2. The reaction mixture was warmed to 25° C. and stirred at 25° C. for 16 hours under N2. LC-MS showed propane-2-sulfonyl chloride was consumed completely and desired mass was detected. The reaction mixture was quenched by addition H2O 40 mL, and extracted with EtOAc 80 mL (20 mL*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 by column chromatography (SiO2, petroleum ether/Ethyl acetate=1/0 to 0/1) to give desired 1-isopropylsulfonyl-2, 5-dimethyl-pyrrole (600 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C9H15NO2S 201.08 m/z found 202.1 [M+H]+.

Step 2: A solution of 1-isopropylsulfonyl-2, 5-dimethyl-pyrrole (300 mg, 1.49 mmol, 1 eq) in CH3CN (5 mL) was cooled to 0° C. followed by the dropwise addition of HSO3Cl (347 mg, 2.98 mmol, 198 μL, 2 eq). The resulting solution was allowed to warm to 25° C. for 12 hours. TLC (SiO2, petroleum ether/Ethyl acetate=3/1) indicated 1-isopropylsulfonyl-2, 5-dimethyl-pyrrole was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The reaction mixture was quenched by addition H2O 40 mL, and extracted with EtOAc 40 mL (10 mL*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 by prep-TLC (SiO2, petroleum ether/Ethyl acetate=3/1) to give desired 1-isopropylsulfonyl-2, 5-dimethyl-pyrrole-3-sulfonyl chloride (40 mg, crude) as a white solid.

Step 2: To a solution of 1-bromo-3-isopropylsulfanyl-benzene (1.2 g, 5.19 mmol, 1 eq) in DCM (10 mL) was added m-CPBA (3.16 g, 15.6 mmol, 85% purity, 3 eq) at 0° C. The mixture was stirred at 20° C. for 1 hour. TLC (petroleum ether/ethyl acetate=3/1) indicated 1-bromo-3-isopropylsulfanyl-benzene was consumed completely and one new spot formed. Then it was partitioned between 30 mL of sat. Na2SO3 and 100 mL of DCM. The organic phase was separated, washed with 30 mL of sat. Na2SO3, 30 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 1-bromo-3-isopropylsulfonyl-benzene (2 g, crude) as a white solid.

Step 3: A mixture of phenylmethanethiol (1.04 g, 8.36 mmol, 980 μL, 1.1 eq), 1-bromo-3-isopropylsulfonyl-benzene (2 g, 7.60 mmol, 1 eq), DIEA (1.96 g, 15.2 mmol, 2.65 mL, 2 eq), Xantphos (440 mg, 760 μmol, 0.1 eq) and Pd(dppf)C12 (139 mg, 190 μmol, 0.025 eq) in Tol. (20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110° C. for 12 hours under the atmosphere of nitrogen. TLC (petroleum ether/ethyl acetate=3/1) indicated phenylmethanethiol was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to remove Tol. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 1/1) to give desired 1-benzylsulfanyl-3-isopropylsulfonyl-benzene (1.2 g, crude) as an orange oil.

Step 4: To a solution of 1-benzylsulfanyl-3-isopropylsulfonyl-benzene (1.2 g, 3.92 mmol, 1 eq) in AcOH (10 mL) and H2O (2.5 mL) was added NCS (1.57 g, 11.8 mmol, 3 eq) at 0° C. The mixture was stirred at 20° C. for 12 hours. TLC (petroleum ether/ethyl acetate=3/1) showed 1-benzylsulfanyl-3-isopropylsulfonyl-benzene was consumed completely and one major new spot with larger polarity was detected. The reaction mixture was diluted with water 50 mL and extracted with EtOAc (50 mL*3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 0/1) to give desired 3-isopropylsulfonylbenzenesulfonyl chloride (600 mg, crude) as a white solid.

Step 2: To a solution of N—[(E)-[[4-(5-chloropyrimidin-2-yl)-2-cyclopropyl-piperazin-1-yl]-(2, 6-dichlorophenyl) methylene]amino]-4-methyl-benzenesulfonamide (470 mg, 810 μmol, 1 eq) in DMF (5 mL) was added K2CO3 (1.12 g, 8.10 mmol, 10 eq). The mixture was stirred at 100° C. for 12 hours. LC-MS showed N—[(E)-[[4-(5-chloropyrimidin-2-yl)-2-cyclopropyl-piperazin-1-yl]-(2, 6-dichlorophenyl) methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and 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 desired 4-chloro-3-[4-(5-chloropyrimidin-2-yl)-2-cyclopropyl-piperazin-1-yl]-1-(p-tolylsulfonyl)indazole (700 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C25H24C12N6O2S 542.11, m/z found 543.1 [M+H]+.

Step 3: To a solution of 4-chloro-3-[4-(5-chloropyrimidin-2-yl)-2-cyclopropyl-piperazin-1-yl]-1-(p-tolylsulfonyl) indazole (700 mg, 1.29 mmol, 1 eq) in MeOH (10 mL) was added K2CO3 (890 mg, 6.44 mmol, 5 eq). The mixture was stirred at 80° C. for 1 hour. LC-MS showed 4-chloro-3-[4-(5-chloropyrimidin-2-yl)-2-cyclopropyl-piperazin-1-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and 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 (SiO2, petroleum ether/ethyl acetate=2/1) to give desired 4-chloro-3-[4-(5-chloropyrimidin-2-yl)-2-cyclopropyl-piperazin-1-yl]-1H-indazole (80 mg, 206 μmol, 16.0% yield) as a yellow solid. MS (ESI): mass calcd. For C18H18C12N6 388.1 m/z found 389.1 [M+H]+.

Step 3: To a solution of 1-(4, 7-diazaspiro [2.5]octan-7-yl)-2, 2, 2-trifluoro-ethanone (1.09 g, 4.45 mmol, 1.2 eq, HCl) in THF (5 mL) was added TEA (1.13 g, 11.1 mmol, 1.55 mL, 3 eq). The mixture was stirred at 0° C. for 20 minutes. Then (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (1.4 g, 3.71 mmol, 1 eq) was added to the mixture at 0° C. The mixture was stirred at 20° C. for 40 minutes. LC-MS showed (1E)-2, 6-dichloro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (60 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give desired N—[(E)-[(2,6-dichlorophenyl)-[7-(2,2,2-trifluoroacetyl)-4,7-diazaspiro[2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (2 g, crude) as a yellow oil. MS (ESI): mass calcd. For C22H21Cl2F3N4O3S 548.07 m/z found 549.1 [M+H]+.

Step 4: To a solution of N—[(E)-[(2,6-dichlorophenyl)-[7-(2,2,2-trifluoroacetyl)-4,7-diazaspiro[2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (2 g, 3.64 mmol, 1 eq) in DMF (20 mL) was added K2CO3 (5.03 g, 36.4 mmol, 10 eq). The mixture was stirred at 80° C. for 12 hours. LC-MS showed N—[(E)-[(2,6-dichlorophenyl)-[7-(2,2,2-trifluoroacetyl)-4,7-diazaspiro[2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (150 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous 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˜25% EtOAc/Petroleum ether gradient @50 mL/min) to give desired 1-[4-[4-chloro-1-(p-tolylsulfonyl)indazol-3-yl]-4,7-diazaspiro[2.5]octan-7-yl]-2,2,2-trifluoro-ethanone (860 mg, 1.68 mmol, 46.1% yield) as a pale yellow oil. MS (ESI): mass calcd. For C22H20ClF3N4O3S 512.09 m/z found 513.1 [M+H]+.

Step 6: To a solution of 4-chloro-1-(p-tolylsulfonyl)-3-[7-(2, 2, 2-trifluoroethyl)-4, 7-diazaspiro [2.5]octan-4-yl]indazole (150 mg, 301 μmol, 1 eq) in MeOH (5 mL) was added K2CO3 (208 mg, 1.50 mmol, 5 eq). The mixture was stirred at 50° C. for 1 hour. LC-MS showed 4-chloro-1-(p-tolylsulfonyl)-3-[7-(2, 2, 2-trifluoroethyl)-4, 7-diazaspiro [2.5]octan-4-yl]indazole was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (5 mL) and extracted with EtOAc (30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/EtOAc=2/1) to give desired 4-chloro-3-[7-(2, 2, 2-trifluoroethyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1H-indazole (80 mg, 232 μmol, 77.2% yield) as a colorless oil. MS (ESI): mass calcd. For C15H16ClF3N4 344.10 m/z found 345.0 [M+H]+.

Step 3: To a solution of 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-7-oxa-4-azaspiro[2.5]octane (278 mg, 665 μmol, 1 eq) in MeOH (5 mL) was added K2CO3 (460 mg, 3.33 mmol, 5 eq). The mixture was stirred at 80° C. for 1 hour. LC-MS showed 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-7-oxa-4-azaspiro [2.5]octane was consumed completely and 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 (SiO2, petroleum ether:EtOAc=2:1) to give desired 4-(4-chloro-1H-indazol-3-yl)-7-oxa-4-azaspiro [2.5]octane (90 mg, 341 μmol, 51.30% yield) as a yellow solid. MS (ESI): mass calcd. For C13H14ClN3O 263.08 m/z found 264.1 [M+H]+.

Step 1: To the solution of 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-4-azaspiro [2.5]octan-7-one (100 mg, 233 μmol, 1 eq) in EtOH (2 mL) was added NaBH4 (70 mg, 1.85 mmol, 7.95 eq) at 0° C. and the solution was stirred at 20° C. for 1 hour. TLC showed 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-4-azaspiro [2.5]octan-7-one was consumed completely. The reaction was quenched with NH4Cl solution (2 mL) and stirred for 15 minutes. The mixture was concentrated to get a residue. The residue was added water (2 mL) and extracted with EtOAc (2*5 mL). The combined organics were dried over anhydrous sodium sulfate and concentrated to give desired 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-4-azaspiro [2.5]octan-7-ol (100 mg, crude) as a yellow solid.

Step 3: The mixture of 4-chloro-3-(7-fluoro-4-azaspiro [2.5]octan-4-yl)-1-(p-tolylsulfonyl)indazole (96.0 mg, 221 μmol, 1 eq) and K2CO3 (305 mg, 2.21 mmol, 10 eq) in MeOH (2 mL) was stirred at 50° C. for 1 hour. LCMS showed 4-chloro-3-(7-fluoro-4-azaspiro [2.5]octan-4-yl)-1-(p-tolylsulfonyl)indazole remained and desired mass was detected. The reaction was concentrated to get a residue. The residue was added water (5 mL) and extracted with MTBE (2*20 mL). The combined organics were concentrated to get a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/ethyl acetate=2/1) to give desired 4-chloro-3-(7-fluoro-4-azaspiro [2.5]octan-4-yl)-1H-indazole (30 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C14H15N3ClF 279.09, m/z found 280.1 [M+H]+.

Step 2: The mixture of 4-chloro-3-(7, 7-difluoro-4-azaspiro [2.5]octan-4-yl)-1-(p-tolylsulfonyl) indazole (105 mg, 233 μmol, 1 eq) and K2CO3 (321 mg, 2.32 mmol, 10 eq) in MeOH (2 mL) was stirred at 50° C. for 1 hour. LCMS showed 4-chloro-3-(7, 7-difluoro-4-azaspiro [2.5]octan-4-yl)-1-(p-tolylsulfonyl) indazole was consumed completely and desired mass was detected. The reaction was concentrated to get a residue. The residue was added water (5 mL) and extracted with MTBE (2*20 mL). The combined organics were concentrated to get a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/ethyl acetate=2/1) to give desired 4-chloro-3-(7, 7-difluoro-4-azaspiro [2.5]octan-4-yl)-1H-indazole (10 mg, crude) was a yellow oil. MS (ESI): mass calcd. For C14H14N3ClF2 297.08 m/z found 298.0 [M+H]+.

Step 3: To a solution of 3-[7-(5-chloropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]-4-fluoro-1-(p-tolylsulfonyl) indazole (400 mg, 780 μmol, 1 eq) in MeOH (20 mL) was added K2CO3 (539 mg, 3.90 mmol, 5 eq). The mixture was stirred at 80° C. for 0.5 hour. TLC showed 3-[7-(5-chloropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]-4-fluoro-1-(p-tolylsulfonyl) indazole was consumed completely and a new spot. The reaction mixture was added to water (20 mL), the aqueous phase was extracted with EtOAc (15 mL*3). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/Ethyl acetate=2/1) to give desired 3-(7-(5-chloropyrimidin-2-yl)-4,7-diazaspiro[2.5]octan-4-yl)-4-fluoro-1H-indazole (85 mg, 237 μmol, 30.38% yield) as a brown oil.

Step 3: To a solution of 4-fluoro-3-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (400 mg, 806 μmol, 1 eq) in MeOH (20 mL) was added K2CO3 (557 mg, 4.03 mmol, 5 eq). The mixture was stirred at 80° C. for 0.5 hour. TLC showed 4-fluoro-3-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and a new spot. The reaction mixture was added to water (20 mL), the aqueous phase was extracted with EtOAc (15 mL*3). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/Ethyl acetate=2/1) to give desired 4-fluoro-3-(7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl)-1H-indazole (85 mg, 248 μmol, 30.8% yield) as a brown oil.

Step 1: To the solution of 4-azaspiro[2.4]heptane (0.15 g, 1.12 mmol, 1 eq, HCl) in THF (3 mL) was added TEA (1.14 g, 11.2 mmol, 1.56 mL, 10 eq) at 15° C. and the solution was stirred at 15° C. for 0.5 hour. To the reaction mixture was added (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (424 mg, 1.12 mmol, 1 eq) at −15° C. and the solution was stirred at 15° C. for 0.5 hour. LC-MS showed 4-azaspiro [2.4]heptane was consumed completely and one main peak with desired mass was detected. Then it was separated between water (20 mL) and ethyl acetate (15 mL*3). The organic phase was separated, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give desired (E)-N′-((2,6-dichlorophenyl)(4-azaspiro[2.4]heptan-4-yl)methylene)-4-methylbenzenesulfonohydrazide (492 mg, crude) as a brown oil. MS (ESI): mass calcd. For C20H21C12N3O2S 437.07, m/z found 438.1 [M+H]+.

Step 3: The mixture of 3-(4-azaspiro [2.4]heptan-4-yl)-4-chloro-1-(p-tolylsulfonyl) indazole (451 mg, 1.12 mmol, 1 eq) and K2CO3 (775 mg, 5.61 mmol, 5 eq) in MeOH (5 mL) was stirred at 50° C. for 1 hour. LC-MS showed 3-(4-azaspiro [2.4]heptan-4-yl)-4-chloro-1-(p-tolylsulfonyl) indazole was consumed completely and desired mass was detected. The reaction mixture was added to water (20 mL), the aqueous phase was extracted with EtOAc (15 mL*3). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/Ethyl acetate=2/1) to give desired 4-chloro-3-(4-azaspiro [2.4]heptan-4-yl)-1H-indazole (100 mg, crude) as a brown oil. MS (ESI): mass calcd. For C13H14ClN3 247.09, m/z found 248.1 [M+H]+.

Step 1: To a solution of 7-(5-fluoro-2-pyridyl)-4,7-diazaspiro[2.5]octane (250 mg, 1.21 mmol, 1 eq) in THF (3 mL) was added TEA (1.22 g, 12.1 mmol, 1.68 mL, 10 eq) dropwise at 25° C. After addition, the mixture was stirred at this temperature for 10 minutes, and then (1Z)-2, 6-difluoro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride (459 mg, 1.33 mmol, 1.1 eq) in THF (3 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 20 minutes. LC-MS showed 7-(5-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octane was consumed completely and one main peak with 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, filtered and concentrated under reduced pressure to give desired N—[(Z)-[(2,6-difluorophenyl)-[7-(5-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (750 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C25H24F3N5O2S 515.15, m/z found 516.1 [M+H]+.

Step 2: To a solution of N—[(Z)-[(2, 6-difluorophenyl)-[7-(5-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (750 mg, 1.45 mmol, 1 eq) in DMF (10 mL) was added K2CO3 (804 mg, 5.82 mmol, 4 eq). The mixture was stirred at 60° C. for 12 hours. LC-MS showed N—[(Z)-[(2, 6-difluorophenyl)-[7-(5-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and desired mass was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine 20 mL and dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 4-fluoro-3-[7-(5-fluoro-2-pyridyl)-4,7-diazaspiro[2.5]octan-4-yl]-1-(p-tolylsulfonyl)indazole (720 mg, crude) as an orange oil. MS (ESI): mass calcd. For C25H23F2N5O2S 495.15, m/z found 496.0 [M+H]+.

Step 3: To a solution of 4-fluoro-3-[7-(5-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (720 mg, 1.45 mmol, 1 eq) in MeOH (10 mL) was added K2CO3 (1.00 g, 7.26 mmol, 5 eq). The mixture was stirred at 70° C. for 1 hour. LC-MS showed 4-fluoro-3-[7-(5-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and desired compound was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine 20 mL and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/Ethyl acetate=3/1) to give desired 4-fluoro-3-[7-(5-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1H-indazole (180 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C18H17F2N5 341.15, m/z found 342.1 [M+H]+.

Step 1: To a solution of 7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octane (250 mg, 1.11 mmol, 1 eq) in THF (3 mL) was added dropwise TEA (1.12 g, 11.1 mmol, 1.54 mL, 10 eq) at 25° C. After addition, the mixture was stirred at this temperature for 10 minutes, and then (1Z)-2,6-difluoro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride (421 mg, 1.22 mmol, 1.1 eq) in THF (3 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 20 minutes. LC-MS showed 7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octane was consumed completely and one main peak with 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, filtered and concentrated under reduced pressure to give desired N—[(Z)-[(2, 6-difluorophenyl)-[7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (600 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C25H23F4N5O2S 533.15, m/z found 534.1 [M+H]+.

