WO2022076383A1 - Dérivés de sulfonanilide et benzylsulfonyle, et compositions et procédés associés - Google Patents

Dérivés de sulfonanilide et benzylsulfonyle, et compositions et procédés associés Download PDF

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WO2022076383A1
WO2022076383A1 PCT/US2021/053533 US2021053533W WO2022076383A1 WO 2022076383 A1 WO2022076383 A1 WO 2022076383A1 US 2021053533 W US2021053533 W US 2021053533W WO 2022076383 A1 WO2022076383 A1 WO 2022076383A1
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compound
mmol
alkyl
nrr
reaction
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Yongchang Qiu
Congxin Liang
Xiang Yang Yu
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Lysoway Therapeutics, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • the invention generally relates to novel compounds and therapeutic uses thereof. More particularly, the invention provides novel sulfonanilide and benzylsulfonyl derivatives, their salts, solvates, hydrates and polymorphs thereof as transient receptor potential cation channel, mucolipin subfamily (TRPML) modulators.
  • TRPML mucolipin subfamily
  • 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, age-related common neurodegenerative diseases, reactive oxygen species (ROS) or oxidative stress related diseases, and ageing.
  • TRPML mucolipin subfamily
  • 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 Ca 2+ 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
  • ML1 a member of the TRP-type Ca 2+ channel superfamily
  • ML4 Type IV Mucolipidosis
  • TRPML1 - - 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).
  • TGN Trans-Golgi Network
  • 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 Ca 2+ from lysosomes (lysosomal Ca 2+ release) is essential for both trafficking steps, it is hypothesized that ML1 is indeed the Ca 2+ release channel that regulates lysosomal trafficking.
  • PI(3,5)P2 is a low-abundance phosphoinositide, is the primary activator of ML1, and a positive regulator of lysosomal trafficking.
  • Both TRPML1 -lacking and PI(3,5)P2-deficient cells exhibit defects in LEL-to-Golgi retrograde trafficking and autophagosome-lysosome fusion, suggesting that the TRPML1-PI(3,5)P2 system represents a common signaling pathway essential for late endocytic trafficking.
  • lysosomes 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, common 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).
  • lysosomal membrane is potentially an accessible and direct target of ROS signaling.
  • ROS reportedly regulate ion channels
  • lysosomal conductances particularly through lysosomal Ca 2+ channels such as TRPML1
  • 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 neuro degenerative diseases, as well as ageing (Barnham c/ a/. 2004 Nat Rev DrugDiscov 3, 205-214; Scherz-Shouval, et al. 2011 Trends Biochem Sci 36, 30-38).
  • TRPML1 TRPML1 agonist might be able to clear the excessive ROS, thereby ameliorating the ROS related diseases and ageing, especially photo ageing in the skin.
  • TFEB Transcription factor
  • Overexpression of TFEB has been reportedly induce cellular clearance in a number of lysosome storage diseases, including Pombe Disease, Cystinosis, multiple sulfatase deficiency, as well as common neurodegenerative diseases, including Parkinson’s disease and Huntinton’s disease (Settieri, 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.
  • ML-SA1 (10 ⁇ M) activation of whole-endolysosome ZMLI was comparable to the effect of the endogenous TRPML agonist PI(3,5)P2 (I ⁇ M), and these agonists were synergistic with each other.
  • ML-SA1 activated an endogenous whole-endolysosome TRPML-like current (ZML-L) in all mammalian cell types that were investigated, including Chinese Hamster Ovary (CHO), Cos-1, HEK293, skeletal muscle, pancreatic P and macrophage cells.
  • ML-SA1 activated whole- endolysosome ZML L in wild-type (WT; ML1 +/+ ), but not ML4 (MLI z ) human fibroblasts, suggesting that although ML-SA1 targets all three TRPMLs, the expression levels of TRPML2 and TRPML3 are very low, and TRPML 1 is the predominant lysosomal TRPML channel in this cell type.
  • 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, and ageing.
  • the invention is based in part on novel sulfonanilide and benzylsulfonyl-containing compounds, pharmaceutical compositions thereof and methods of their preparation and use in treating or reducing various diseases or disorders.
  • compounds, compositions and methods of the invention are useful in treating diseases or disorders mediated by or associated with TRPMLs.