Step 2: To a solution of N—[(Z)-[(2, 6-difluorophenyl)-[7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (600 mg, 1.12 mmol, 1 eq) in DMF (10 mL) was added K2CO3 (622 mg, 4.50 mmol, 4 eq). The mixture was stirred at 60° C. for 50 minutes. LC-MS showed was consumed completely and desired mass was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine 20 mL and dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 3-[7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-4-fluoro-1-(p-tolylsulfonyl)indazole (600 mg, crude) as an orange oil. MS (ESI): mass calcd. For C25H22F3N5O2S 513.14, m/z found 514.0 [M+H]+.

Step 3: To a solution of 3-[7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-4-fluoro-1-(p-tolylsulfonyl) indazole (600 mg, 1.17 mmol, 1 eq) in MeOH (10 mL) was added K2CO3 (807 mg, 5.84 mmol, 5 eq). The mixture was stirred at 70° C. for 1 hour. LC-MS showed 3-[7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-4-fluoro-1-(p-tolylsulfonyl) indazole was consumed completely and desired compound was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine 20 mL and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/Ethyl acetate=3/1) to give desired 3-[7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-4-fluoro-1H-indazole (200 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C18H16F3N5 359.14, m/z found 360.1 [M+H]+.

Step 3: To a solution of 4-chloro-3-[7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-6-fluoro-1-(p-tolylsulfonyl) indazole (1.6 g, 2.83 mmol, 1 eq) in MeOH (20 mL) was added K2CO3 (1.96 g, 14.2 mmol, 5 eq). The mixture was stirred at 70° C. for 0.2 hour. LC-MS showed 4-chloro-3-[7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-6-fluoro-1-(p-tolylsulfonyl) indazole was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude was added H2O (40 mL) and extracted with EtOAc (30 mL*3). The combined organic layers were washed with brine (40 mL), dried over anhydrous 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˜35% EtOAc/petroleum ethergradient @100 mL/min) to give desired 4-chloro-3-(7-(5-chloro-3-fluoropyridin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl)-6-fluoro-1H-indazole (300 mg, 731.27 μmol, 25.80% yield) as a yellow oil. MS (ESI): mass calcd. For C18H15C12F2N5 409.07, m/z found 410.0 [M+H]+.

Step 1: To a solution of 5-chloro-2-(4, 7-diazaspiro [2.5]octan-7-yl)thiazole (244 mg, 918 μmol, 1 eq, HCl) in THF (5 mL) was added dropwise TEA (930 mg, 9.18 mmol, 1.28 mL, 10 eq) at 25° C. After addition, the mixture was stirred at this temperature for 10 minutes, and then (1Z)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (382 mg, 1.01 mmol, 1.1 eq) in THF (2 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 20 minutes. LC-MS showed 5-chloro-2-(4, 7-diazaspiro [2.5]octan-7-yl) thiazole was consumed completely and one main peak with 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, filtered and concentrated under reduced pressure to give desired N—[(Z)—[[7-(5-chlorothiazol-2-yl)-4,7-diazaspiro [2.5]octan-4-yl]-(2,6-dichlorophenyl)methylene]amino]-4-methyl-benzenesulfonamide (520 mg, crude) was obtained as a yellow solid. For C23H22Cl3N5O2S2 569.03, m/z found 570.1 [M+H]+.

Step 3: To a solution of 5-chloro-2-[4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-4, 7-diazaspiro [2.5]octan-7-yl]thiazole (500 mg, 936 μmol, 1 eq) in MeOH (10 mL) was added K2CO3 (652 mg, 4.72 mmol, 5 eq). The mixture was stirred at 70° C. for 1 hour. LC-MS showed 5-chloro-2-[4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-4, 7-diazaspiro [2.5]octan-7-yl]thiazole was consumed completely and desired compound was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/Ethyl acetate=1/0 to 1/1) to give desired 5-chloro-2-[4-(4-chloro-1H-indazol-3-yl)-4, 7-diazaspiro [2.5]octan-7-yl]thiazole (130 mg, 342 μmol) as a yellow oil. MS (ESI): mass calcd. For C16H15C12N5S 379.04, m/z found 379.9 [M+H]+.

Step 1: To a solution of 7-(5-chloro-2-pyridyl)-4,7-diazaspiro[2.5]octane (320 mg, 1.43 mmol, 1 eq) in THF (3 mL) was added dropwise TEA (1.45 g, 14.3 mmol, 1.99 mL, 10 eq) at 25° C. After addition, the mixture was stirred at this temperature for 10 minutes, and then(1Z)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (594 mg, 1.57 mmol, 1.1 eq) in THF (1 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 20 minutes. LC-MS showed 7-(5-chloro-2-pyridyl)-4, 7-diazaspiro [2.5]octane was consumed completely and 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 desired N—[(Z)—[[7-(5-chloro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-(2, 6-dichlorophenyl) methylene]amino]-4-methyl-benzenesulfonamide (980 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C25H24C13N5O2S 563.07 m/z found 564.1 [M+H]+.

Step 3: To a solution of 4-chloro-3-[7-(5-chloro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (980 mg, 1.85 mmol, 1 eq) in MeOH (10 mL) was added K2CO3 (1.28 g, 9.27 mmol, 5 eq). The mixture was stirred at 70° C. for 1 hour. LC-MS showed 4-chloro-3-[7-(5-chloro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and desired mass was detected. The reaction mixture was filtered and the filter liquor was concentrated under reduced pressure to give a residue. 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 column chromatography (SiO2, petroleum ether/Ethyl acetate=10/1 to 2/1) to give desired 4-chloro-3-[7-(5-chloro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1H-indazole (240 mg, 641 μmol, 34.6% yield) as a white oil. MS (ESI): mass calcd. For C18H17C12N5 373.09, m/z found 374.1 [M+H]+.

Step 1: To the solution of 4-(trifluoromethylsulfonyl) aniline (1 g, 4.44 mmol, 1 eq) in HCl (10.2 g, 100 mmol, 10 mL, 36% purity, 22.7 eq) was added the solution of NaNO2 (352 mg, 5.11 mmol, 1.15 eq) in H2O (10 mL) at 0° C. and the solution was stirred at 0° C. for 0.25 h (Solution A). To H2O (10 mL) was added SOCl2 (2.11 g, 17.76 mmol, 1.29 mL, 4 eq) dropwise at 0° C. and the solution was stirred at 20° C. for 0.25 h. To the solution was added CuCl (44.0 mg, 444 μmol, 10.6 uL, 0.1 eq) at 0° C. and the solution was stirred at 0° C. for 0.25 hour. (Solution B). Solution A was added to Solution B at 0° C. and the solution was stirred at 0° C. for 0.25 h. TLC showed 1-benzylsulfanyl-4-(trifluoromethylsulfonyl) benzene remained and a new spot. The reaction was filtered and the cake was washed with water (50 mL). The cake was dried under reduce pressure to give desired 4-(trifluoromethylsulfonyl) benzenesulfonyl chloride (950 mg, crude) as a yellow solid.

Step 2: To a solution of 4-chloro-3-(7, 7-difluoro-4-azaspiro [2.5]octan-4-yl)-1-(p-tolylsulfonyl) indazole (210 mg, 465 μmol, 1 eq) in MeOH (4 mL) was added K2CO3 (1.28 g, 9.29 mmol, 20 eq). The mixture was stirred at 70° C. for 1 hour. LC-MS showed 4-chloro-3-(7, 7-difluoro-4-azaspiro [2.5]octan-4-yl)-1-(p-tolylsulfonyl) indazole was consumed completely and desired compound was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (20 mL) and 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 desired 4-chloro-3-(7, 7-difluoro-4-azaspiro [2.5]octan-4-yl)-1H-indazole (120 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C14H14ClF2N3 297.08, mass found 298.0 [M+H]+.

Step 1: To a solution of 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-4-azaspiro [2.5]octan-7-one (160 mg, 372 μmol, 1 eq) in Tol. (2 mL) was added PCl5 (194 mg, 930 μmol, 2.5 eq). The mixture was stirred at 20° C. for 1 hour. LC-MS showed 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-4-azaspiro [2.5]octan-7-one was consumed completely and desired mass was detected. The pH value of the mixture was adjusted to 10˜11 with NaOH (2 N). The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine 20 mL and dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 4-chloro-3-(7,7-dichloro-4-azaspiro[2.5]octan-4-yl)-1-(p-tolylsulfonyl) indazole (220 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C21H20Cl3N3O2S 483.03, mass found 483.9 [M+H]+.

Step 2: To a solution of 4-chloro-3-(7, 7-dichloro-4-azaspiro [2.5]octan-4-yl)-1-(p-tolylsulfonyl) indazole (220 mg, 454 μmol, 1 eq) in MeOH (2 mL) was added K2CO3 (314 mg, 2.27 mmol, 5 eq). The mixture was stirred at 40° C. for 0.5 hour. TLC (petroleum ether/ethyl acetate=5/1) indicated 4-chloro-3-(7, 7-dichloro-4-azaspiro [2.5]octan-4-yl)-1-(p-tolylsulfonyl) indazole was consumed completely and one new spot was formed. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (20 mL) and 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 desired 4-chloro-3-(7, 7-dichloro-4-azaspiro [2.5]octan-4-yl)-1H-indazole (65 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C14H14Cl3N3 329.03, mass found 330.0 [M+H]+.

Step 4: To a solution of 4-chloro-6-fluoro-1-(p-tolylsulfonyl)-3-[7-(2, 2, 2-trifluoroethyl)-4, 7-diazaspiro [2.5]octan-4-yl]indazole (200 mg, 386 μmol, 1 eq) in MeOH (10 mL) was added K2CO3 (267 mg, 1.93 mmol, 5 eq). The mixture was stirred at 70° C. for 1 hour. LC-MS showed 4-chloro-6-fluoro-1-(p-tolylsulfonyl)-3-[7-(2, 2, 2-trifluoroethyl)-4, 7-diazaspiro [2.5]octan-4-yl]indazole was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH and then it was diluted with H2O (20 mL) and extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (10 mL*1), 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 desired 4-chloro-6-fluoro-3-[7-(2, 2, 2-trifluoroethyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1H-indazole (50 mg, crude) as a white solid. MS (ESI): mass calcd. For C15H15N4ClF4 362.09, mass found 363.1 [M+H]+.

Step 1: To a solution of 4-bromo-2-fluoro-benzenethiol (3 g, 14.5 mmol, 1 eq) in THF (30 mL) was added K2CO3 (6.01 g, 43.5 mmol, 3 eq) and 2-bromopropane (2.67 g, 21.7 mmol, 2.04 mL, 1.5 eq). The mixture was stirred at 50° C. for 12 hours. TLC indicated 4-bromo-2-fluoro-benzenethiol was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine 20 mL and dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 4-bromo-2-fluoro-1-isopropylsulfanyl-benzene (3.6 g, crude) as a white solid.

Step 2: To a solution of 4-bromo-2-fluoro-1-isopropylsulfanyl-benzene (3.6 g, 14.5 mmol, 1 eq) in DCM (40 mL) was added m-CPBA (8.80 g, 43.4 mmol, 85% purity, 3 eq) at 0° C. The mixture was stirred at 20° C. for 12 hours. TLC (petroleum ether/ethyl acetate=3/1) indicated 4-bromo-2-fluoro-1-isopropylsulfanyl-benzene was consumed completely and one new spot formed. The reaction was clean according to TLC. Then it was partitioned between of sat.aq.Na2SO3 (30 mL) and DCM (100 mL). The organic phase was separated, washed with sat. Na2SO3 (30 mL), brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 4-bromo-2-fluoro-1-isopropylsulfonyl-benzene (4 g, crude) as a colourless oil.

Step 3: A mixture of phenylmethanethiol (1.46 g, 11.7 mmol, 1.38 mL, 1.1 eq), 4-bromo-2-fluoro-1-isopropylsulfonyl-benzene (3 g, 10.7 mmol, 1 eq), DIEA (2.76 g, 21.3 mmol, 3.72 mL, 2 eq), Xantphos (617 mg, 1.07 mmol, 0.1 eq) and Pd(dppf)Cl2 (195 mg, 267 μmol, 0.025 eq) in Tol. (30 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110° C. for 12 hours under N2 atmosphere. TLC (petroleum ether/ethyl acetate=3/1) indicated 4-bromo-2-fluoro-1-isopropylsulfonyl-benzene was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was concentrated under reduced pressure to remove Tol. The reaction mixture was added to water (50 mL), extracted with EtOAc (30 mL*3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0˜20% Ethyl acetate/petroleum ether gradient @50 mL/min) to give desired 4-benzylsulfanyl-2-fluoro-1-isopropylsulfonyl-benzene (3.4 g, crude) as an orange oil.

Step 4: To a solution of 4-benzylsulfanyl-2-fluoro-1-isopropylsulfonyl-benzene (3.4 g, 10.5 mmol, 1 eq) in AcOH (20 mL) and H2O (4 mL) was added NCS (4.20 g, 31.4 mmol, 3 eq). The mixture was stirred at 20° C. for 4 hours. TLC (petroleum ether/ethyl acetate=3/1) showed 4-benzylsulfanyl-2-fluoro-1-isopropylsulfonyl-benzene was consumed completely and one major new spot with larger polarity was detected. The reaction mixture was diluted with water 50 mL and extracted with EtOAc (50 mL*3). The combined organic layers were washed with brine 50 mL, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0˜20% Ethyl acetate/petroleum ether gradient @50 mL/min) to give desired 3-fluoro-4-isopropylsulfonyl-benzenesulfonyl chloride (580 mg, crude) as a white solid.

Step 1: To a solution of 2-cyclopropylpiperidine (50 mg, 309 μmol, 1 eq, HCl) in THF (3 mL) was added dropwise TEA (313 mg, 3.09 mmol, 430 μL, 10 eq) at 25° C. After addition, the mixture was stirred at this temperature for 10 mins, and then (1Z)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (128 mg, 340 μmol, 1.1 eq) in THF (3 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 20 mins. LC-MS showed 2-cyclopropylpiperidine was consumed completely and one main peak with 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 brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give desired N-[(E)-[(2-cyclopropyl-1-piperidyl)-(2, 6-dichlorophenyl) methylene]amino]-4-methyl-benzenesulfonamide (145 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C22H25Cl2N3O2S 465.10, mass found 466.1 [M+H]+.

Step 2: To a solution of N-[(E)-[(2-cyclopropyl-1-piperidyl)-(2, 6-dichlorophenyl) methylene]amino]-4-methyl-benzenesulfonamide (145 mg, 311 μmol, 1 eq) in DMF (5 mL) was added K2CO3 (172 mg, 1.24 mmol, 4 eq). The mixture was stirred at 100° C. for 12 hours. LC-MS showed N-[(E)-[(2-cyclopropyl-1-piperidyl)-(2, 6-dichlorophenyl) methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and desired mass was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 4-chloro-3-(2-cyclopropyl-1-piperidyl)-1-(p-tolylsulfonyl) indazole (130 mg, crude) as an orange oil. MS (ESI): mass calcd. For C22H24ClN3O2S 429.13, mass found 430.0 [M+H]+.

Step 3: To a solution of 4-chloro-3-(2-cyclopropyl-1-piperidyl)-1-(p-tolylsulfonyl) indazole (130 mg, 302 μmol, 1 eq) in MeOH (5 mL) was added K2CO3 (209 mg, 1.51 mmol, 5 eq). The mixture was stirred at 70° C. for 1 hour. LC-MS showed 4-chloro-3-(2-cyclopropyl-1-piperidyl)-1-(p-tolylsulfonyl) indazole was consumed completely and desired compound was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by by prep-TLC (Silica gel, petroleum ether/=3/1) to give desired 4-chloro-3-(2-cyclopropyl-1-piperidyl)-1H-indazole (80 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C15H18ClN3 275.12, mass found 276.0 [M+H]+.

Step 1: To a solution of 7-pyrimidin-2-yl-4, 7-diazaspiro [2.5]octane (229 mg, 1.01 mmol, 1 eq, HCl) in THF (3 mL) was added dropwise TEA (1.02 g, 10.1 mmol, 1.41 mL, 10 eq) at 25° C. After addition, the mixture was stirred at this temperature for 10 mins, and then (1Z)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (420 mg, 1.11 mmol, 1.1 eq) in THF (3 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 20 mins. LC-MS showed 7-pyrimidin-2-yl-4, 7-diazaspiro [2.5]octane was consumed completely and one main peak with 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, filtered and concentrated under reduced pressure to give desired N—[(Z)-[(2,6-dichlorophenyl)-(7-pyrimidin-2-yl-4,7-diazaspiro[2.5]octan-4-yl)methylene]amino]-4-methyl-benzenesulfonamide (540 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C24H24Cl2N6O2S 530.11, mass found 531.2 [M+H]+.

Step 2: To a solution of N—[(Z)-[(2, 6-dichlorophenyl)-(7-pyrimidin-2-yl-4, 7-diazaspiro [2.5]octan-4-yl) methylene]amino]-4-methyl-benzenesulfonamide (540 mg, 1.02 mmol, 1 eq) in DMF (20 mL) was added K2CO3 (562 mg, 4.06 mmol, 4 eq). The mixture was stirred at 100° C. for 2 hours. LC-MS showed N—[(Z)-[(2, 6-dichlorophenyl)-(7-pyrimidin-2-yl-4, 7-diazaspiro [2.5]octan-4-yl) methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and desired mass was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine 20 mL and dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 4-chloro-1-(p-tolylsulfonyl)-3-(7-pyrimidin-2-yl-4,7-diazaspiro[2.5]octan-4-yl) indazole (500 mg, crude) as an orange oil. MS (ESI): mass calcd. For C24H23ClN6O2S 494.13, mass found 495.2 [M+H]+.

Step 3: To a solution of 4-chloro-1-(p-tolylsulfonyl)-3-(7-pyrimidin-2-yl-4, 7-diazaspiro [2.5]octan-4-yl) indazole (500 mg, 1.01 mmol, 1 eq) in MeOH (20 mL) was added K2CO3 (698 mg, 5.05 mmol, 5 eq). The mixture was stirred at 70° C. for 1 hour. LC-MS showed 4-chloro-1-(p-tolylsulfonyl)-3-(7-pyrimidin-2-yl-4, 7-diazaspiro [2.5]octan-4-yl) indazole was consumed completely and desired compound was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine 20 mL and 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 desired 4-chloro-3-(7-pyrimidin-2-yl-4, 7-diazaspiro [2.5]octan-4-yl)-1H-indazole (180 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C17H17ClN6 340.12, mass found 341.0 [M+H]+.

Step 1: To a solution of (1E)-2, 6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (111 mg, 294 μmol, 1.5 eq) and 2-(trifluoromethyl)piperidine (30 mg, 196 μmol, 1 eq) in THF (5 mL) was added TEA (198 mg, 1.96 mmol, 273 μL, 10 eq) at 0° C. The mixture was stirred at 25° C. for 1 hour. LC-MS showed (1E)-2, 6-dichloro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride was consumed completely and 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 desired N-[(E)-[(2,6-dichlorophenyl)-[2-(trifluoromethyl)-1-piperidyl]methylene]amino]-4-methyl-benzenesulfonamide (60 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C20H21ClF3N3O2S 459.1 mass found 460.1 [M+H]+.

Step 2: To a solution of N-[(E)-[(2, 6-dichlorophenyl)-[2-(trifluoromethyl)-1-piperidyl]methylene]amino]-4-methyl-benzenesulfonamide (590 mg, 1.19 mmol, 1 eq) in DMF (6 mL) was added K2CO3 (825 mg, 5.97 mmol, 5 eq). The mixture was stirred at 100° C. for 4 hours. LC-MS showed N-[(E)-[(2, 6-dichlorophenyl)-[2-(trifluoromethyl)-1-piperidyl]methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and desired mass was detected. The reaction mixture was partitioned between 5 mL of H2O and 5 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 desired 4-chloro-1-(p-tolylsulfonyl)-3-[2-(trifluoromethyl)-1-piperidyl]indazole (550 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C20H19ClF3N3O2S 457.1 mass found 458.1 [M+H]+.

Step 3: To a solution of 4-chloro-1-(p-tolylsulfonyl)-3-[2-(trifluoromethyl)-1-piperidyl]indazole (550 mg, 1.20 mmol, 1 eq) in MeOH (6 mL) was added K2CO3 (830 mg, 6.01 mmol, 5 eq). The mixture was stirred at 80° C. for 2 hours. LC-MS showed 4-chloro-1-(p-tolylsulfonyl)-3-[2-(trifluoromethyl)-1-piperidyl]indazole was consumed completely and 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=3/1) to give desired 4-chloro-3-[2-(trifluoromethyl)-1-piperidyl]-1H-indazole (160 mg, 527 μmol, 43.86% yield) as a white solid. MS (ESI): mass calcd. For C13H13ClF3N3 303.1 mass found 304.1 [M+H]+.

Step 1: To a solution of (1E)-2,6-difluoro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (847 mg, 2.46 mmol, 2 eq) and 1-benzyl-3-(trifluoromethyl) piperazine (300 mg, 1.23 mmol, 1 eq) in THE (10 mL) was added TEA (621 mg, 6.14 mmol, 855 μL, 5 eq) at 0′C. The mixture was stirred at 25° C. for 1 hour. LC-MS showed 1-benzyl-3-(trifluoromethyl) piperazine was consumed completely and desired mass was detected. The reaction mixture was partitioned between 20 mL of H2O and 20 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 desired N-[(E)-[[4-benzyl-2-(trifluoromethyl)piperazin-1-yl]-(2,6-difluorophenyl) methylene]amino]-4-methyl-benzenesulfonamide (1.13 g, crude) as a yellow oil. MS (ESI): mass calcd. For C26H25F5N4O2S 552.1 mass found 553.1 [M+H]+.

Step 3: To a solution of 3-[4-benzyl-2-(trifluoromethyl) piperazin-1-yl]-4-fluoro-1-(p-tolylsulfonyl) indazole (1.1 g, 2.07 mmol, 1 eq) in MeOH (11 mL) was added K2CO3 (1.43 g, 10.3 mmol, 5 eq). The mixture was stirred at 40° C. for 1 hour. LC-MS showed 3-[4-benzyl-2-(trifluoromethyl) piperazin-1-yl]-4-fluoro-1-(p-tolylsulfonyl) indazole was consumed completely and 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 prep-TLC (Silica gel, petroleum ether/ethyl acetate=2/1) to give desired 3-[4-benzyl-2-(trifluoromethyl)piperazin-1-yl]-4-fluoro-1H-indazole (320 mg, 846 μmol, 41.0% yield) as a yellow oil. MS (ESI): mass calcd. For C19H18F4N4 378.1, mass found 379.1 [M+H]+.

Step 1: To a solution of 4-chloro-1-(4-isopropylsulfonylphenyl) sulfonyl-3-[2-(trifluoromethyl) piperazin-1-yl]indazole (200 mg, 363 μmol, 1 eq) in MeOH (2 mL) was added K2CO3 (250 mg, 1.81 mmol, 50.5 μL, 5 eq). The mixture was stirred at 40° C. for 1 hour. LC-MS showed 4-chloro-1-(4-isopropylsulfonylphenyl) sulfonyl-3-[2-(trifluoromethyl) piperazin-1-yl]indazole was consumed completely and desired mass was detected. The reaction mixture was filtered and the filter liquor was concentrated under reduced pressure to give a residue and it 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 desired 4-chloro-3-[2-(trifluoromethyl) piperazin-1-yl]-1H-indazole (100 mg, crude) as a white solid. MS (ESI): mass calcd. For C12H12N4F3Cl 304.07 mass found 305.0 [M+H]+.

Step 2: To a solution of 4-chloro-3-[4-(5-fluoropyrimidin-2-yl)-2-(trifluoromethyl) piperazin-1-yl]-1-(4-isopropylsulfonylphenyl) sulfonyl-indazole (140 mg, 216 μmol, 1 eq) in MeOH (2 mL) was added K2CO3 (149 mg, 1.08 mmol, 5 eq). The mixture was stirred at 40° C. for 1 hour. LC-MS showed 4-chloro-3-[4-(5-fluoropyrimidin-2-yl)-2-(trifluoromethyl) piperazin-1-yl]-1-(4-isopropylsulfonylphenyl) sulfonyl-indazole was consumed completely and desired mass was detected. The reaction mixture was filtered and the filter liquor was concentrated under reduced pressure to give a residue then it 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 desired 4-chloro-3-[4-(5-fluoropyrimidin-2-yl)-2-(trifluoromethyl)piperazin-1-yl]-1H-indazole (92 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C16H13N6F4Cl 400.08 mass found 401.0 [M+H]+.

Step 1: To a solution of 1-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-2-(trifluoromethyl) piperidin-4-one (110 mg, 233 μmol, 1 eq) in Tol. (1 mL) was added PCl5 (121 mg, 583 μmol 2.5 eq). The mixture was stirred at 20° C. for 1 hour. LC-MS showed 1-[4-chloro-α-(p-tolylsulfonyl) indazol-3-yl]-2-(trifluoromethyl) piperidin-4-one was consumed completely and desired mass was detected. The pH of the mixture was adjusted to 10-11 with 2N NaOH. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 4-chloro-3-[4-chloro-6-(trifluoromethyl)-3, 6-dihydro-2H-pyridin-1-yl]-1-(p-tolylsulfonyl) indazole (50 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C20H16Cl2F3N3O2S 489.03, mass found 489.9 [M+H]+.

Step 2: To a solution of 4-chloro-3-[4-chloro-6-(trifluoromethyl)-3, 6-dihydro-2H-pyridin-1-yl]-1-(p-tolylsulfonyl) indazole (50 mg, 102 μmol, 1 eq) in MeOH (2 mL) was added K2CO3 (70.5 mg, 510 μmol, 5 eq). The mixture was stirred at 70° C. for 0.5 hour. TLC (petroleum ether/ethyl acetate=5/1) indicated 4-chloro-3-[4-chloro-6-(trifluoromethyl)-3, 6-dihydro-2H-pyridin-1-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (20 mL) and 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 desired 4-chloro-3-[4-chloro-6-(trifluoromethyl)-3,6-dihydro-2H-pyridin-1-yl]-1H-indazole (20 mg, 59.5 μmol, 58.4% yield) as a yellow solid.

Step 2: To a solution of 2-(trifluoromethyl) piperidin-4-one (2.16 g, 10.6 mmol, 1 eq, HCl) in THE (3 mL) was added dropwise TEA (10.7 g, 106 mmol, 14.8 mL, 10 eq) at 25° C. After addition, the mixture was stirred at this temperature for 10 mins, and then (1Z)-2, 6-dichloro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride (4.41 g, 11.7 mmol, 1.1 eq) in THF (3 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 20 mins. LC-MS showed 2-(trifluoromethyl) piperidin-4-one was consumed completely and one main peak with desired mass was detected. Then it was separated between 200 mL of water and 400 mL of ethyl acetate. The organic phase was separated, washed with 300 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (Silica gel, petroleum ether/ethyl acetate=1/0 to 1/1) to give desired N-[(E)-[(2, 6-dichlorophenyl)-[4-oxo-2-(trifluoromethyl)-1-piperidyl]methylene]amino]-4-methyl-benzenesulfonamide (5 g, crude) as a yellow solid. MS (ESI): mass calcd. For C20H18Cl2F3N3O3S 507.04, mass found 508.0 [M+H]+.

Step 4: To a solution of N-[(E)-[(2, 6-dichlorophenyl)-[7-(trifluoromethyl)-1, 4-dioxa-8-azaspiro [4.5]decan-8-yl]methylene]amino]-4-methyl-benzenesulfonamide (540 mg, 978 μmol, 1 eq) in DMF (10 mL) was added K2CO3 (540 mg, 3.91 mmol, 4 eq). The mixture was stirred at 90° C. for 2 hours. TLC indicated N-[(E)-[(2, 6-dichlorophenyl)-[7-(trifluoromethyl)-1, 4-dioxa-8-azaspiro [4.5]decan-8-yl]methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and one new spot formed. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 8-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-7-(trifluoromethyl)-1,4-dioxa-8-azaspiro[4.5]decane (500 mg, crude) as an orange oil.

Step 5: To a solution of 8-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-7-(trifluoromethyl)-1, 4-dioxa-8-azaspiro [4.5]decane (500 mg, 969 μmol, 1 eq) in MeOH (10 mL) was added K2CO3 (670 mg, 4.85 mmol, 5 eq). The mixture was stirred at 60° C. for 0.5 hour. LC-MS showed 8-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-7-(trifluoromethyl)-1, 4-dioxa-8-azaspiro [4.5]decane was consumed completely and desired mass was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (20 mL) and 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=1/1) to give desired 8-(4-chloro-1H-indazol-3-yl)-7-(trifluoromethyl)-1, 4-dioxa-8-azaspiro [4.5]decane (140 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C15H15ClF3N3O2 361.08, mass found 362.0 [M+H]+.

Step 1: To a solution of 1-[4-chloro-1-(4-isopropylsulfonylphenyl) sulfonyl-indazol-3-yl]-2-(trifluoromethyl) piperidin-4-one (0.2 g, 355 μmol, 1 eq) in EtOH (1 mL) was added NaBH4 (20.1 mg, 532 μmol, 1.5 eq) at 0° C. The mixture was stirred at 25° C. for 0.5 hour. LC-MS showed 1-[4-chloro-1-(4-isopropylsulfonylphenyl) sulfonyl-indazol-3-yl]-2-(trifluoromethyl) piperidin-4-one was consumed completely and one main peak with desired mass was detected. The residue was diluted with HCl (1N, 8 mL) and the resulting mixture was allowed to return to room temperature. The EtOH was evaporated in vacuo. The reaction mixture was added to water (20 mL), extracted with DCM (10 mL*3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 1-[4-chloro-1-(4-isopropylsulfonylphenyl)sulfonyl-indazol-3-yl]-2-(trifluoromethyl)piperidin-4-ol (0.2 g, crude) as a yellow oil. MS (ESI): mass calcd. For C22H23S2O5N3ClF3 565.07, mass found 566.0 [M+H]+.

Step 1: To a solution of 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-4-azaspiro [2.5]octan-7-one (0.5 g, 1.16 mmol, 1 eq) in EtOH (5 mL) was added NaBH4 (66.0 mg, 1.74 mmol, 1.5 eq). The mixture was stirred at 20° C. for 1 hour. LC-MS showed 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-4-azaspiro [2.5]octan-7-one was consumed completely and one main peak with desired mass was detected. The residue was diluted with HCl (1 N, 8 mL) and the resulting mixture was allowed to return to room temperature. The EtOH was evaporated in vacuo. The reaction mixture was added to water (20 mL), extracted with DCM (10 mL*3). The combined organic layers were washed with brine (20 mL) and 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=2/1) to give desired 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-4-azaspiro [2.5]octan-7-ol (0.4 g, 926 μmol, 79.6% yield) as a yellow solid. MS (ESI): mass calcd. For C21H22N3ClO3S 431.11, mass found 432.1[M+H]+.

Step 2: To a solution of 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-4-azaspiro [2.5]octan-7-ol (0.2 g, 463 μmol, 1 eq) in ACN (2 mL) was added CuI (17.6 mg, 92.6 μmol, 0.2 eq) and heated to 45° C. under N2 atmosphere. To this mixture was added a solution of 2, 2-difluoro-2-fluorosulfonyl-acetic acid (107 mg, 602 μmol, 1.3 eq) in ACN (0.5 mL) was added dropwise at 45° C. The resulting mixture was stirred at 45° C. for 0.5 hour. LC-MS showed 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-4-azaspiro [2.5]octan-7-ol was consumed completely and one main peak with desired mass was detected. The residue was diluted with H2O (10 mL) and extracted with EtOAc (5 mL*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=4/1) to give desired 4-chloro-3-[7-(difluoromethoxy)-4-azaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (150 mg, 311 μmol, 67.2% yield) as a yellow oil. MS (ESI): mass calcd. For C22H22N3ClO3SF2 481.1, mass found 482.0[M+H]+.

Step 3: To a solution of 4-chloro-3-[7-(difluoromethoxy)-4-azaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (150 mg, 311 μmol, 1 eq) in MeOH (2 mL) was added K2CO3 (108 mg, 778 μmol, 2.5 eq). The mixture was stirred at 40° C. for 0.5 hour. LC-MS showed 4-chloro-3-[7-(difluoromethoxy)-4-azaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and one main peak with desired mass was detected. The residue was diluted with H2O (10 mL) and extracted with Ethyl acetate (5 mL*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 desired 4-chloro-3-[7-(difluoromethoxy)-4-azaspiro [2.5]octan-4-yl]-1H-indazole (40 mg, 122 μmol, 39.1% yield) as a yellow solid. MS (ESI): mass calcd. For C15H16N3ClOF2 327.1, mass found 328.0[M+H]+.

Step 1: To a solution of EtOAc (215 mg, 2.44 mmol, 239 μL, 1.5 eq) in THF (1 mL) was added dropwise LiHMDS (1 M, 2.44 mL, 1.5 eq) at −70° C. After addition, the mixture was stirred at this temperature for 0.5 hour, and then 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-4-azaspiro[2.5]octan-7-one (0.7 g, 1.63 mmol, 1 eq) in THF (7 mL) was added dropwise at −70° C. The resulting mixture was stirred at −70° C. for 1 hour. LC-MS showed 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-4-azaspiro [2.5]octan-7-one was consumed completely and one main peak with desired mass was detected. The residue was diluted with H2O (10 mL) and extracted with EtOAc (5 mL*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 flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0˜25% EtOAc/petroleum ether gradient @100 mL/min) to give desired ethyl 2-[4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-7-hydroxy-4-azaspiro [2.5]octan-7-yl]acetate (0.63 g, 1.22 mmol, 74.7% yield) as a yellow solid. MS (ESI): mass calcd. For C25H28N3SO5Cl 517.14, mass found 518.0[M+H]+.

Step 2: To a solution of ethyl 2-[4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-7-hydroxy-4-azaspiro [2.5]octan-7-yl]acetate (0.4 g, 772 μmol, 1 eq) in THF (4 mL) was added LAH (87.9 mg, 2.32 mmol, 3 eq) at 0° C. The mixture was stirred at 0° C. for 0.5 hour. LC-MS showed ethyl 2-[4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-7-hydroxy-4-azaspiro [2.5]octan-7-yl]acetate was consumed completely and one main peak with desired mass was detected. The reaction mixture was quenched by addition of 0.09 mL of H2O at 0° C., followed by 0.09 mL of 15% aqueous NaOH at 0° C., followed by 0.27 mL of H2O at 0° C. under N2. After being stirred at room temperature for 0.5 hour, the solid was removed by filtration. The filtrate was concentrated to dryness to give desired 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-7-(2-hydroxyethyl)-4-azaspiro [2.5]octan-7-ol (0.37 g, crude) as a yellow oil. MS (ESI): mass calcd. For C23H26N3SO4Cl 475.13, mass found 476.1[M+H]+.