  • the invention generally relates to a compound having the structural formula I: or a pharmaceutically acceptable form or an isotope derivative thereof, wherein:
  • X is CR 6 R 7 , or NR 6 , wherein each of R 6 and R 7 is independently H, or C1-C3 alkyl; and n is 0, 1 or 2.
  • the invention generally relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed herein, effective to treat or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.
  • the invention generally relates to a pharmaceutical composition comprising an amount of a compound of formula I: or a pharmaceutically acceptable form or an isotope derivative thereof, wherein:
  • X is CR 6 R 7 , or NR 6 , wherein each of R 6 and R 7 is independently H, or C 1 -C 3 alkyl; and n is 0, 1 or 2, effective to treat, or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.
  • the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.
  • 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.
  • 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.
  • the invention generally relates to a method for treating or reducing oxidative stress or reactive oxygen species 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.
  • the invention generally relates to a method for treating or reducing oxidative stress or reactive oxygen species related diseases or disorder, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound disclosed herein.
  • 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.
  • 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.
  • compositions or methods disclosed herein can be combined with one or more of any of the other compositions and methods provided herein.
  • C 1-6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 alkyl.
  • compositions and methods are intended to mean that the compositions and methods include the recited elements, but do not exclude other elements.
  • compositions and methods consisting essentially of does not exclude pharmacologically inactive or inert agents, e.g., pharmaceutically acceptable excipients, carriers or diluents.
  • 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.
  • 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.
  • hydrate means a compound which further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • 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.
  • 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.
  • the pharmaceutically acceptable form is a pharmaceutically acceptable salt.
  • 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • 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.
  • 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
  • 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 + (Ci-4alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • compositions 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 isopropyl amine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt can be chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • the pharmaceutically acceptable form is a "solvate” (e.g., a hydrate).
  • solvate refers to compounds that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermol ecul ar 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.
  • the pharmaceutically acceptable form is a prodrug.
  • prodrug 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).
  • hydrolysis e.g., hydrolysis in blood
  • 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., "Prodrugs 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.
  • 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.
  • other prodrug derivatives may be combined with other features disclosed herein to enhance bioavailability.
  • those of skill in the art will appreciate that certain of the presently disclosed compounds having free amino, amido, 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.
  • prodrugs and prodrug salts are those that increase the bio avail ability 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.
  • 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.
  • 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.
  • 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.
  • materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com 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, com 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
  • wetting agents 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.
  • 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).
  • 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
  • mechanical characteristics e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph
  • 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
  • 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 intermol ecul ar forces.
  • 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).
  • stereoisomer refers to both enantiomers and diastereomers.
  • 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.
  • 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.
  • treatment 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.
  • acyl refers to an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent, any of which may be further substituted by substituents.
  • alk or “alkyl” refer to straight or branched chain or cyclic hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, containing no unsaturation.
  • lower alkyl refers to alkyl groups of 1 to 4 carbon atoms (inclusive).
  • 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.
  • “alkyl” can be a C 1-6 alkyl group. In some embodiments, “alkyl” can be a C 1-3 alkyl group.
  • 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.
  • alkoxy refers to an -O-alkyl radical
  • alkylenedioxo refers to a divalent species of the structure -O-R- O-, in which R represents an alkylene.
  • 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.
  • alkylene refers to a divalent straight chain bridge of 1 to 5 carbon atoms connected by single bonds (e.g., -(CH 2 ) X - , wherein x is 1 to 5), which may be substituted with 1 to 3 lower alkyl groups.
  • 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.
  • 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.
  • arylalkyl refers to a moiety in which an alkyl hydrogen atom is replaced by an aryl group.
  • cycloalkyl and cycloalkenyl refer to a cyclic alkyl group and includes saturated and partially unsaturated cyclic, respectively, hydrocarbon groups having 3 to 12 carbons, preferably 3 to 8 carbons.
  • aromatic refers to a radical with 6 to 14 ring atoms (e.g., C 6-14 aromatic or C 6-14 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.
  • halo or "halogen” refers to any radical of fluorine, chlorine, bromine or iodine.
  • 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 n 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.
  • 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.
  • 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.
  • heteroaryl 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.
  • heteroaryl groups examples, without limitation, of heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, quinazoline, isoquinoline, purine and carbazole.
  • heterocycle 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 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 quatemized.
  • the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system.
  • 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 quatemized.
  • the heterocyclyl group may be attached at any heteroatom or carbon atom of the ring or ring system.
  • 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.
  • substituted refers to a group “substituted” on any functional group delineated herein, e.g., alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, or heteroaryl group at any atom of that group.
  • Suitable substituents include, without limitation halogen, CN, NO2, OR 15 , SR 15 , S(O) 2 OR 15 , NR 15 R 16 , C 1 -C 2 perfluoroalkyl, C 1 -C 2 perfluoroalkoxy, 1,2- methylenedioxy, C(O)OR 15 , C(O)NR 15 R 16 , OC(O)NR 15 R 16 , NR 15 C(O)NR 15 R 16 , C(NR 16 )NR 15 R 16 , NR 15 C(NR 16 )NR 15 R 16 , S(O) 2 NR 15 R 16 , R 17 , C(O)R 17 , NR 15 C(O)R 17 , S(O)R 17 , S(O) 2 R 17 , R 16 , OXO, C(O)R 16 , C(O)(CH 2 )nOH, (CH 2 )nOR 15 , (CH 2 )nC(O)NR 15 R 16 ,
  • Each R 15 is independently hydrogen, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl.
  • Each R 16 is independently hydrogen, alkenyl, alkynyl, C 3 -C 6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted with C 3 -C 6 cycloalkyl, aryl, heterocyclyl or heteroaryl.
  • Each R 17 is independently C 3 -C 6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted with C 3 -C 6 cycloalkyl, aryl, heterocyclyl or heteroaryl.
  • Each Cs-Ce cycloalkyl, aryl, heterocyclyl, heteroaryl and C 1 -C 4 alkyl in each R 15 , R 16 and R 17 can optionally be substituted with halogen, CN, C 1 -C 4 alkyl, OH, C 1 -C 4 alkoxy, NH 2 , C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, C 1 -C 2 perfluoroalkyl, C 1 -C 2 perfluoroalkoxy, or 1,2-methylenedioxy.
  • 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.
  • the invention provides novel sulfonanilide and benzylsulfonyl 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, age-related common neurodegenerative diseases, ROS or oxidative stress related diseases, and damages caused in skin or photoaging.
  • the invention generally relates to a compound having the structural formula I: or a pharmaceutically acceptable form or an isotope derivative thereof, wherein:
  • X is CR 6 R 7 , or NR 6 , wherein each of R 6 and R 7 is independently H, or C1-C3 alkyl; and n is 0, 1 or 2.
  • R 1 is a 5-membered heteroaryl substituted with S(O) 2 NRR’, wherein each of R and R’ is C 1-3 alkyl (e.g., Ci, C 2 or C3 alkyl).
  • R 1 is a 5-membered heteroaryl substituted with S(O) 2 NRR’, wherein R and R’, together with the nitrogen to which they are attached to, form a 4- to 6-membered (e.g., 4-, 5- or 6-membered) ring.
  • the 5-membered heteroaryl comprises the heteroatom S.
  • R 1 is a 5-membered heteroaryl substituted with S(O) 2 R, wherein R is a linear, branched or cyclic C 1-5 alkyl (e.g., a linear or branched C 1-5 alkyl or a cyclic C 3-5 alkyl).
  • R 2 and R 3 together with the nitrogen to which they are attached to, are linked to form a 6-membered heterocyclyl substituted with 2 C 1-3 alkyl (e.g., C 1 , C 2 or C 3 alkyl) groups.
  • R 5 is H.
  • R 1 is selected from the group consisting of:
  • NR 2 R 3 is selected from the group consisting of:
  • the compound of the invention has the structural formula Ila:
  • Z is CR a R b , NR C or SO 2 ;
  • R 4 is H, C 1-3 alkyl or halogen; each of R a , R b and R c is independent H, C 1-3 alkyl or halogen, or two of R a , R b and R c together with the carbon or hetero atoms to which they are attached to, are linked to form a 3- to 7-membered ring.
  • the compound of the invention has the structural formula lib: wherein
  • R 4 is H, C 1-3 alkyl or halogen; each of R a , R b and R c is independent H, C 1-3 alkyl or halogen, or two of R a , R b and R c together with the carbon or hetero atoms to which they are attached to, are linked to form a 3- to 7-membered ring.