Step 3: To a solution of 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-7-(2-hydroxyethyl)-4-azaspiro [2.5]octan-7-ol (370 mg, 777 μmol, 1 eq) in Py (4 mL) was added 4-methylbenzenesulfonyl chloride (193 mg, 1.01 mmol, 1.3 eq). The mixture was stirred at 20° C. for 12 hour. The residue was diluted with H2O (10 mL) and extracted with EtOAc (5 mL*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 in THF (4 mL) was added NaH (124 mg, 3.11 mmol, 60% purity, 4 eq) at 0° C. The mixture was stirred at 20° C. for 1 hour. LC-MS showed 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-7-(2-hydroxyethyl)-4-azaspiro [2.5]octan-7-ol was consumed completely and one main peak with desired mass was detected. The residue was diluted with H2O (10 mL) and extracted with EtOAc (5 mL*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=1/1) to give desired 11-(4-chloro-1H-indazol-3-yl)-8-oxa-11-azadispiro [2.1.35.33]undecane (15 mg, 49.4 μmol, 6.35% yield) as a yellow solid. MS (ESI): mass calcd. For C16H18N3ClO 303.11, mass found 304.1[M+H]+.

Step 2: To a solution of 3-(4-benzylsulfanylphenyl) oxetan-3-ol (440 mg, 1.62 mmol, 1 eq) in AcOH (4 mL) and H2O (1 mL) was added NCS (647 mg, 4.85 mmol, 3 eq) at 0° C. The mixture was stirred at 20° C. for 1 hour. TLC indicated 3-(4-benzylsulfanylphenyl) oxetan-3-ol was consumed, and one major new spot with larger polarity was detected. Then it was partitioned between 5 mL of water and 15 mL of ethyl acetate. The organic phase was separated, washed with 5 mL of brine, 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=1/1) to give desired 4-(3-hydroxyoxetan-3-yl) benzenesulfonyl chloride (150 mg, 603 μmol, 37.3% yield) as a white gum.

Step 2: To a solution of 1-(4-benzylsulfanylphenyl)-2-methyl-propan-1-one (1 g, 3.70 mmol, 1 eq) in CH3COOH (6 mL) and H2O (2 mL) was added NCS (1.48 g, 11.1 mmol, 3 eq) at 0° C. The mixture was stirred at 20° C. for 1 hour. TLC indicated 1-(4-benzylsulfanylphenyl)-2-methyl-propan-1-one (1 g, 3.70 mmol, 1 eq) was remained, and one major new spot with larger polarity was detected. The reaction mixture was diluted with water (10 mL) and extracted with MTBE (5 mL*6). The combined organic layers were washed with brine 10 mL, dried over NaSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0˜8% Ethyl acetate/petroleum ether gradient @80 mL/min) to give desired 4-(2-methylpropanoyl) benzenesulfonyl chloride (700 mg, 2.84 mmol, 87.5% yield) as a yellow oil.

Step 2: To the solution of (4-benzylsulfanylphenyl)-cyclopropyl-methanone (500 mg, 1.86 mmol, 1 eq) in AcOH (1 mL) and H2O (0.2 mL) was added NCS (995 mg, 7.45 mmol, 4 eq) at 0° C. and the solution was stirred at 25° C. for 1 hour. LCMS showed (4-benzylsulfanylphenyl)-cyclopropyl-methanone was consumed completely and desired mass was detected (the sample was quenched with piperidine). The reaction was added water (5 mL) and extracted with MTBE (2*20 mL). The combined organics were washed with sodium bicarbonate solution (2*10 mL), dried over anhydrous sodium sulfate and concentrated to get a yellow oil. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0˜10% ethyl acetate/petroleum ether gradient @50 mL/min) to give desired 4-(cyclopropanecarbonyl) benzenesulfonyl chloride (450 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C01H9O3SCl 244.00 mass found 294.0 [M+49+H]+.

Step 3: To a solution of 4-chloro-3-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-[4-[(4-methoxyphenyl) methylsulfanyl]phenyl]sulfonyl-indazole (140 mg, 215 μmol, 1 eq) in TFA (2 mL) was stirred at 70° C. for 3 hours. LC-MS showed 4-chloro-3-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-[4-[(4-methoxyphenyl) methylsulfanyl]phenyl]sulfonyl-indazole was consumed completely and one main peak with 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/ethyl acetate=3/1) to give desired 4-[4-chloro-3-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]indazol-1-yl]sulfonylbenzenethiol (50 mg, 94.2 μmol, 43.8% yield) as a pale yellow gum. MS (ESI): mass calcd. For C23H20S2O2NClF 530.08 mass found 531.1[M+H]+.

Step 1: 1, 4-dibromobenzene (5 g, 21.2 mmol, 2.72 mL, 1 eq) was dissolved in THF (50 mL). The reaction solution was cooled to −78° C., and n-BuLi (2.5 M, 8.90 mL, 1.05 eq) was added dropwise to the reaction solution. After the dropwise addition, the reaction solution was stirred at −78° C. for 0.5 hour under N2. To the reaction solution was added ethyl 2, 2-difluoroacetate (5.79 g, 46.6 mmol, 2.2 eq). After the addition, the reaction solution was stirred at −78° C. for 1 hour under N2. TLC showed 1, 4-dibromobenzene was consumed completely and desired mass was detected. Then it was separated between sat. NH4Cl (50 mL) and ethyl acetate (30 mL). The organic phase was separated, washed with brine (60 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by chromatography give desired 1-(4-bromophenyl)-2, 2-difluoroethan-1-one (4.69 g, 20.0 mmol, 94.2% yield) as a yellow oil.

Step 1: To a solution of 3-(4-benzylsulfanylphenyl)-3-methyl-butan-1-ol (220 mg, 768 μmol, 1 eq) in DCM (2 mL) was added DAST (136 mg, 845 μmol, 112 μL, 1.1 eq) at 0° C. The mixture was stirred at 20° C. for 2 hours. TLC indicated 3-(4-benzylsulfanylphenyl)-3-methyl-butan-1-ol was consumed, and one major new spot with lower polarity was detected. The reaction mixture was quenched by sat. aq. NaHCO3 (2 mL) and extracted with DCM (5 mL), washed with 5 mL of brine, 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 desired 1-benzylsulfanyl-4-(3-fluoro-1, 1-dimethyl-propyl) benzene (90 mg, 312 μmol, 40.6% yield) as a pale yellow oil.

Step 2: To a solution of 1-benzylsulfanyl-4-(2-fluoro-1, 1-dimethyl-ethyl) benzene (90.0 mg, 328 μmol, 1 eq) in AcOH (1 mL) and H2O (0.2 mL) was added NCS (131 mg, 984 μmol, 3 eq) at 0° C. The mixture was stirred at 20° C. for 1 hour. TLC indicated 1-benzylsulfanyl-4-(2-fluoro-1, 1-dimethyl-ethyl) benzene was consumed completely, and one major new spot with larger polarity 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/ethyl acetate=5/1) to give desired 4-(2-fluoro-1, 1-dimethyl-ethyl) benzenesulfonyl chloride (70 mg, 279 μmol, 85.1% yield) as a white gum.

Step 2: To a solution of 2-(4-benzylsulfanylphenyl) propan-2-ol (0.5 g, 1.94 mmol, 1 eq) in AcOH (4 mL) and H2O (1 mL) was added NCS (775 mg, 5.81 mmol, 3 eq) at 0° C. The mixture was stirred at 25° C. for 0.5 hour. TLC (petroleum ether/EtOAc=5/1) indicated 2-(4-benzylsulfanylphenyl) propan-2-ol was consumed completely and two new spots formed. The residue was diluted with H2O (10 mL) and extracted with MTBE (5 mL*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 desired 4-(1-hydroxy-1-methyl-ethyl) benzenesulfonyl chloride (230 mg, 980 μmol, 50.6% yield) as a yellow oil.

Step 1: To a solution of 2-bromo-1-(4-bromophenyl) ethanone (3 g, 10.8 mmol, 1 eq) was added 3HF·TEA (19.8 g, 123 mmol, 20 mL, 11.4 eq). The mixture was stirred at 120° C. for 2 hours. TLC (petroleum ether/ethyl acetate=10/1) indicated 2-bromo-1-(4-bromophenyl) ethanone was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was added to ice water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine 20 mL and 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 5/1) to give desired 1-(4-bromophenyl)-2-fluoro-ethanone (1.8 g, crude) as a white solid.

Step 3: To a solution of 1-(4-benzylsulfanylphenyl)-2-fluoro-ethanone (540 mg, 2.07 mmol, 1 eq) in DCM (3 mL) was added DAST (1.67 g, 10.4 mmol, 1.37 mL, 5 eq) at 0° C. The mixture was stirred at 0° C. for 0.5 hour. TLC (petroleum ether/ethyl acetate=5/1) indicated 1-(4-benzylsulfanylphenyl)-2-fluoro-ethanone was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine 20 mL and 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 1/1) to give desired 1-benzylsulfanyl-4-(1, 1, 2-trifluoroethyl) benzene (400 mg, crude) as a colourless oil.

Step 4: To a solution of 1-benzylsulfanyl-4-(1, 1, 2-trifluoroethyl) benzene (400 mg, 1.42 mmol, 1 eq) in AcOH (2 mL) and H2O (0.4 mL) was added NCS (568 mg, 4.25 mmol, 3 eq). The mixture was stirred at 20° C. for 1 hour. LC-MS showed 1-benzylsulfanyl-4-(1, 1, 2-trifluoroethyl) benzene was consumed completely and desired compound was detected. (The sample was quenched with pyrrolidine) The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine 10 mL, dried over anhydrous 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 desired 4-(1, 1, 2-trifluoroethyl) benzenesulfonyl chloride (360 mg, crude) as a colourless oil. MS (ESI): mass calcd. For C8H6ClF3O2S 257.97, mass found 294.0 [M+H+35]+.

Step 1: To a solution of methyl 2-(4-benzylsulfanylphenyl)-2-methyl-propanoate (250 mg, 832 μmol, 1 eq) in THF (5 mL) was added LAH (94.8 mg, 2.50 mmol, 3 eq) at 0° C. under N2. The mixture was stirred at 20° C. for 1 hour under N2 atmosphere. TLC indicated methyl 2-(4-benzylsulfanylphenyl)-2-methyl-propanoate was consumed completely, and one major new spot with larger polarity was detected. The reaction mixture was added dropwise 0.08 mL of water at 0° C. and then it was added dropwise 0.08 mL of 15% aq.NaOH at 0° C. Then it was added dropwise 0.24 mL of water at 0° C. The mixture was dried over anhydrous sodium sulfate, 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 desired 2-(4-benzylsulfanylphenyl)-2-methyl-propan-1-ol (200 mg, 734 μmol, 88.2% yield) as a colorless oil.

Step 2: To a solution of 2-(4-benzylsulfanylphenyl)-2-methyl-propan-1-ol (200 mg, 734 μmol, 1 eq) in DCM (2 mL) was added DMP (343 mg, 808 μmol, 250 μL, 1.1 eq) at 0° C. The mixture was stirred at 20° C. for 2 hours. TLC indicated 2-(4-benzylsulfanylphenyl)-2-methyl-propan-1-ol remained, and one major new spot with lower polarity was detected. The mixture quenched by sat.aq.Na2SO3 (3 mL) and extracted with ethyl acetate (5 mL), washed with 5 mL of brine, 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 desired 2-(4-benzylsulfanylphenyl)-2-methyl-propanal (60 mg, 222 μmol, 30.2% yield) as a colorless oil.

Step 3: To a solution of 2-(4-benzylsulfanylphenyl)-2-methyl-propanal (60 mg, 222 μmol, 1 eq) in DCM (1 mL) was added DAST (71.5 mg, 444 μmol, 58.6 uL, 2 eq) at 0° C. The mixture was stirred at 20° C. for 1 hour. TLC indicated 2-(4-benzylsulfanylphenyl)-2-methyl-propanal was consumed, and one major new spot with lower polarity was detected. The reaction mixture was quenched by sat. aq. NaHCO3 (1 mL) and extracted with DCM(5 mL), washed with 5 mL of brine, 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=10/1) to give desired 1-benzylsulfanyl-4-(2, 2-difluoro-1, 1-dimethyl-ethyl) benzene (50 mg, 171 μmol, 77.1% yield) as a colorless oil.

Step 2: To a solution of 5-benzylsulfanyl-2-tert-butyl-pyrimidine (100 mg, 387 μmol, 1 eq) in AcOH (1 mL) and H2O (0.2 mL) was added NCS (155 mg, 1.16 mmol, 3 eq). The mixture was stirred at 20° C. for 1 hour. LC-MS showed 5-benzylsulfanyl-2-tert-butyl-pyrimidine was consumed completely and desired compound was detected. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give desired 2-tert-butylpyrimidine-5-sulfonyl chloride (130 mg, crude) as a colourless oil. MS (ESI): mass calcd. For C8H11ClN2O2S 234.02, mass found 284.0 [M+H+49]+.

Step 2: To a solution of 1-benzylsulfanyl-4-[1-(trifluoromethyl) cyclopropyl]benzene (400 mg, 1.30 mmol, 1 eq) in AcOH (3 mL) H2O (1 mL) was added NCS (693 mg, 5.19 mmol, 4 eq) at 0° C. The mixture was stirred at 20° C. for 1 hour. LC-MS showed 1-benzylsulfanyl-4-[1-(trifluoromethyl) cyclopropyl]benzene was consumed completely and desired mass was detected (the sample was quenched with piperidine). The reaction mixture was diluted with water (10 mL) and extracted with MTBE (20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 4-[1-(trifluoromethyl) cyclopropyl]benzenesulfonyl chloride (350 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C10H8SO2ClF3 283.99, mass found 334.1 [M+49+H]+.

Step 2: To a solution of 1-(4-benzylsulfanylphenyl) propan-1-one (500 mg, 1.95 mmol, 1 eq) in AcOH (5 mL) and H2O (1 mL) was added NCS (1.04 g, 7.80 mmol, 4 eq) at 0° C. The mixture was stirred at 20° C. for 1 hour. TLC indicated 1-(4-benzylsulfanylphenyl) propan-1-one was consumed completely and one major new spot with larger polarity 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/ethyl acetate=5/1) to give desired 4-propanoylbenzenesulfonyl chloride (320 mg, 1.38 mmol, 70.5% yield) as a yellow gum.

Step 1: To a solution of 4-chloro-7-fluoro-3-[7-(5-fluoropyrimidin-2-yl)-4,7-diazaspiro[2.5]octan-4-yl]-1H-indazole (110 mg, 292 μmol, 1 eq) and 4-acetylbenzenesulfonyl chloride (128 mg, 584 μmol, 2 eq) in DCM (2 mL) was added TEA (73.9 mg, 730 μmol, 2.5 eq) and DMAP (3.57 mg, 29.2 μmol, 0.1 eq). The mixture was stirred at 25° C. for 0.5 hour. LC-MS showed 4-chloro-7-fluoro-3-[7-(5-fluoropyrimidin-2-yl)-4,7-diazaspiro[2.5]octan-4-yl]-1H-indazole was consumed completely and one main peak with desired mass was detected. The residue was diluted with H2O (10 mL) and extracted with EtOAc (5 mL*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=2/1) to give desired 1-[4-[4-chloro-7-fluoro-3-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]indazol-1-yl]sulfonylphenyl]ethanone (130 mg, 233 μmol, 79.7% yield) as a yellow oil. MS (ESI): mass calcd. For C25H21N6O3SClF2 558.11, mass found 559.1[M+H]+.

Step 2: To a solution of N-[(E)-[(2, 6-dichlorophenyl)-[2-(rifluoromethyl) azetidin-1-yl]methylene]amino]-4-methyl-benzenesulfonamide (860 mg, 1.84 mmol, 1 eq) in DMF (10 mL) as added K2CO3 (1.02 g, 7.38 mmol, 4 eq). The mixture was stirred at 100° C. for 3 hours. LC-MS showed N-[(E)-[(2, 6-dichlorophenyl)-[2-(rifluoromethyl) azetidin-1-yl]methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and desired mass was detected. The reaction mixture was partitioned between water (30 mL) and EtOAc (90 mL). The organic phase was separated, washed with brine (100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 4-chloro-1-(p-tolylsulfonyl)-3-[2-(trifluoromethyl) azetidin-1-yl]indazole (660 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C18H15N3ClSO2F3 429.05, mass found 430.0 [M+H]+.

Step 3: To a solution of 4-chloro-1-(p-tolylsulfonyl)-3-[2-(trifluoromethyl) azetidin-1-yl]indazole (660 mg, 1.54 mmol, 1 eq) in MeOH (10 mL) was added K2CO3 (1.06 g, 7.68 mmol, 5 eq). The mixture was stirred at 40° C. for 1 hour. LC-MS showed 4-chloro-1-(p-tolylsulfonyl)-3-[2-(trifluoromethyl) azetidin-1-yl]indazole was consumed completely and desired mass was detected. The reaction mixture was partitioned between water (20 mL) and EtOAc (60 mL). The organic phase was separated, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 4-chloro-3-[2-(trifluoromethyl) azetidin-1-yl]-1H-indazole (423 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C11H9N3ClF3 275.04, mass found 276.1 [M+H]+.

Step 6: To the solution of 2-[1-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-4-(5-fluoropyrimidin-2-yl)piperazin-2-yl]propan-2-ol (90 mg, 165 μmol, 1 eq) in DCM (3 mL) was added DAST (266 mg, 1.65 mmol, 10 eq) at −78° C. and the solution was stirred at −78° C. for 0.5 hour. Then the solution was stirred at 20° C. for 1 hour. TLC showed 2-[1-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-4-(5-fluoropyrimidin-2-yl) piperazin-2-yl]propan-2-ol was consumed completely and a new spot with lower priority. The reaction was quenched with MeOH (0.2 mL) and concentrated to give desired 4-chloro-3-[2-(1-fluoro-1-methyl-ethyl)-4-(5-fluoropyrimidin-2-yl) piperazin-1-yl]-1-(p-tolylsulfonyl) indazole (90 mg, crude) as a yellow solid.

Step 2: To a solution of tert-butyl 2-tert-butyl-4-(5-fluoropyrimidin-2-yl) piperazine-1-carboxylate (410 mg, 1.21 mmol, 1 eq) in HCl/EtOAc (4M, 5 mL). The mixture was stirred at 20° C. for 1 hour. LC-MS showed tert-butyl 2-tert-butyl-4-(5-fluoropyrimidin-2-yl) piperazine-1-carboxylate was consumed completely and desired mass was detected. The reaction mixture was partitioned between H2O (10 mL) and EtOAc (10 mL). The organic phase was separated, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 2-(3-tert-butylpiperazin-1-yl)-5-fluoro-pyrimidine (330 mg, crude, HCl) as a white solid. MS (ESI): mass calcd. For C12H20N4FCl 238.16, mass found 239.1 [M+H]+.

Step 5: To a solution of 3-[2-tert-butyl-4-(5-fluoropyrimidin-2-yl) piperazin-1-yl]-4-chloro-1-(p-tolylsulfonyl) indazole (640 mg, 1.18 mmol, 1 eq) in MeOH (7 mL) was added K2CO3 (814 mg, 5.89 mmol, 5 eq). The mixture was stirred at 40° C. for 1 hour. LC-MS showed 3-[2-tert-butyl-4-(5-fluoropyrimidin-2-yl) piperazin-1-yl]-4-chloro-1-(p-tolylsulfonyl) indazole was consumed completely and 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 prep-TLC (Silica gel, petroleum ether/ethyl acetate=2/1) to give desired 3-[2-tert-butyl-4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]-4-chloro-1H-indazole (220 mg, 566 μmol, 48.00% yield) as a yellow oil. MS (ESI): mass calcd. For C19H22N6ClF 388.16, mass found 389.1 [M+H]+.

Step 1: To a solution of 7-(5-fluoropyrimidin-2-yl)-4,7-diazaspiro[2.5]octane (778 mg, 3.18 mmol, 1.5 eq, HCl) in THF (5 mL) was added dropwise TEA (2.14 g, 21.2 mmol, 2.95 mL, 10 eq) at 25° C. After addition, the mixture was stirred at this temperature for 10 mins, and then (1Z)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (800 mg, 2.12 mmol, 1 eq) in THF (3 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 20 mins. LC-MS showed 7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octane was consumed completely and 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 desired N—[(Z)-[(2, 6-dichlorophenyl)-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (1.35 g, crude) as a white solid. MS (ESI): mass calcd. For C24H23Cl2FN6O2S 548.10, m/z found 549.1 [M+H]+.

Step 2: To a solution of N—[(Z)-[(2, 6-dichlorophenyl)-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (1.3 g, 2.37 mmol, 1 eq) in DMF (14 mL) was added K2CO3 (1.63 g, 11.8 mmol, 5 eq). The mixture was stirred at 80° C. for 12 hours. LC-MS showed N—[(Z)-[(2, 6-dichlorophenyl)-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and desired mass was detected. The reaction mixture was partitioned between 20 mL of H2O and 20 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 desired 4-chloro-3-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (1.5 g, crude) as a yellow oil. MS (ESI): mass calcd. For C24H22ClFN6O2S 512.12, m/z found 513.0 [M+H]+.

Step 1: To a solution of trifluoromethylsulfanylbenzene (500 mg, 2.81 mmol, 400 μL, 1 eq) in HSO3Cl (9.16 g, 78.6 mmol, 5.23 mL, 28 eq) at 0° C. The mixture was stirred at 0° C. for 0.5 hour. TLC (petroleum ether/Ethyl acetate=10/1) indicated trifluoromethylsulfanylbenzene was consumed completely and new spot formed. The reaction was clean according to TLC. The reaction mixture was added to water (20 mL), extracted with DCM (10 mL*3). The combined organic layers were washed with brine 20 mL and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product 4-(trifluoromethylsulfanyl) benzenesulfonyl chloride (650 mg, crude) as yellow oil was used into the next step without further purification.

Step 2: To a solution of 4-chloro-1-(4-isopropylsulfonylphenyl) sulfonyl-3-[4-(oxetan-3-yl)-2-(trifluoromethyl) piperazin-1-yl]indazole (70 mg, 115 μmol, 1 eq) in MeOH (2 mL) was added K2CO3 (79.7 mg, 577 μmol, 5 eq). The mixture was stirred at 40° C. for 1 hour. LC-MS showed 4-chloro-1-(4-isopropylsulfonylphenyl) sulfonyl-3-[4-(oxetan-3-yl)-2-(trifluoromethyl) piperazin-1-yl]indazole was consumed completely and desired mass was detected. The reaction mixture was filtered and the filter liquor was concentrated under reduced pressure to give desired 4-chloro-3-[4-(oxetan-3-yl)-2-(trifluoromethyl) piperazin-1-yl]-1H-indazole (40 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C15H16ClF3N4O 360.1, m/z found 361.1 [M+H]+.

Step 3: To a solution of (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (471 mg, 1.25 mmol, 1.5 eq) and 7-(4-chloro-2-fluoro-phenyl)-4,7-diazaspiro[2.5]octane (200 mg, 831 μmol, 1 eq) in THF (5 mL) was added TEA (420 mg, 4.15 mmol, 578 μL, 5 eq). The mixture was stirred at 15° C. for 1 hour. TLC showed (1E)-2,6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (471 mg, 1.25 mmol, 1.5 eq) was consumed completely and a new spot 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. LC-MS showed 7-(4-chloro-2-fluoro-phenyl)-4, 7-diazaspiro [2.5]octane was consumed completely and desired mass was detected. The reaction mixture was partitioned between water (30 mL) and EtOAc (90 mL). The organic phase was separated, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give desired N-[(E)-[[7-(4-chloro-2-fluoro-phenyl)-4,7-diazaspiro[2.5]octan-4-yl]-(2,6-dichlorophenyl)methylene]amino]-4-methyl-benzenesulfonamide (500 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C26H24C13FN4O2S 580.1, m/z found 581.1 [M+H]+.

Step 5: To a solution of 4-chloro-3-[7-(2-chloro-4-fluoro-phenyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (370 mg, 678 μmol, 1 eq) in MeOH (5 mL) was added K2CO3 (1.88 g, 13.6 mmol, 20 eq). The mixture was stirred at 70° C. for 0.5 hour. LC-MS showed 4-chloro-3-[7-(2-chloro-4-fluoro-phenyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and desired mass was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/ethyl acetate=2/1) to give desired 4-chloro-3-[7-(2-chloro-4-fluoro-phenyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1H-indazole (120 mg, crude) as an orange oil. MS (ESI): mass calcd. For C19H17Cl2FN4 390.08, m/z found 391.1 [M+H]+.

Step 4: To a solution of N-[(E)-[(2,6-dichlorophenyl)-[7-(2, 4-difluorophenyl)-4,7-diazaspiro[2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (500 mg, 884 μmol, 1 eq) in DMF (10 mL) was added K2CO3 (611 mg, 4.42 mmol, 5 eq). The mixture was stirred at 100° C. for 12 hours. LC-MS showed N-[(E)-[(2,6-dichlorophenyl)-[7-(2, 4-difluorophenyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude was added H2O (20 mL), and extracted with EtOAc (15 mL*3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 4-chloro-3-[7-(2,4-difluorophenyl)-4,7-diazaspiro[2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (470 mg, crude) as a brown oil. MS (ESI): mass calcd. For C26H23ClF2N4O2S 529.00, m/z found 529.1 [M+H]+.

Step 3: The mixture of 2-[4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-4, 7-diazaspiro [2.5]octan-7-yl]-2-methyl-propane-1,3-diol (300 mg, 594 μmol, 1 eq) in DCM (6 mL) was added DAST (383 mg, 2.38 mmol, 4 eq) at 0° C., the reaction was stirred at 25° C. for 1 hour. LCMS showed 2-[4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-4, 7-diazaspiro [2.5]octan-7-yl]-2-methyl-propane-1, 3-diol was consumed completely and desired mass was detected. The reaction mixture was quenched by addition saturated aqueous NaHCO3 solution (20 mL) at 0° C., and then extracted with DCM (20 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/Ethyl acetate=5/1 to 3/1) to give desired 4-chloro-3-[7-[2-fluoro-1-(fluoromethyl)-1-methyl-ethyl]-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (200 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C24H27ClF2N4O2S 508.15 m/z found 509.2 [M+H]+.

Step 4: The mixture of 4-chloro-3-[7-[2-fluoro-1-(fluoromethyl)-1-methyl-ethyl]-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (100 mg, 196 μmol, 1 eq) in MeOH (3 mL) was added K2CO3 (54.3 mg, 393 μmol, 2 eq), the reaction was stirred at 50° C. for 1 hour. LCMS showed 4-chloro-3-[7-[2-fluoro-1-(fluoromethyl)-1-methyl-ethyl]-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and desired mass was detected. The reaction mixture was quenched by addition water (10 mL) at 0° C., and then extracted with Ethyl acetate (10 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=5/1 to 3/1) to give desired 4-chloro-3-[7-[2-fluoro-1-(fluoromethyl)-1-methyl-ethyl]-4, 7-diazaspiro [2.5]octan-4-yl]-1H-indazole (80 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C17H21ClF2N4 354.14 m/z found 355.2 [M+H]+.

Step 1: To a solution of 7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octane (300 mg, 1.44 mmol, 1 eq) in THF (10 mL) was added dropwise TEA (1.46 g, 14.4 mmol, 2.0 mL, 10 eq) at 25° C. After addition, the mixture was stirred at this temperature for 10 mins, and then (1Z)-2, 6-difluoro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride (745 mg, 2.16 mmol, 1.5 eq) in THF (3 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 20 mins. LC-MS showed 7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octane was consumed completely and one main peak with desired mass was detected. Then it was separated between 20 mL of H2O and 40 mL of EtOAc. The organic phase was separated, washed with 30 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give desired N—[(Z)-[(2,6-difluorophenyl)-[7-(5-fluoropyrimidin-2-yl)-4,7-diazaspiro[2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (740 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C24H23F3N6SO2 516.16 m/z found 517.2 [M+H]+

Step 2: To a solution of methyl 2-benzyloxy-6-fluoro-benzoate (500 mg, 1.92 mmol, 1 eq) in THF (5 mL) and H2O (1 mL) was added NaOH (154 mg, 3.84 mmol, 2 eq). The mixture was stirred at 20° C. for 1 hour. TLC (petroleum ether/EtOAc=3/1) indicated methyl 2-benzyloxy-6-fluoro-benzoate was consumed completely and one new spot formed. The reaction was clean according to TLC (petroleum ether/EtOAc=3/1). The mixture to pH 2 with 1M HCl. Add EtOAc to the suspension and rinse with water. The organic layer is dried on Na2SO4, filtered, and the solvent removed in a vacuum to give desired 2-benzyloxy-6-fluoro-benzoic acid (330 mg, crude) as a white oil.

Step 3: To a solution of 2-benzyloxy-6-fluoro-benzoic acid (330 mg, 1.34 mmol, 1 eq) and (COCl)2 (204 mg, 1.61 mmol, 141 μL, 1.2 eq) in DCM (5 mL) was added DMF (9.8 mg, 134 μmol, 10.3 μL, 0.1 eq). The mixture was stirred at 15° C. for 1 hour. TLC (petroleum ether/EtOAc=3/1) indicated 2-benzyloxy-6-fluoro-benzoic acid was consumed completely and one new spot formed. The reaction was clean according to TLC (petroleum ether/EtOAc=3/1). The reaction mixture was partitioned between H2O (30 mL) and DCM (50 mL). The organic phase was separated, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 2-benzyloxy-6-fluoro-benzoyl chloride (350 mg, crude) as a white oil.

Step 6: To a solution of (2-benzyloxy-6-fluoro-phenyl)-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]methanethione (100 mg, 221 μmol, 1 eq) in NMP (0.5 mL) was added NH2NH2·H2O (0.5 mL). The mixture was stirred at 150° C. for 3 hours. LC-MS showed (2-benzyloxy-6-fluoro-phenyl)-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]methanethione remained and one main peak with desired mass was detected. Three reactions were combined for workup. The reaction mixture was partitioned between H2O (30 mL) and EtOAc (30 mL). The organic phase was separated, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 4-benzyloxy-3-[7-(5-fluoropyrimidin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl]-1H-indazole (530 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C24H23FN6O 430.19, m/z found 431.2 [M+H]+.

Step 1: To a solution of 1-(2-chloropyrimidin-5-yl)ethanone (2 g, 12.8 mmol, 1 eq) in DCM (50 mL) was added DAST (10.3 g, 63.9 mmol, 8.44 mL, 5 eq) at −78° C. The mixture was stirred at 20° C. for 12 hours. LC-MS showed 1-(2-chloropyrimidin-5-yl)ethanone was consumed completely and one main peak with desired mass was detected. The reaction mixture was added to sat. NaHCO3 aq. (20 mL), extracted with DCM (10 mL*3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/Ethyl acetate=1/0 to 0/1) to give desired 2-chloro-5-(1, 1-difluoroethyl) pyrimidine (1.87 g, crude) as a white solid. MS (ESI): mass calcd. For C6H5ClF2N2 178.01 m/z found 179.0 [M+H]+.

Step 1: To a solution of 1-(5-BROMOPYRIMIDIN-2-YL) ETHANONE (2 g, 9.95 mmol, 1 eq) in DCM (120 mL) and Tol. (10 mL) was added BAST (8.80 g, 39.8 mmol, 8.72 mL, 4 eq) at 0° C. under N2. The mixture was stirred at 20° C. for 12 hours. LC-MS showed 1-(5-BROMOPYRIMIDIN-2-YL) ETHANONE was consumed completely and one main peak with desired mass was detected. Then it was separated between 30 mL of NaHCO3 solution and 60 mL of EtOAc. The organic phase was separated, washed with 30 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®; 2 g SepaFlash® Silica Flash Column, Eluent of 0˜20% ethyl acetate/petroleum ether gradient @60 mL/min) to give desired 5-bromo-2-(1, 1-difluoroethyl) pyrimidine (2.16 g, 9.69 mmol, 97.3% yield) as a yellow oil. MS (ESI): mass calcd. For C6H5BrF2N2 221.96 m/z found 223.0 [M+H]+.

Step 3: To a solution of HCl (0.3 mL) in ACN (3 mL) was added NCS (602 mg, 4.51 mmol, 4 eq) at 0° C. The mixture was stirred at 0° C. for 5 min. 5-benzylsulfanyl-2-(1, 1-difluoroethyl) pyrimidine (300 mg, 1.13 mmol, 1 eq) in ACN (3 mL) was added dropwise to the reaction. The mixture was stirred at 0° C. for 30 min. LC-MS showed 5-benzylsulfanyl-2-(1, 1-difluoroethyl) pyrimidine was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated to give the crude product. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 2-(1,1-difluoroethyl)pyrimidine-5-sulfonyl chloride (270 mg, crude) as a white solid. MS (ESI): mass calcd. For C6H5ClF2N2O2S 241.97 m/z found 292.1 [M+H+49]+.

Step 3: To a solution of 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-3, 5-dimethyl-morpholine (2.3 g, 5.48 mmol, 1 eq) in MeOH (20 mL) was added K2CO3 (3.79 g, 27.4 mmol, 5 eq). The mixture was stirred at 70° C. for 2 hours. LC-MS showed 4-[4-chloro-1-(p-tolylsulfonyl) indazol-3-yl]-3, 5-dimethyl-morpholine remained and the desired compound was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (30 mL). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/EtOAc=3/1) to give desired 4-(4-chloro-1H-indazol-3-yl)-3, 5-dimethyl-morpholine (450 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C13H16ClN3O 265.10, m/z found 266.1 [M+H]+.

Step 3: To a solution of 4-chloro-3-[7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (225 mg, 412 μmol, 1 eq) in MeOH (4 mL) was added K2CO3 (285 mg, 2.06 mmol, 5 eq). The mixture was stirred at 70° C. for 4 hours. LC-MS showed 4-chloro-3-[7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and one main peak with desired m/z was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (10 mL) and extracted with DCM (30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/EtOAc=3/1) to give desired 4-chloro-3-[7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1H-indazole (200 mg, 510 μmol, 61.9% yield) as a yellow oil. MS (ESI): mass calcd. For C18H16Cl2FN5 391.08, m/z found 392.1 [M+H]+.

Step 1: To a solution of (1Z)-2, 6-dichloro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (649 mg, 1.72 mmol, 1.5 eq) in THF (3 mL) was added dropwise TEA (348 mg, 3.44 mmol, 3 eq) at 20° C. After addition, the mixture was stirred at this temperature for 5 mins, and then 7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octane (300 mg, 1.15 mmol, 1 eq, HCl) in THF (2 mL) was added dropwise at 0° C. The resulting mixture was stirred at 20° C. for 25 mins. LC-MS showed 7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octane was consumed completely and one main peak with desired mass was detected. The reaction mixture was added to water (90 mL), extracted with EtOAc (90 mL). The combined organic layers were washed with brine (90 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/EtOAc=3/1) to give desired N—[(Z)-[(2, 6-dichlorophenyl)-[7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (260 mg, 459 μmol, 40.0% yield) as a yellow oil. MS (ESI): mass calcd. For C25H23N5SO2Cl2F2 565.09, m/z found 566.0 [M+H]+.