  • the compound of the invention has the structural formula lIc: wherein
  • R 4 is H, C 1-3 alkyl or halogen; each of R a , R b and R c is independent H, C 1-3 alkyl or halogen, or two of R a , R b and R c together with the carbon or hetero atoms to which they are attached to, are linked to form a 3- to 7-membered ring.
  • the compound of the invention has the structural formula lid: wherein
  • R 4 is H, C 1-3 alkyl or halogen; each of R a , R b and R c is independent H, C 1-3 alkyl or halogen, or two of R a , R b and R c together with the carbon or hetero atoms to which they are attached to, are linked to form a 3- to 7-membered ring.
  • each of R a and R b is H.
  • each of R a and R b is a halogen atom.
  • each of R a and R b is methyl.
  • each of R a and R b is ethyl.
  • R a is methyl and R b is ethyl.
  • R a and R b together with the carbon to which they are attached to, are linked to form cyclopropyl.
  • each of R and R’ is C 1-3 alkyl.
  • each of R and R’ is methyl.
  • R and R’ together with the nitrogen to which they are attached to, form a 4- to 6-membered ring optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1-3 alkyl, halo, OH, OC 1-3 alkyl, and CN.
  • R 4 is F or Cl.
  • R 4 is C 1-3 alkyl.
  • R 4 is methyl
  • Exemplary compounds of the invention include but not limited to:
  • a compound of the invention has one or more (e.g., 1, 2, 3) deuterium atoms replacing one or more (e.g., 1, 2, 3) hydrogen atoms. In certain embodiments, a compound of the invention has one deuterium atom replacing one hydrogen atom.
  • the invention generally relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed herein, effective to treat or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.
  • the invention generally relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound of formula I: or a pharmaceutically acceptable form or an isotope derivative thereof, wherein:
  • X is CR 6 R 7 , or NR 6 , wherein each of R 6 and R 7 is independently H, or C1-C3 alkyl; and n is 0, 1 or 2, effective to treat, or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.
  • the pharmaceutical composition is suitable for oral administration. In certain embodiments, the pharmaceutical composition is suitable for topital administration.
  • the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.
  • the unit dosage form is a tablet or a capsule.
  • 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.
  • the disease or disorder is mediated by loss-of-function in TRPML1, including ML4 and NPC.
  • the disease or disorder is a lysosome storage disease, or a related disease or disorder.
  • 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.
  • the disease or disorder is muscular dystrophy, or a related disease or disorder.
  • the disease or disorder is oxidative stress or ROS, or a related disease or disorder.
  • 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.
  • the effect of aging comprises skin aging.
  • the effect of aging comprises photoaging.
  • 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.
  • 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.
  • administration is via oral administration.
  • administration is via topical administration.
  • 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.
  • 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.
  • the disease or disorder is muscular dystrophy, or a related disease or disorder.
  • the disease or disorder is oxidative stress or ROS, or a related disease or disorder.
  • the disease or disorder is skin aging or photoaging.
  • the compound is any of those shown in Table 1.
  • 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).
  • Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and /raw.s-isomers, atropisomers, R- and 5-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • 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.
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic methods well known in the art, and subsequent recovery of the pure enantiomers.
  • 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.
  • 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.
  • 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.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphat
  • 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.
  • 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.
  • ingredients such as the carrier that constitutes one or more accessory ingredients.
  • 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.
  • 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.
  • compositions of pharmaceutically active ingredients are known in the art and described in several issued US Patents, some of which include, but are not limited to, US Patent Nos. 4,369,172; and 4,842,866, and references cited therein.
  • Coatings can be used for delivery of compounds to the intestine (see, e.g., U.S. Patent Nos. 6,638,534, 5,217,720, and 6,569,457, 6,461,631, 6,528,080, 6,800,663, and references cited therein).
  • a useful formulation for the compounds of this invention is the form of enteric pellets of which the enteric layer comprises hydroxypropylmethylcellulose acetate succinate.
  • carriers that are commonly used include lactose and com starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • 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.
  • compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and nonaqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol.
  • suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
  • the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration.
  • compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
  • the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the second therapeutic agent is an agent useful in the treatment or prevention of cancer.