Step 3: To a solution of 4-chloro-3-[7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-6-fluoro-1-(p-tolylsulfonyl) indazole (1.6 g, 2.83 mmol, 1 eq) in MeOH (20 mL) was added K2CO3 (1.96 g, 14.2 mmol, 5 eq). The mixture was stirred at 70° C. for 0.2 hour. LC-MS showed 4-chloro-3-[7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-6-fluoro-1-(p-tolylsulfonyl) indazole was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude was added H2O (40 mL) and extracted with EtOAc (30 mL*3). The combined organic layers were washed with brine (40 mL), dried over anhydrous 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˜35% EtOAc/petroleum ether gradient @100 mL/min) to give desired 4-chloro-3-(7-(5-chloro-3-fluoropyridin-2-yl)-4, 7-diazaspiro [2.5]octan-4-yl)-6-fluoro-1H-indazole (300 mg, 731 μmol, 25.8% yield) as a yellow oil. MS (ESI): mass calcd. For C18H15Cl2F2N5 409.07, m/z found 410.0 [M+H]+.

Step 1: To a solution of 3, 5-dichloropyridine-4-carboxylic acid (4 g, 20.8 mmol, 1 eq) in DCM (40 mL) was added oxalyl dichloride (7.93 g, 62.5 mmol, 5.47 mL, 3 eq) and DMF (76.1 mg, 1.04 mmol, 80.2 μL, 0.05 eq). The mixture was stirred at 20° C. for 1 hour. The reaction mixture was quenched by addition MeOH (0.5 mL). TLC (petroleum ether/Ethyl acetate=2/1) indicated 3, 5-dichloropyridine-4-carboxylic acid was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was concentrated under reduced pressure to remove DCM to give desired 3, 5-dichloropyridine-4-carbonyl chloride (4.73 g, crude) as a yellow solid.

Step 2: To a solution of 4-methylbenzenesulfonohydrazide (1.59 g, 8.55 mmol, 1.5 eq) in DCM (10 mL) was added TEA (1.44 g, 14.3 mmol, 1.98 mL, 2.5 eq). Then 3, 5-dichloropyridine-4-carbonyl chloride (1.2 g, 5.70 mmol, 1 eq) in DCM (5 mL) was added dropwise at 0° C. The mixture was stirred at 20° C. for 0.5 hour. LC-MS showed 4-methylbenzenesulfonohydrazide was consumed completely and 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 desired 3, 5-dichloro-N′-(p-tolylsulfonyl)pyridine-4-carbohydrazide (1.95 g, crude) as a white solid. MS (ESI): mass calcd. For C13H11Cl2N3O3S 358.99, m/z found 360.1 [M+H]+.

Step 6: To a solution of 4-chloro-3-[7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) pyrazolo [3, 4-c]pyridine (73 mg, 133 μmol, 1 eq) in MeOH (2 mL) was added K2CO3 (92.2 mg, 667 μmol, 5 eq). The mixture was stirred at 70° C. for 1 hour. LC-MS showed 4-chloro-3-[7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) pyrazolo [3, 4-c]pyridine was consumed completely and desired mass was detected. The reaction mixture was filtered and the filter liquor was concentrated under reduced pressure to give a residue. 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 (SiO2, petroleum ether/Ethyl acetate=1/1) to give desired 4-chloro-3-[7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1H-pyrazolo [3, 4-c]pyridine (23 mg, 58.5 μmol, 43.9% yield) as a white solid. MS (ESI): mass calcd. For C17H15Cl2FN6 392.07, m/z found 393.0 [M+H]+.

Step 2: To a solution of 4-chloro-3-[7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) pyrazolo [3, 4-b]pyridine and 4-chloro-3-(7-(5-chloro-3-fluoropyridin-2-yl)-4,7-diazaspiro[2.5]octan-4-yl)-1-tosyl-1H-pyrazolo[4,3-c]pyridine (180 mg, 329 μmol, 1 eq) in MeOH (3 mL) was added K2CO3 (227 mg, 1.64 mmol, 5 eq). The mixture was stirred at 70° C. for 3 hours. LC-MS showed the starting material were consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (5 mL) and extracted with DCM (50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/EtOAc=2/1) to give two isomers. The structures were assigned randomly. 4-Chloro-3-[7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1H-pyrazolo [3, 4-b]pyridine (14 mg, 35.6 μmol, 10.8% yield) was obtained as a yellow oil. MS (ESI): mass calcd. For C17H15Cl2FN6 392.07, m/z found 393.0 [M+H]+. 4-Chloro-3-(7-(5-chloro-3-fluoropyridin-2-yl)-4,7-diazaspiro[2.5]octan-4-yl)-1H-pyrazolo[4,3-c]pyridine (10 mg, 18.3 μmol, 35.71% yield) was obtained as a yellow oil. MS (ESI): mass calcd. For C17H15Cl2FN6 392.07, m/z found 393.0 [M+H]+.

Note: Since the structure of 4-chloro-3-[7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1H-pyrazolo [3, 4-b]pyridine and 4-Chloro-3-(7-(5-chloro-3-fluoropyridin-2-yl)-4,7-diazaspiro[2.5]octan-4-yl)-1H-pyrazolo[4,3-c]pyridine were not confirmed by 2D NMR and they are assigned randomly, after treatment with the isopropylsulfonylpyrrole-3-sulfonyl chloride, the final compounds 4-chloro-3-[7-(5-chloro-3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(1-isopropylsulfonylpyrrol-3-yl) sulfonyl-pyrazolo [3, 4-b]pyridine and 4-chloro-3-(7-(5-chloro-3-fluoropyridin-2-yl)-4,7-diazaspiro[2.5]octan-4-yl)-1-((1-(isopropylsulfonyl)-1H-pyrrol-3-yl)sulfonyl)-1H-pyrazolo[4,3-c]pyridine were also assigned randomly.

Step 2: To a solution of tert-butyl 7-(3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octane-4-carboxylate (260 mg, 846 μmol, 1 eq) in HCl/MeOH (5 mL). The mixture was stirred at 15° C. for 0.5 hour. TLC (petroleum ether/EtOAc=5/1) indicated 7-(3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octane-4-carboxylate was consumed completely and one new spot formed. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give desired 7-(3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octane (0.26 g, crude) as a white solid.

Step 3: To a solution of 7-(3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octane (0.26 g, 1.07 mmol, 1 eq, HCl) in THF (4 mL) was added dropwise TEA (1.08 g, 10.7 mmol, 1.48 mL, 10 eq) at 25° C. After addition, the mixture was stirred at this temperature for 10 mins, and then (1Z)-2, 6-dichloro-4-fluoro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride (464 mg, 1.17 mmol, 1.1 eq) in THF (2 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 0.5 hour. LC-MS showed 7-(3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octane was consumed completely and 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 desired N—[(Z)-[(2, 6-dichloro-4-fluoro-phenyl)-[7-(3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (960 mg, crude) as a white solid. MS (ESI): mass calcd. For C25H23Cl2F2N5O2S 565.1 found 566.1 [M+H]+.

Step 4: To a solution of N—[(Z)-[(2, 6-dichloro-4-fluoro-phenyl)-[7-(3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (480 mg, 847 μmol, 1 eq) in DMF (10 mL) was added K2CO3 (586 mg, 4.24 mmol, 5 eq). The mixture was stirred at 80° C. for 1 hour. LC-MS showed N—[(Z)-[(2, 6-dichloro-4-fluoro-phenyl)-[7-(3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and 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 desired 4-chloro-6-fluoro-3-[7-(3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (670 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C25H22ClF2N5O2S 529.1 found 530.1 [M+H]+.

Step 5: To a solution of 4-chloro-6-fluoro-3-[7-(3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (670 mg, 1.26 mmol, 1 eq) in MeOH (5 mL) was added K2CO3 (874 mg, 6.32 mmol, 5 eq). The mixture was stirred at 70° C. for 1 hour. LC-MS showed 4-chloro-6-fluoro-3-[7-(3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. 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 (SiO2, petroleum ether/EtOAc=2/1) to give desired 4-chloro-6-fluoro-3-[7-(3-fluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1H-indazole (240 mg, 639 μmol, 50.52% yield) as a yellow solid. MS (ESI): mass calcd. For C18H16ClF2N5 375.1 found 376.1 [M+H]+.

Step 1: A mixture of tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (806 mg, 3.80 mmol, 2 eq), 2-bromopyridine (300 mg, 1.90 mmol, 181 μL, 1 eq), BINAP (118.23 mg, 190 μmol, 0.1 eq), Pd2(dba)3 (86.9 mg, 94.9 μmol, 0.05 eq) and t-BuONa (547 mg, 5.70 mmol, 3 eq) in Tol (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100° C. for 12 hours under N2 atmosphere. TLC indicated tert-butyl 4, 7-diazaspiro [2.5]octane-4-carboxylate was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was added to water (20 mL), the aqueous phase was extracted with EtOAc (20 mL*3). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/EtOAc=1/0 to 0/1) to give desired tert-butyl 7-(2-pyridyl)-4, 7-diazaspiro [2.5]octane-4-carboxylate (440 mg, crude) as a white solid.

Step 3: To a solution of (1Z)-2, 6-dichloro-4-fluoro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride (418 mg, 1.06 mmol, 1 eq) in THF (3 mL) was added dropwise TEA (1.07 g, 10.6 mmol, 1.47 mL, 10 eq) at 25° C. After addition, the mixture was stirred at this temperature for 10 mins, and then 7-(2-pyridyl)-4, 7-diazaspiro [2.5]octane (200 mg, 1.06 mmol, 1 eq) in THF (1 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 0.5 hour. LC-MS showed desired mass was detected. The reaction mixture was added to water (20 mL), the aqueous phase was extracted with EtOAc (20 mL*3). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated to give desired N—[(Z)-[(2,6-dichloro-4-fluoro-phenyl)-[7-(2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (460 mg, crude) as a white solid. MS (ESI): mass calcd. For C25H24Cl2FN5O2S 547.1, m/z found 548.1 [M+H]+.

Step 4: To a solution of N—[(Z)-[(2, 6-dichloro-4-fluoro-phenyl)-[7-(2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (460 mg, 839 μmol, 1 eq) in DMF (5 mL) was added K2CO3 (579.58 mg, 4.19 mmol, 5 eq). The mixture was stirred at 80° C. for 12 hours. LC-MS showed desired mass was detected. The reaction mixture was added to water (20 mL), the aqueous phase was extracted with EtOAc (20 mL*3). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated to give desired 4-chloro-6-fluoro-1-(p-tolylsulfonyl)-3-[7-(2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]indazole (450 mg, crude) as a white solid. MS (ESI): mass calcd. For C25H23ClFN5O2S 511.12, m/z found 512.1 [M+H]+.

Step 5: To a solution of 4-chloro-6-fluoro-1-(p-tolylsulfonyl)-3-[7-(2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]indazole (450 mg, 879 μmol, 1 eq) in MeOH (5 mL) was added K2CO3 (486 mg, 3.52 mmol, 4 eq). The mixture was stirred at 80° C. for 0.5 hour. LC-MS showed 4-chloro-6-fluoro-1-(p-tolylsulfonyl)-3-[7-(2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]indazole was consumed completely and desired mass was detected. The reaction mixture was added to water (20 mL), the aqueous phase was extracted with EtOAc (20 mL*3). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/EtOAc=1/1) to give desired 4-chloro-6-fluoro-3-[7-(2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1H-indazole (140 mg, crude) as a white solid. MS (ESI): mass calcd. For C18H17ClFN5 357.12, m/z found 358.1 [M+H]+.

Step 1: To a solution of (1Z)-2, 6-dichloro-4-fluoro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (416 mg, 1.05 mmol, 1 eq) in THF (3 mL) was added dropwise TEA (1.06 g, 10.5 mmol, 1.46 mL, 10 eq) at 25° C. After addition, the mixture was stirred at this temperature for 10 mins, and then 7-pyrimidin-2-yl-4, 7-diazaspiro [2.5]octane (200 mg, 1.05 mmol, 1 eq) in THF (1 mL) was added dropwise at 0° C. The mixture was stirred at 25° C. for 0.5 hour. LC-MS showed (1Z)-2, 6-dichloro-4-fluoro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride was consumed completely and desired mass was detected. The reaction mixture was added to water (20 mL), the aqueous phase was extracted with EtOAc (20 mL*3). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated to give desired N—[(Z)-[(2, 6-dichloro-4-fluoro-phenyl)-(7-pyrimidin-2-yl-4, 7-diazaspiro [2.5]octan-4-yl) methylene]amino]-4-methyl-benzenesulfonamide (480 mg, crude) as a white solid. MS (ESI): mass calcd. For C24H23Cl2FN6O2S 548.1, m/z found 549.1 [M+H]+.

Step 2: To a solution of N—[(Z)-[(2, 6-dichloro-4-fluoro-phenyl)-(7-pyrimidin-2-yl-4, 7-diazaspiro [2.5]octan-4-yl) methylene]amino]-4-methyl-benzenesulfonamide (480 mg, 874 μmol, 1 eq) in DMF (5 mL) was added K2CO3 (603.71 mg, 4.37 mmol, 5 eq). The mixture was stirred at 80° C. for 12 hours. LC-MS showed desired mass was detected. The reaction mixture was added to water (20 mL), the aqueous phase was extracted with EtOAc (20 mL*3). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated to give desired 4-chloro-6-fluoro-1-(p-tolylsulfonyl)-3-(7-pyrimidin-2-yl-4, 7-diazaspiro [2.5]octan-4-yl) indazole (450 mg, crude) as a white solid. MS (ESI): mass calcd. For C24H22ClFN6O2S 512.12, m/z found 513.1 [M+H]+.

Step 3: To a solution of 4-chloro-6-fluoro-1-(p-tolylsulfonyl)-3-(7-pyrimidin-2-yl-4, 7-diazaspiro [2.5]octan-4-yl) indazole (450 mg, 877 μmol, 1 eq) in MeOH (5 mL) was added K2CO3 (484.95 mg, 3.51 mmol, 4 eq). The mixture was stirred at 80° C. for 0.5 hour. LC-MS showed 4-chloro-6-fluoro-1-(p-tolylsulfonyl)-3-(7-pyrimidin-2-yl-4, 7-diazaspiro [2.5]octan-4-yl) indazole was consumed completely and desired mass was detected. The reaction mixture was added to water (20 mL), the aqueous phase was extracted with EtOAc (20 mL*3). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/EtOAc=1/1) to give desired 4-chloro-6-fluoro-3-(7-pyrimidin-2-yl-4, 7-diazaspiro [2.5]octan-4-yl)-1H-indazole (160 mg, crude) as a white solid. MS (ESI): mass calcd. For C17H16ClFN6 358.11, m/z found 359.1 [M+H]+.

Step 1: To a solution of 7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octane (216 mg, 827 μmol, 1 eq, HCl) in THF (10 mL) was added dropwise TEA (418 mg, 4.14 mmol, 576 μL, 5 eq) at 25° C. After addition, the mixture was stirred at this temperature for 10 mins, and then (1Z)-4-chloro-2, 6-difluoro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (345 mg, 910 μmol, 1.1 eq) in was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 20 mins. LC-MS showed 7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octane was consumed completely and one main peak with 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, filtered and concentrated under reduced pressure to give desired N—[(Z)-[(4-chloro-2, 6-difluoro-phenyl)-[7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (450 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C25H22ClF4N5O2S 567.11, m/z found 568.2 [M+H]+.

Step 3: To a solution of 6-chloro-3-[7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-4-fluoro-1-(p-tolylsulfonyl) indazole (430 mg, 785 μmol, 1 eq) in MeOH (20 mL) was added K2CO3 (542 mg, 3.92 mmol, 5 eq). The mixture was stirred at 70° C. for 1 hour. LC-MS showed 6-chloro-3-[7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-4-fluoro-1-(p-tolylsulfonyl) indazole was consumed completely and desired compound was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine 20 mL and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/Ethyl acetate=1/0 to 1/1) to give desired 6-chloro-3-[7-(3, 5-difluoro-2-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-4-fluoro-1H-indazole (140 mg, 356 μmol, 45.3% yield) as a yellow oil. MS (ESI): mass calcd. For C18H15ClF3N5 393.10, m/z found 394.2 [M+H]+.

Step 3: To a solution of 7-(4-fluorophenyl)-4, 7-diazaspiro [2.5]octane (419 mg, 1.73 mmol, 1 eq, HCl) in THF (10 mL) was added dropwise TEA (1.75 g, 17.3 mmol, 2.40 mL, 10 eq) at 25° C. After addition, the mixture was stirred at this temperature for 10 mins, and then (1Z)-2, 6-dichloro-4-fluoro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (750 mg, 1.90 mmol, 1.1 eq) in THF (2 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 20 mins. LC-MS showed 7-(4-fluorophenyl)-4, 7-diazaspiro [2.5]octane was consumed completely and one main peak with 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, filtered and concentrated under reduced pressure to give desired N—[(Z)-[(2, 6-dichloro-4-fluoro-phenyl)-[7-(4-fluorophenyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (1 g, crude) as a yellow solid. MS (ESI): mass calcd. For C26H24Cl2F2N4O2S 564.10, m/z found 565.2 [M+H]+.

Step 4: To a solution of N—[(Z)-[(2, 6-dichloro-4-fluoro-phenyl)-[7-(4-fluorophenyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (1 g, 1.77 mmol, 1 eq) in DMF (5 mL) was added K2CO3 (1.22 g, 8.84 mmol, 5 eq). The mixture was stirred at 80° C. for 1 hour. LC-MS showed N—[(Z)-[(2, 6-dichloro-4-fluoro-phenyl)-[7-(4-fluorophenyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and desired mass was detected. The reaction mixture was added to 20 mL of water, the aqueous phase was extracted with 30 mL of EtOAc. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated to give desired 4-chloro-6-fluoro-3-[7-(4-fluorophenyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (1.1 g, crude) as a black oil. MS (ESI): mass calcd. For C26H23ClF2N4O2S 528.12, m/z found 529.2 [M+H]+.

Step 5: To a solution of 4-chloro-6-fluoro-3-[7-(4-fluorophenyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole (1.1 g, 2.08 mmol, 1 eq) in MeOH (5 mL) was added K2CO3 (1.15 g, 8.32 mmol, 4 eq). The mixture was stirred at 80° C. for 0.5 hour. LC-MS showed 4-chloro-6-fluoro-3-[7-(4-fluorophenyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and desired mass was detected. The reaction mixture was added to 20 mL of water, the aqueous phase was extracted with 60 mL of EtOAc. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/Ethyl acetate=1/1) to give desired 4-chloro-6-fluoro-3-[7-(4-fluorophenyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1H-indazole (290 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C18H16ClF2N5 374.11, m/z found 375.1 [M+H]+.

Step 3: To a solution of 7-(4-pyridyl)-4, 7-diazaspiro [2.5]octane (390 mg, 1.73 mmol, 1 eq, HCl) in THF (10 mL) was added dropwise TEA (1.75 g, 17.3 mmol, 2.40 mL, 10 eq) at 25° C. After addition, the mixture was stirred at this temperature for 10 mins, and then (1Z)-2, 6-dichloro-4-fluoro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (750 mg, 1.90 mmol, 1.1 eq) in THF (2 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 20 mins. LC-MS showed 7-(4-pyridyl)-4, 7-diazaspiro [2.5]octane was consumed completely and one main peak with 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, filtered and concentrated under reduced pressure to give desired N—[(Z)-[(2, 6-dichloro-4-fluoro-phenyl)-[7-(4-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (1.2 g, crude) as a yellow solid. MS (ESI): mass calcd. For C25H24Cl2FN5O2S 547.10, m/z found 548.2 [M+H]+.

Step 4: To a solution of N—[(Z)-[(2, 6-dichloro-4-fluoro-phenyl)-[7-(4-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (1.2 g, 2.19 mmol, 1 eq) in DMF (5 mL) was added K2CO3 (1.51 g, 10.9 mmol, 5 eq). The mixture was stirred at 80° C. for 1 hour. LC-MS showed N—[(Z)-[(2, 6-dichloro-4-fluoro-phenyl)-[7-(4-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and desired mass was detected. The reaction mixture was added to water (20 mL), the aqueous phase was extracted with EtOAc (20 mL*3). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated to give desired 4-chloro-6-fluoro-1-(p-tolylsulfonyl)-3-[7-(4-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]indazole (1.1 g, crude) as a black oil. MS (ESI): mass calcd. For C25H23ClFN5O2S 511.12, m/z found 512.2 [M+H]+.

Step 5: To a solution of 4-chloro-6-fluoro-1-(p-tolylsulfonyl)-3-[7-(4-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]indazole (1.1 g, 2.15 mmol, 1 eq) in MeOH (5 mL) was added K2CO3 (1.19 g, 8.59 mmol, 4 eq). The mixture was stirred at 80° C. for 0.5 hour. LC-MS showed 4-chloro-6-fluoro-1-(p-tolylsulfonyl)-3-[7-(4-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]indazole was consumed completely and desired mass was detected. The reaction mixture was added to water (20 mL), the aqueous phase was extracted with EtOAc (20 mL*3). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/Ethyl acetate=1/1) to give desired 4-chloro-6-fluoro-3-[7-(4-pyridyl)-4, 7-diazaspiro [2.5]octan-4-yl]-1H-indazole (200 mg, crude) as a white solid. MS (ESI): mass calcd. For C18H17ClFN5 357.12, m/z found 358.2 [M+H]+.

Step 1: To a solution of 2-chloro-5-fluoro-pyrimidine (500 mg, 3.77 mmol, 467 μL, 1 eq) and tert-butyl (2S)-2-methylpiperazine-1-carboxylate (831 mg, 4.15 mmol, 1.1 eq) in ACN (5 mL) was added K2CO3 (1.56 g, 11.3 mmol, 3 eq). The mixture was stirred at 80° C. for 12 hours. LC-MS showed 2-chloro-5-fluoro-pyrimidine was consumed completely and desired mass was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/Ethyl acetate=1/0 to 1/1) to give desired tert-butyl (2S)-4-(5-fluoropyrimidin-2-yl)-2-methyl-piperazine-1-carboxylate (800 mg, crude) as a colourless oil. MS (ESI): mass calcd. For C14H21FN4O2 296.16, m/z found 241.1 [M+H]+.

Step 3: To a solution of 5-fluoro-2-[(3S)-3-methylpiperazin-1-yl]pyrimidine (200 mg, 1.02 mmol, 1 eq) in THF (5 mL) was added dropwise TEA (1.03 g, 10.2 mmol, 1.42 mL, 10 eq) at 25° C. After addition, the mixture was stirred at this temperature for 10 mins, and then (1Z)-2, 6-dichloro-4-fluoro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (444 mg, 1.12 mmol, 1.1 eq) in THF (5 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 20 mins. LC-MS showed 5-fluoro-2-[(3S)-3-methylpiperazin-1-yl]pyrimidine was consumed completely and one main peak with 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 brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give desired N—[(Z)-[(2, 6-dichloro-4-fluoro-phenyl)-[(2S)-4-(5-fluoropyrimidin-2-yl)-2-methyl-piperazin-1-yl]methylene]amino]-4-methyl-benzenesulfonamide (600 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C23H22Cl2F2N6O2S 554.09, m/z found 555.2 [M+H]+.

Step 4: To a solution of N—[(Z)-[(2, 6-dichloro-4-fluoro-phenyl)-[(2S)-4-(5-fluoropyrimidin-2-yl)-2-methyl-piperazin-1-yl]methylene]amino]-4-methyl-benzenesulfonamide (600 mg, 1.08 mmol, 1 eq) in DMF (10 mL) was added K2CO3 (597 mg, 4.32 mmol, 4 eq). The mixture was stirred at 80° C. for 1 hour. LC-MS showed N—[(Z)-[(2, 6-dichloro-4-fluoro-phenyl)-[(2S)-4-(5-fluoropyrimidin-2-yl)-2-methyl-piperazin-1-yl]methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and desired mass was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine 20 mL and dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 4-chloro-6-fluoro-3-[(2S)-4-(5-fluoropyrimidin-2-yl)-2-methyl-piperazin-1-yl]-1-(p-tolylsulfonyl) indazole (560 mg, crude) as a black oil. MS (ESI): mass calcd. For C23H21ClF2N6O2S 518.11, m/z found 519.2 [M+H]+.

Step 5: To a solution of 4-chloro-6-fluoro-3-[(2S)-4-(5-fluoropyrimidin-2-yl)-2-methyl-piperazin-1-yl]-1-(p-tolylsulfonyl) indazole (560 mg, 1.08 mmol, 1 eq) in MeOH (20 mL) was added K2CO3 (542 mg, 3.92 mmol, 5 eq). The mixture was stirred at 70° C. for 1 hour. LC-MS showed 4-chloro-6-fluoro-3-[(2S)-4-(5-fluoropyrimidin-2-yl)-2-methyl-piperazin-1-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and desired compound was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (20 Ml) and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/Ethyl acetate=1/0 to 1/1) to give desired 4-chloro-6-fluoro-3-[(2S)-4-(5-fluoropyrimidin-2-yl)-2-methyl-piperazin-1-yl]-1H-indazole (150 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C16H15ClF2N6 364.10, m/z found 365.1 [M+H]+.

Step 1: To a solution of 2-chloro-5-fluoro-pyrimidine (500 mg, 3.77 mmol, 467 μL, 1 eq) and tert-butyl (2R)-2-methylpiperazine-1-carboxylate (831 mg, 4.15 mmol, 1.1 eq) in ACN (5 mL) was added K2CO3 (1.56 g, 11.3 mmol, 3 eq). The mixture was stirred at 80° C. for 12 hours. LC-MS showed 2-chloro-5-fluoro-pyrimidine was consumed completely and desired mass was detected. The reaction mixture was added to 20 mL of water, extracted with 30 mL of EtOAc. The combined organic layers were washed with 20 mL of brine and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/EtOAc=1/0 to 1/1) to give desired tert-butyl (2R)-4-(5-fluoropyrimidin-2-yl)-2-methyl-piperazine-1-carboxylate (900 mg, crude) as a colourless oil. MS (ESI): mass calcd. For C14H21FN4O2 296.16, m/z found 241.1 [M+H−56]+.

Step 3: To a solution of 5-fluoro-2-[(3R)-3-methylpiperazin-1-yl]pyrimidine (200 mg, 860 μmol, 1 eq, HCl) in THF (3 mL) was added dropwise TEA (870 mg, 8.60 mmol, 1.20 mL, 10 eq) at 25° C. After addition, the mixture was stirred 25° C. for 10 mins, and then (1Z)-2, 6-dichloro-4-fluoro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride (374 mg, 945 μmol, 1.1 eq) in THF (3 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 20 mins. LC-MS showed 5-fluoro-2-[(3R)-3-methylpiperazin-1-yl]pyrimidine was consumed completely and one main peak with desired mass was detected. Then it was separated between 20 mL of water and 40 mL of EtOAc. The organic phase was separated, washed with 30 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give desired N—[(Z)-[(2, 6-dichloro-4-fluoro-phenyl)-[(2R)-4-(5-fluoropyrimidin-2-yl)-2-methyl-piperazin-1-yl]methylene]amino]-4-methyl-benzenesulfonamide (470 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C23H22Cl2F2N6O2S 554.09, m/z found 555.0 [M+H]+.

Step 4: To a solution of N—[(Z)-[(2, 6-dichloro-4-fluoro-phenyl)-[(2R)-4-(5-fluoropyrimidin-2-yl)-2-methyl-piperazin-1-yl]methylene]amino]-4-methyl-benzenesulfonamide (470 mg, 846 μmol, 1 eq) in DMF (10 mL) was added K2CO3 (468 mg, 3.38 mmol, 4 eq). The mixture was stirred at 80° C. for 1 hour. LC-MS showed N—[(Z)-[(2, 6-dichloro-4-fluoro-phenyl)-[(2R)-4-(5-fluoropyrimidin-2-yl)-2-methyl-piperazin-1-yl]methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and desired mass was detected. The reaction mixture was added to 20 mL of water, extracted with 30 mL of EtOAc. The combined organic layers were washed with 20 mL of brine and dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 4-chloro-6-fluoro-3-[(2R)-4-(5-fluoropyrimidin-2-yl)-2-methyl-piperazin-1-yl]-1-(p-tolylsulfonyl) indazole (440 mg, crude) as a black oil. MS (ESI): mass calcd. For C23H21ClF2N6O2S 518.11, m/z found 519.1 [M+H]+.

Step 5: To a solution of 4-chloro-6-fluoro-3-[(2R)-4-(5-fluoropyrimidin-2-yl)-2-methyl-piperazin-1-yl]-1-(p-tolylsulfonyl) indazole (440 mg, 848 μmol, 1 eq) in MeOH (20 mL) was added K2CO3 (586 mg, 4.24 mmol, 5 eq). The mixture was stirred at 70° C. for 1 hour. LC-MS showed 4-chloro-6-fluoro-3-[(2R)-4-(5-fluoropyrimidin-2-yl)-2-methyl-piperazin-1-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and desired compound was detected. The reaction mixture was added to 20 mL of water, extracted with 30 mL of EtOAc. The combined organic layers were washed with 20 mL of brine and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/EtOAc=1/0 to 1/1) to give desired 4-chloro-6-fluoro-3-[(2R)-4-(5-fluoropyrimidin-2-yl)-2-methyl-piperazin-1-yl]-1H-indazole (150 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C16H15ClF2N6 364.10, m/z found 365.1 [M+H]+.

Step 5: To a solution of 4-chloro-6-fluoro-3-[8-(5-fluoropyrimidin-2-yl)-5, 8-diazaspiro [3.5]nonan-5-yl]-1-(p-tolylsulfonyl) indazole (300 mg, 550 μmol, 1 eq) in MeOH (5 mL) was added K2CO3 (380 mg, 2.75 mmol, 5 eq). The mixture was stirred at 80° C. for 1 hour. LC-MS showed 4-chloro-6-fluoro-3-[8-(5-fluoropyrimidin-2-yl)-5, 8-diazaspiro [3.5]nonan-5-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude was added H2O (20 mL), and extracted with EtOAc (45 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 column prep-TLC (SiO2, petroleum ether/Ethyl acetate=2/1) to give desired 4-chloro-6-fluoro-3-(8-(5-fluoropyrimidin-2-yl)-5, 8-diazaspiro [3.5]nonan-5-yl)-1H-indazole (160 mg, 409 μmol, 74.4% yield) as a yellow oil. MS (ESI): mass calcd. For C18H17ClF2N6 390.12, m/z found 391.1 [M+H]+.

Step 2: To the solution of 1-(1-chloro-1-methyl-ethyl)sulfonyl-2,3,4,5-tetradeuterio-pyrrole (420 mg, 1.98 mmol, 1 eq) in ACN (10 mL) was added HSO3Cl (1.16 g, 9.92 mmol, 5 eq) and the solution was stirred at 80° C. for 1 hour. TLC showed 1-(1-chloro-1-methyl-ethyl) sulfonyl-2, 3, 4, 5-tetradeuterio-pyrrole was consumed completely and a main new spot was detected. The reaction was poured into water (20 mL) and extracted with MTBE (2*10 mL). The combined organics were concentrated to get a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0˜20% Ethyl acetate/petroleum ether gradient @50 mL/min) to give desired 1-(1-chloro-1-methyl-ethyl)sulfonyl-2,4,5-trideuterio-pyrrole-3-sulfonyl chloride (300 mg, 970 μmol, 48.9% yield) as a white solid.

Step 4: To a solution of N—[(Z)-[(2, 6-dichloro-4-fluoro-phenyl)-[7-(2, 6-difluorophenyl)-4, 7-diazaspiro [2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide (700 mg, 1.20 mmol, 1 eq) in DMF (10 mL) was added K2CO3 (1.66 g, 12.00 mmol, 10 eq). The mixture was stirred at 80° C. for 1 hour. LC-MS showed N—[(Z)-[(2,6-dichloro-4-fluoro-phenyl)-[7-(2,6-difluorophenyl)-4,7-diazaspiro[2.5]octan-4-yl]methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and desired mass was detected. The reaction mixture was added to water (20 mL), the aqueous phase was extracted with EtOAc (15 mL*3). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated to give desired 4-chloro-3-(7-(2,6-difluorophenyl)-4, 7-diazaspiro [2.5]octan-4-yl)-6-fluoro-1-tosyl-1H-indazole (600 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C26H22ClF3N4O2S 546.11, m/z found 547.2 [M+H]+.

Step 1: To the solution of tert-butyl 4, 7-diazaspiro [2.5]octane-4-carboxylate (200 mg, 942 μmol, 1 eq) and TEA (286 mg, 2.83 mmol, 3 eq) in THF (2 mL) was added methylsulfonyl methanesulfonate (197 mg, 1.13 mmol, 1.2 eq) at 20° C. and the solution was stirred at 20° C. for 2 hours. TLC showed tert-butyl 4, 7-diazaspiro [2.5]octane-4-carboxylate was consumed completely and a new spot was formed. The reaction was quenched with NH4Cl solution (1 mL) and the stirred for 15 min. The mixture was extracted with EtOAc (50 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated to give desired tert-butyl 7-methylsulfonyl-4, 7-diazaspiro [2.5]octane-4-carboxylate (273 mg, crude) as a white solid.

Step 1: To a solution of (1E)-2,6-dichloro-4-fluoro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (853 mg, 2.16 mmol, 1.5 eq) and 2-(trifluoromethyl)pyrrolidine (200 mg, 1.44 mmol, 1 eq) in THF (10 mL) was added TEA (364 mg, 3.59 mmol, 500 μL, 2.5 eq). The mixture was stirred at 20° C. for 1 hour. LC-MS showed (1E)-2, 6-dichloro-4-fluoro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride was consumed completely and 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 desired N-[(E)-[(2, 6-dichloro-4-fluoro-phenyl)-[2-(trifluoromethyl)pyrrolidin-1-yl]methylene]amino]-4-methyl-benzenesulfonamide (1.25 g, crude) as a yellow solid. MS (ESI): mass calcd. For C19H17Cl2F4N3O2S 497.0 m/z found 498.0 [M+H]+.

Step 2: To a solution of N-[(E)-[(2, 6-dichloro-4-fluoro-phenyl)-[2-(trifluoromethyl) pyrrolidin-1-yl]methylene]amino]-4-methyl-benzenesulfonamide (1.25 g, 2.51 mmol, 1 eq) in DMF (13 mL) was added K2CO3 (3.47 g, 25.1 mmol, 10 eq). The mixture was stirred at 100° C. for 12 hours. LC-MS showed N-[(E)-[(2, 6-dichloro-4-fluoro-phenyl)-[2-(trifluoromethyl) pyrrolidin-1-yl]methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and 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 desired 4-chloro-6-fluoro-1-(p-tolylsulfonyl)-3-[2-(trifluoromethyl)pyrrolidin-1-yl]indazole (1.16 g, crude) as a yellow solid. MS (ESI): mass calcd. For C19H16ClF4N3O2S 461.1, m/z found 462.1 [M+H]+.