  • the second therapeutic agent co-formulated with a compound of this invention is an agent useful in the treatment of TRPML mediated disease/disorders.
  • the invention provides separate dosage forms of a compound of this invention and a second therapeutic agent that are associated with one another.
  • association with one another 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).
  • the compound of the present invention is present in an effective amount.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the disease is one of the lysosomal storage diseases, such as Niemen-Pick C (NPC) disease.
  • NPC Niemen-Pick C
  • 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.
  • the methods disclosed herein are suitable for treating type IV Mucolipidosis (ML4), a neurodegenerative LSD caused by human mutations in TRPML1.
  • ML4 type IV Mucolipidosis
  • TRPML1 type IV Mucolipidosis
  • the methods disclosed herein are suitable for treating a ROS or oxidative stress related disease or disorder.
  • the methods disclosed herein are suitable for treating diseases or disorders due or related to ageing.
  • co-administered 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.
  • 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.
  • 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.
  • 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.
  • the methods herein include those further comprising monitoring subject response to the treatment administrations.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • suitable technique 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.
  • 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.
  • tablets may be contained in a bottle, which is in turn contained within a box.
  • 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 structures depicted herein, including the Table 1 structures, 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.
  • a stick bond is drawn and is meant to depict a methyl group.
  • **EC50 of TFEB activation “+++” ⁇ 1 uM; “++” > 1 uM to ⁇ 10 uM; “+” > 10 uM;
  • Step 5 To a 500 mL round-bottom flask was added 1,4-dioxane 100 mL, l-fluoro-2- nitrobenzene (20 g, 0.235 mol, 1.0 eq), potassium carbonate (30 g, 0.587 mol, 2.5 eq) and piperidine (30 g, 0.2114 mol, 0.9 eq) was dropped into the stirred mixture and refluxed for 3h. This reaction was added water 200 mL and extracted with ethyl acetate (50 mL*3). The organic solution was dried over sodium sulfate, filtered and concentrated to afford the title compound 4E (32 g). Yield: 66.8%.
  • Step 6 To a 500mL round-bottom flask was added methanol 200 mL, compound 4E (32 g, 0.156 mol, 1.0 eq), Raney Ni catalyst (3 g) was added into the stirred mixture at room temperature overnight. The solution was filtered and concentrated to afford the title compound 4F (10 g, HPLC: 94%). Yield: 36%.
  • Example 5 Synthesis of N2-[3-chloro-2-(l-piperidyl)phenyl]-N5,N5-dimethylthiophene- 2,5- disulfonamide [00182] Step 1. To a 500 mL round-bottom flask was added 1,4-dioxane 100 mL, l-chloro-2- fluoro-3 -nitrobenzene (10 g, 0.142 mol, 0.9 eq) and potassium carbonate (22 g, 0.4 mol, 2.5 eq). Piperidine (5.6 g, 0.158 mol, 1.0 eq) was dropped into the stirred mixture and refluxed for 3 h. This reaction was added water 50mL and extracted with ethyl acetate (30 mL*3). The organic solution was dried over sodium sulfate, filtered and concentrated to afford the title compound 5A (10 g). Yield: 30%.
  • Step 2' To a 250 mL round-bottom flask was added methanol 100 mL, compound 5A (10 g), Raney Ni catalyst (3 g, 30%wt) was added to the stirred mixture at room temperature overnight. The solution was filtered and concentrated to afford the title compound 5B (4.3 g). Yield: 49%
  • Step 3 To a 25 mL round-bottom flask was added pyridine 5 mL, compound 5B (60 mg, 0.287 mmol, 1.0 eq) and compound 4D (100 mg, 0.347 mmol, 1.3 eq) was dropped into the stirred mixture at room temperature for 2 h. The solution was concentrated and subjected to silica gel to afford the title compound 5 (20 mg, HPLC: 99%). Yield: 15% Overall Yield: 2.25%.
  • Step 1 To a 100 mL three necked flask was added CuBr2 (713 mg, 3.19 mmol, 1.5 eq), acetonitrile (10 mL) and tert-butyl nitrite (500 mg, 4.68 mmol, 2.2 eq), the mixture was controlled under 60 °C in the nitrogen atmosphere. The reaction was kept at the temperature for 20min. Next, a solution of 2,4-difluoro-6-nitro-phenylamine (371 mg.2.13 mmol,l eq) in acetonitrile (10 mL) was slowly added into the mixture. The reaction was stirred for 0.5 h.
  • compound 6A 300 mg, 1.26 mmol, 1 eq
  • CS 2 CO 3 814 mg, 2.5 m
  • Step 1 To a 250 mL three-necked flask was added 120 mL diethyl ether and 2- bromothiazole (5.0 g, 0.030 mol, 1.0 eq) which was degassed with N2 three times. n-BuLi (2.5M) (13.4 mL, 0.033 mol, 1.1 eq) was dropped into the stirred mixture (T ⁇ -78 °C). After stirring for 1 h at -78 °C, sulfur dioxide solution in diethyl ether (200 g/L) (48 mL, 0.15 mol, 5.0 eq) was dropped into the stirred mixture (T ⁇ -78 °C). The reaction mixture was warmed to room temperature slowly and then concentrated under vacuum to afford the compound 8A (10 g, crude).
  • 2- bromothiazole 5.0 g, 0.030 mol, 1.0 eq
  • Step 2 ⁇ To a 250 mL round-bottom flask was added 125 mL dichloromethane, compound 8A (4.65 g, 0.030 mol, 1.0 eq) and N-chlorosuccinimide (4.5 g, 0.033 mol, 1.1 eq). The mixture was stirred at room temperature for 30 min with N 2 and then filtered. The filtrate was concentrated under vacuum to afford the compound 8B (7.0 g, crude).
  • Step 4 To a 100mL three-necked flask was added 40mL tetrahydrofuran and compound 8C (1.0 g, 5.2 mmol, 1.0 eq) which was degassed with N2 three times. n-BuLi (2.5 M) (2.3 mL, 5.73 mol, 1.1 eq) was dropped into the stirred mixture (T ⁇ -78 °C). After stirring for Ih at -78 °C, sulfur dioxide solution in diethyl ether (200 g/L) (8.5 mL, 26 mmol, 5.0 eq) was dropped into the stirred mixture (T ⁇ -78 °C). The reaction mixture was warmed to room temperature slowly and then concentrated under vacuum to afford the compound 8D (2 g, crude).
  • Step 5 40 mL dichloromethane, compound 8D (1.36 g, 5.2 mmol, 1.0 eq) and N- chlorosuccinimide (1.39 g, 10.4 mmol, 2.0 eq) were added to a 100 mL round-bottom flask. The mixture was stirred at room temperature for 1 h with N2 and then filtered. The filtrate was concentrated under vacuum to afford the compound 8E (2.1 g, crude).
  • Step 2 ⁇ To a 100 mL three necked flask was added 20 mL tetrahydrofuran, compound 9A (1g, 3mmol, l.Oeq), the mixture controlled to -70-80 °C, then n-BuLi (6.2 mL, 5 mmol, 2.2 eq) was added dropwise to the reaction mixture in the nitrogen atmosphere, the mixture was stirred for 1 h under -70-80°C, then sulfur dioxide solution in diethyl ether (5 mL, 15 mmol, 5 eq) was added dropwise to the reaction mixture in the nitrogen atmosphere, the reaction was slowly warmed at room temperature and then concentrated under reduced pressure to obtain the crude compound 9B.
  • N-chlorosuccinimide 440 mg, 3.3 mmol, 1.1 eq
  • Step 1 To a 100 mL three necked flask was added 50 mL 1,4-dioxane. To the stirred mixture was added l-Chloro-2-fluoro-3 -nitro-benzene (5.0 g, 28.5 mmol, 1.0 eq), 4-Methyl- piperidine (3.1 g, 31.3 mmol, 1.1 eq) and K 2 CO 3 (7.9 g, 57 mmol, 2 eq). The reaction was heated to reflux overnight. TLC(PE) showed the reaction was completed. The reaction was allowed to cool at room temperature. The reaction mixture filtered and concentrated under vacuum, the crude compound was purified by column chromatography on silica gel to afford compound 10A (6 g, HPLC:92%) as a yellow oil. Yield: 82.5 %.