Step 3: To a solution of 4-chloro-6-fluoro-1-(p-tolylsulfonyl)-3-[2-(trifluoromethyl) pyrrolidin-1-yl]indazole (1.16 g, 2.51 mmol, 1 eq) in MeOH (12 mL) was added K2CO3 (1.74 g, 12.6 mmol, 5 eq). The mixture was stirred at 80° C. for 1 hour. LC-MS showed 4-chloro-6-fluoro-1-(p-tolylsulfonyl)-3-[2-(trifluoromethyl) pyrrolidin-1-yl]indazole was consumed completely and 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 (SiO2, petroleum ether:EtOAc=3:1) to give desired 4-chloro-6-fluoro-3-[2-(trifluoromethyl)pyrrolidin-1-yl]-1H-indazole (65 mg, 211 μmol, 8.41% yield) was obtained as a yellow solid. MS (ESI): mass calcd. For Cl2H10ClF4N3 307.1, m/z found 308.1 [M+H]+.

Step 1: To a solution of 2-(3, 3-dimethylpiperazin-1-yl)-5-fluoro-pyrimidine (200 mg, 811 μmol, 1 eq, HCl) in THF (3 mL) was added dropwise TEA (820 mg, 8.11 mmol, 1.13 mL, 10 eq) at 25° C. After addition, the mixture was stirred at this temperature for 10 mins, and then (1Z)-2, 6-dichloro-4-fluoro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (353 mg, 892 μmol, 1.1 eq) in THF (3 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 20 mins. LC-MS showed 2-(3, 3-dimethylpiperazin-1-yl)-5-fluoro-pyrimidine was consumed completely and one main peak with desired mass was detected. Then it was separated between 20 mL of water and 40 mL of EtOAc. The organic phase was separated, washed with 30 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give desired N-[(E)-[(2, 6-dichloro-4-fluoro-phenyl)-[4-(5-fluoropyrimidin-2-yl)-2, 2-dimethyl-piperazin-1-yl]methylene]amino]-4-methyl-benzenesulfonamide (500 mg, crude) as a yellow solid. MS (ESI): mass calcd. For C24H24Cl2F2N6O2S 568.1, m/z found 569.1[M+H]+.

Step 2: To a solution of N-[(E)-[(2, 6-dichloro-4-fluoro-phenyl)-[4-(5-fluoropyrimidin-2-yl)-2, 2-dimethyl-piperazin-1-yl]methylene]amino]-4-methyl-benzenesulfonamide (500 mg, 878 μmol, 1 eq) in DMF (10 mL) was added K2CO3 (485 mg, 3.51 mmol, 4 eq). The mixture was stirred at 100° C. for 12 hours. LC-MS showed N-[(E)-[(2, 6-dichloro-4-fluoro-phenyl)-[4-(5-fluoropyrimidin-2-yl)-2, 2-dimethyl-piperazin-1-yl]methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and desired mass was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine 20 mL and dried over Na2SO4, filtered and concentrated under reduced pressure to give desired 4-chloro-6-fluoro-3-[4-(5-fluoropyrimidin-2-yl)-2, 2-dimethyl-piperazin-1-yl]-1-(p-tolylsulfonyl) indazole (460 mg, crude) as an orange oil. MS (ESI): mass calcd. For C24H23ClF2N6O2S 532.1, m/z found 533.2 [M+H]+.

Step 3: To a solution of 4-chloro-6-fluoro-3-[4-(5-fluoropyrimidin-2-yl)-2, 2-dimethyl-piperazin-1-yl]-1-(p-tolylsulfonyl) indazole (460 mg, 863 μmol, 1 eq) in MeOH (10 mL) was added K2CO3 (596 mg, 4.32 mmol, 5 eq). The mixture was stirred at 70° C. for 1 hour. LC-MS showed 4-chloro-6-fluoro-3-[4-(5-fluoropyrimidin-2-yl)-2, 2-dimethyl-piperazin-1-yl]-1-(p-tolylsulfonyl) indazole was consumed completely and desired compound was detected. The reaction mixture was added to water (20 mL), extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine 20 mL and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/EtOAc=1/0 to 1/1) to give desired 4-chloro-6-fluoro-3-[4-(5-fluoropyrimidin-2-yl)-2, 2-dimethyl-piperazin-1-yl]-1H-indazole (200 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C17H17ClF2N6 378.1, m/z found 379.0 [M+H]+.

Step 2: To a solution of 4-[4-chloro-6-fluoro-1-(p-tolylsulfonyl) indazol-3-yl]-N, N-dimethyl-4-azaspiro [2.5]octan-7-amine (53 mg, 111 μmol, 1 eq) in MeOH (2 mL) was added K2CO3 (76.8 mg, 556 μmol, 5 eq). The mixture was stirred at 50° C. for 1 hour. LC-MS showed 4-[4-chloro-6-fluoro-1-(p-tolylsulfonyl) indazol-3-yl]-N, N-dimethyl-4-azaspiro [2.5]octan-7-amine was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (5 mL) and extracted with EtOAc (10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition: column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [water(NH4HCO3)-ACN]; B %: 25%-55%, 8 min) to give desired 4-(4-chloro-6-fluoro-1H-indazol-3-yl)-N,N-dimethyl-4-azaspiro [2.5]octan-7-amine (25 mg, 77.5 μmol, 69.7% yield) as a yellow oil which was confirmed by LC-MS. MS (ESI): mass calcd. For C16H20ClFN4 322.1 m/z found 323.1 [M+H]+.

Step 1: To a solution of 4-azaspiro [2.5]octan-7-one (1.35 g, 8.34 mmol, 1.1 eq, HCl) in THF (10 mL) was added TEA (767 mg, 7.58 mmol, 1.06 mL, 1 eq). The mixture was stirred at 0° C. for 10 mins. Then (1E)-2,6-dichloro-4-fluoro-N-(p-tolylsulfonyl)benzohydrazonoyl chloride (3 g, 7.58 mmol, 1 eq) was added to the mixture. The mixture was stirred at 20° C. for 12 hours. LC-MS showed (1E)-2, 6-dichloro-4-fluoro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (150 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give desired N-[(E)-[(2, 6-dichloro-4-fluoro-phenyl)-(7-oxo-4-azaspiro [2.5]octan-4-yl)methylene]amino]-4-methyl-benzenesulfonamide (3.7 g, crude) as a yellow solid. MS (ESI): mass calcd. For C21H20Cl2FN3O3S 483.1 m/z found 484.0 [M+H]+.

Step 2: To a solution of N-[(E)-[(2, 6-dichloro-4-fluoro-phenyl)-(7-oxo-4-azaspiro [2.5]octan-4-yl) methylene]amino]-4-methyl-benzenesulfonamide (3.7 g, 7.64 mmol, 1 eq) in DMF (30 mL) was added K2CO3 (10.6 g, 76.4 mmol, 10 eq). The mixture was stirred at 100° C. for 3 hours. LC-MS showed N-[(E)-[(2, 6-dichloro-4-fluoro-phenyl)-(7-oxo-4-azaspiro [2.5]octan-4-yl) methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with H2O (50 mL) and extracted with MTBE (300 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0˜35% EtOAc/petroleum ether gradient @70 mL/min) to give desired 4-(4-chloro-6-fluoro-1H-indazol-3-yl)-4-azaspiro[2.5]octan-7-one (100 mg, 340 μmol, 4.46% yield) as a yellow solid which was confirmed by LC-MS. MS (ESI): mass calcd. For C14H13ClFN3O 293.1 m/z found 294.0 [M+H]+.

Step 1: To a solution of 1-azaspiro [3.3]heptane (150 mg, 1.12 mmol, 1 eq, HCl) in THF (5 mL) was added TEA (341 mg, 3.37 mmol, 469 μL, 3 eq). The mixture was stirred at 0° C. for 10 mins. Then (1Z)-2,6-dichloro-4-fluoro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride (533 mg, 1.35 mmol, 1.2 eq) was added to the mixture. The mixture was stirred at 20° C. for 12 hours. LC-MS showed (1Z)-2, 6-dichloro-4-fluoro-N-(p-tolylsulfonyl) benzohydrazonoyl chloride was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give desired N-[(E)-[1-azaspiro [3.3]heptan-1-yl-(2, 6-dichloro-4-fluoro-phenyl) methylene]amino]-4-methyl-benzenesulfonamide (510 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C20H20Cl2FN3O2S 455.1 m/z found 456.0 [M+H]+.

Step 2: To a solution of N-[(E)-[1-azaspiro [3.3]heptan-1-yl-(2, 6-dichloro-4-fluoro-phenyl) methylene]amino]-4-methyl-benzenesulfonamide (510 mg, 1.12 mmol, 1 eq) in DMF (5 mL) was added K2CO3 (1.54 g, 11.2 mmol, 10 eq). The mixture was stirred at 100° C. for 3 hours. LC-MS showed N-[(E)-[1-azaspiro [3.3]heptan-1-yl-(2, 6-dichloro-4-fluoro-phenyl) methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with H2O (20 mL) and extracted with MTBE (60 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give desired 3-(1-azaspiro[3.3]heptan-1-yl)-4-chloro-6-fluoro-1-(p-tolylsulfonyl) indazole (470 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C20H19ClFN3O2S 419.1 m/z found 420.1 [M+H]+.

Step 3: To a solution of 3-(1-azaspiro [3.3]heptan-1-yl)-4-chloro-6-fluoro-1-(p-tolylsulfonyl) indazole (470 mg, 1.12 mmol, 1 eq) in MeOH (5 mL) was added K2CO3 (773 mg, 5.60 mmol, 5 eq). The mixture was stirred at 50° C. for 1 hour. LC-MS showed 3-(1-azaspiro [3.3]heptan-1-yl)-4-chloro-6-fluoro-1-(p-tolylsulfonyl) indazole was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (10 mL) and extracted with EtOAc (30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/EtOAc=2/1) to give desired 3-(1-azaspiro[3.3]heptan-1-yl)-4-chloro-6-fluoro-1H-indazole (40 mg, 151 μmol, 13.5% yield) as a yellow solid which was confirmed by LC-MS. MS (ESI): mass calcd. For C13H13ClFN3 265.1 m/z found 266.2 [M+H]+.

Step 2: To a solution of N-[(E)-[(2, 6-dichloro-4-fluoro-phenyl)-(7-oxa-4-azaspiro [2.5]octan-4-yl) methylene]amino]-4-methyl-benzenesulfonamide (480 mg, 1.02 mmol, 1 eq) in DMF (5 mL) was added K2CO3 (1.40 g, 10.2 mmol, 10 eq). The mixture was stirred at 100° C. for 3 hours. LC-MS showed N-[(E)-[(2, 6-dichloro-4-fluoro-phenyl)-(7-oxa-4-azaspiro [2.5]octan-4-yl) methylene]amino]-4-methyl-benzenesulfonamide was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with H2O (20 mL) and extracted with MTBE (60 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give desired 4-[4-chloro-6-fluoro-1-(p-tolylsulfonyl) indazol-3-yl]-7-oxa-4-azaspiro [2.5]octane (440 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C20H19ClFN3O3S 435.1 m/z found 436.1 [M+H]+.

Step 3: To a solution of 4-[4-chloro-6-fluoro-1-(p-tolylsulfonyl) indazol-3-yl]-7-oxa-4-azaspiro [2.5]octane (440 mg, 1.01 mmol, 1 eq) in MeOH (10 mL) was added K2CO3 (698 mg, 5.05 mmol, 5 eq). The mixture was stirred at 50° C. for 1 hour. LC-MS showed 4-[4-chloro-6-fluoro-1-(p-tolylsulfonyl) indazol-3-yl]-7-oxa-4-azaspiro [2.5]octane was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (10 mL) and extracted with EtOAc (20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/EtOAc=2/1) to give desired 4-(4-chloro-6-fluoro-1H-indazol-3-yl)-7-oxa-4-azaspiro[2.5]octane (80 mg, 284 μmol, 28.1% yield) as a yellow oil which was confirmed by LC-MS. MS (ESI): mass calcd. For C13H13ClFN3O 281.1 m/z found 282.1 [M+H]+.

Step 2: To a solution of 4-chloro-3-(7, 7-difluoro-4-azaspiro [2.5]octan-4-yl)-6 fluoro-1-(p-tolylsulfonyl) indazole (80 mg, 170 μmol, 1 eq) in MeOH (3 mL) was added K2CO3 (118 mg, 851 μmol, 5 eq). The mixture was stirred at 50° C. for 1 hour. LCMS showed 4-chloro-3-(7, 7-difluoro-4-azaspiro [2.5]octan-4-yl)-6-fluoro-1-(p-tolylsulfonyl) indazole was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (5 mL) and extracted with EtOAc (20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/EtOAc=2/1) to give desired 4-chloro-3-(7, 7-difluoro-4-azaspiro [2.5]octan-4-yl)-6-fluoro-1H-indazole (30 mg, 95.0 μmol, 55.8% yield) as a pale yellow oil. MS (ESI): mass calcd. For C14H13ClF3N3 315.1 m/z found 316.0 [M+H]+.

Step 1: To a solution of 4-[4-chloro-6-fluoro-1-(p-tolylsulfonyl) indazol-3-yl]-4-azaspiro [2.5]octan-7-one (100 mg, 223 umol, 1 eq) in EtOH (3 mL) was added NaBH4 (16.9 mg, 447 μmol, 2 eq) at 0° C. The mixture was stirred at 20° C. for 1 hour. LC-MS showed 4-[4-chloro-6-fluoro-1-(p-tolylsulfonyl) indazol-3-yl]-4-azaspiro [2.5]octan-7-one was consumed completely and one main peak with desired mass was detected. The reaction was quenched with NH4Cl solution (5 mL) and stirred for 15 minutes. The mixture was concentrated to get a residue. The residue was added water (5 mL) and extracted with EtOAc (20 mL). The combined organics were dried over anhydrous sodium sulfate and concentrated to get a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/EtOAc=1/1) to give desired 4-[4-chloro-6-fluoro-1-(p-tolylsulfonyl) indazol-3-yl]-4-azaspiro [2.5]octan-7-ol (80 mg, 178 μmol, 79.6% yield) as a colourless oil. MS (ESI): mass calcd. For C21H21ClFN3O3S 449.1 m/z found 450.1 [M+H]+.

Step 3: To a solution of 4-chloro-6-fluoro-3-(7-fluoro-4-azaspiro [2.5]octan-4-yl)-1-(p-tolylsulfonyl) indazole (80 mg, 177 μmol, 1 eq) in MeOH (3 mL) was added K2CO3 (122 mg, 885 μmol, 5 eq). The mixture was stirred at 80° C. for 2 hours. LC-MS showed 4-chloro-6-fluoro-3-(7-fluoro-4-azaspiro [2.5]octan-4-yl)-1-(p-tolylsulfonyl) indazole was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (5 mL) and extracted with EtOAc (30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether/EtOAc=2/1) to give desired 4-chloro-6-fluoro-3-(7-fluoro-4-azaspiro [2.5]octan-4-yl)-1H-indazole (17 mg, 57.1 μmol, 32.3% yield) as a yellow oil. MS (ESI): mass calcd. For C14H14ClF2N3 297.1 m/z found 298.1 [M+H]+.

Biological Assays

GCaMP3-ML1 expression was induced in Tet-On HEK-GCaMP3-ML1 cells 20-24 h prior to experiments using 0.01 μg/mL doxycycline. GCaMP3-ML1 fluorescence was monitored at an excitation wavelength of 470 nm (F470) using an EasyRatio Pro system (PTI). Cells were bathed in Tyrode's solution containing 145 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM Glucose, and 20 mM Hepes (pH 7.4). Lysosomal Ca2+ release was measured in a zero Ca2+ solution containing 145 mM NaCl, 5 mM KCl, 3 nM MgCl2, 10 mM glucose, 1 mM EGTA, and 20 mM HEPES (pH 7.4). Ca2+ concentration in the nominally free Ca2+ solution is estimated to be 1-10 μM. With 1 mM EGTA, the free Ca2+ concentration is estimated to be <10 nM based on the Maxchelator software (http://maxchelator.stanford.edu/). Experiments were carried out 0.5 to 6 hrs after plating.

The EC50 data for some of compounds are less than 10 uM.

TFEB is a transcription factor and master regulator of lysosome biogenesis and autophagy. TFEB activation is shown to induce cellular clearance in a variety of LSDs and common neurodegenerative diseases. Hence TFEB activity can be used to evaluate the cellular efficacy of TRPML agonists.

Intracellular TFEB localization is determined either by immunofluorescence in Hela cells or by fluorescent microscopy in Hela cells stably expressing TFEB-GFP. Detailed procedures are as follows.

Cells grown on cover slips were treated with TRPML1 agonist(s) or antagonist(s) for indicated time period and then fixed with 4% paraformaldehyde for 15 minutes at room temperature. For immunofluorescent detection of endogenous TFEB, cells were permeabilized with 0.3% Triton X-100, blocked with 1% bovine serum albumin (BSA) in phosphate buffered saline (PBS) and then immunostained with anti-TFEB antibody (1:200; Cell Signaling Technology) at 4° C. for overnight. The stained cells were then incubated with secondary antibodies conjugated to Alexa Fluor 568 or 488 (ThermoFisher) for 1 h, then 4′,6-diamidino-2-phenylindole (DAPI) for 15 min (to stain the cell nucleus) and mounted on glass slides with Fluoromount-G (Southern Biotech) for observation. Images were acquired with a Spinning-Disk Confocal microscope (Olympus) and Metamorph software (Molecular Devices).

Average ratios of nuclear versus cytosolic TFEB fluorescence intensity (>50 randomly-selected cells per experiment) were determined with ImageJ software (NIH). Exemplary data of TFEB nuclear translocation assay are provided in Table 1.

Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Methods recited herein may be carried out in any order that is logically possible, in addition to a particular order disclosed.

INCORPORATION BY REFERENCE

References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made in this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material. In the event of a conflict, the conflict is to be resolved in favor of the present disclosure as the preferred disclosure.

EQUIVALENTS

The representative examples are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples and the references to the scientific and patent literature included herein. The examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.