  • Step 1 To a 500 mL three necked flask was added 250 mL tetrahydrofuran, and lithium aluminium hydride (6.6 g, 150 mmol, 3.0 eq) was added to the reaction mixture in portions under 10- 15 °C, then 3,3-Dimethylglutarimide (7.05 g, 50 mmol, 1.0 eq) in 100 mL tetrahydrofuran was added to the reaction mixture, then the reaction mixture was stirred at room temperature for 0.5 h, then reflux for 3 h.
  • lithium aluminium hydride 6.6 g, 150 mmol, 3.0 eq
  • Step 1 To a 500 mL round-bottom flask was added 200 mL toluene, 3 -bromo thiophene (10 g, 61.3 mmol, 1.0 eq), benzyl mercaptan (7.62 g, 61.3 mmol, 1.0 eq), N,N-diisopropylethylamine (15.85 g, 0.123 mmol, 2.0 eq), Xantphos (2.13 g, 3.68 mmol, 0.06 eq) and Pd(dppf)C12.CHCls (1.50 g, 1.84 mmol, 0.03 eq). The reaction was heated to 110 °C for 3 h with nitrogen. TLC (PE) showed the reaction was completed. The reaction mixture was cooled, concentrated under vacuum and purified by column chromatography on silica gel to afford the compound 12A (11.6 g) as a colorless oil. Yield: 92.1%.
  • Step 2 ⁇ To a 500 mL round-bottom flask was added 200 mL glacial acetic acid, 60 mL water and compound 12A (11.6 g, 56.3 mmol, 1.0 eq). N-chlorosuccinimide (30.1 g, 225 mmol, 4.0 eq) was added to the stirred mixture at 10 °C. The reaction was stirred at room temperature for 1 h with nitrogen. TLC (PE) showed the reaction was completed. Then the mixture was concentrated and purified by column chromatography on silica gel to afford the title compound 12B (13.2 g) as a colorless oil.
  • N-chlorosuccinimide 30.1 g, 225 mmol, 4.0 eq
  • Step 4 To a 250 mL round-bottom flask was added 80 mL glacial acetic acid and compound 12C (8.1 g, 42.4 mmol, 1.0 eq). N-bromosuccinimide (11.3 g, 63.6 mmol, 1.5 eq) was added to the stirred mixture. The reaction was stirred at 100 °C for 2 h with nitrogen. The reaction mixture was cooled, added 500 mL water and extracted with ethyl acetate (200 mL*2). The organic layer was dried, concentrated under vacuum and purified by column chromatography on silica gel to afford the compound 12D (3.6 g, HPLC: 96%) as a solid. Yield: 31.5%.
  • Step 5 To a 100 mL round-bottom flask was added 20 mL toluene, compound 12D (1 g, 3.70 mmol, 1.0 eq), benzyl mercaptan (460 mg, 3.70 mmol, 1.0 eq), N,N-diisopropylethylamine (957 mg, 7.41 mmol, 2.0 eq), Xantphos (129 mg, 0.22 mmol, 0.06 eq) and Pd(dppf)C12.CHCh (91 mg, 0.11 mmol, 0.03 eq). The reaction was heated to 110 °C for 3 h with nitrogen. The reaction mixture was cooled, concentrated under vacuum and purified by column chromatography on silica gel to afford the compound 12E (1.0 g, HPLC: 89%) as a solid. Yield: 86.2%.
  • Step 1 To a 500 mL round-bottom flask was added 200 mL dimethyl sulfoxide, 2,3,5- Tribromothiophene (25.0 g, 77.9 mmol, 1.0 eq), the mixture controlled to 15-20 °C. Then NaBFL (6 g, 158.6 mmol, 2 eq) was added to the reaction mixture in the nitrogen atmosphere. The reaction was stirred at 20-25 °C for 16 h. TLC (PE) showed the reaction was completed. The reaction mixture was quenched in water 400 mL at 10-15 °C and extracted with tert-butyl methyl ether (200 mL*3). The combined organic layer was washed with water (200 mL). The organic layer was dried with Na 2 SO 4 and concentrated under reduced pressure to afford compound 13A (11 g, GC: 92%) as a white oil. Yield: 58.3%
  • Step 2 ⁇ To a 100 mL three necked flask was added 40 mL tetrahydrofuran and compound 13A (1.5 g, 5 mmol, 1.0 eq), the mixture was cooled to -30 ⁇ -40 °C.
  • Step 3 To a 100 mL three necked flask was added 40 mL di chloromethane, compound 13B, then N-chlorosuccinimide (0.79 g, 5.5 mmol, 1.1 eq) was added to the reaction mixture in portion under room temperature, then the reaction mixture was stirred 1 h, TLC (PE) showed the reaction was completed. The mixture was filter and the filtrate was concentrated under vacuum to yield the crude compound 13C (2.0 g) as a yellow oil.
  • N-chlorosuccinimide (0.79 g, 5.5 mmol, 1.1 eq) was added to the reaction mixture in portion under room temperature, then the reaction mixture was stirred 1 h, TLC (PE) showed the reaction was completed. The mixture was filter and the filtrate was concentrated under vacuum to yield the crude compound 13C (2.0 g) as a yellow oil.
  • Step 5 To a100mL three necked flask was added 20 mL tetrahydrofuran, compound 13D (0.7 g, 2.5 mmol, 1.0 eq), the mixture controlled to -70 ⁇ -80 °C, then n-BuLi (2 mL, 5mmol, 2 eq) was added dropwise to the reaction mixture in the nitrogen atmosphere, the mixture was stirred for 1 h under -70 ⁇ -80 °C, then sulfur dioxide solution in diethyl ether (10 mL, 5Vol) was added dropwise to the reaction mixture in the nitrogen atmosphere, the reaction was slowly warmed at room temperature and then concentrated under reduced pressure to obtain the crude compound 13E.
  • Step 1 To a 500 mL three necked flask was added 250 mL tetrahydrofuran, lithium aluminum hydride(3.42 g, 90 mmol, 3.0 eq) was added to the reaction mixture in portion under 10-15 °C, then 4, 4-dimethylazaperhydroine-2, 6-dione (4.33 g, 30 mmol, 1.0 eq) in 100 mL tetrahydrofuran was added to the reaction mixture, then the reaction mixture was stirred at room temperature for 0.5 h, then reflux for 3 h.
  • Example 17 Synthesis of N2-[2-(4, 4-dimethyl-l-piperidyl) phenyl]-N5, N5-dimethylthiophene- 2, 5-disulfonamide [00229] Step 1. To a 50 mL round-bottom flask was added 4 mL pyridine, compound 15C (89 mg, 0.43 mmol, 1.0 eq) and compound 4D (150 mg, 0.52 mmol, 1.2 eq), the reaction was stirred at 25 °C overnight.
  • Example 20 Synthesis of N2-[2-(8-azaspiro[4.5]decan-8-yl)phenyl]-N5,N5- dimethylthiophene- 2,5-disulfonamide [00234] Step 1. To a 250 mL three necked flask was added 35 mL tetrahydrofuran, lithium aluminum hydride (3.4 g, 89.7 mmol, 3.0 eq) was added to the reaction mixture in portion under 10- 15 °C, then 8-Aza-spiro[4.5]decane-7, 9-dione (5 g, 29.9 mmol, 1.0 eq) in 50 mL tetrahydrofuran was added to the reaction mixture, then the reaction mixture was stirred at room temperature for 0.5 h, then the mixture was cooled to 5 °C and 3.4 mL water, 6.8 mL 15% sodium hydroxide aqueous solution and 3.4 mL water was added to the reaction mixture in portions.
  • Step 2 ⁇ To a 100 mL three necked flask was added 15 mL tetrahydrofuran, compound 23A (530 mg, 1.51 mmol, 1.0 eq), the mixture was controlled to -70— 80°C, then n-BuLi (1.5 mL, 2.6 mmol, 2.5 eq) was added dropwise to the reaction mixture in the nitrogen atmosphere, the mixture was stirred for Ih under -70— 80°C, then sulfur dioxide solution in diethyl ether (10 mL, 10 eq, 2.5 M) was added dropwise to the reaction mixture in the nitrogen atmosphere, the reaction was slowly warmed at room temperature for 1 h and then concentrated under reduced pressure to obtain the crude product.
  • compound 23A 530 mg, 1.51 mmol, 1.0 eq
  • Step 1 To a 250 mL three necked flask was added 50 mL tetrahydrofuran, compound 4- methylthiazole (5 g, 50.4 mmol, 1.0 eq), the mixture was controlled to -70 to -80°C, then n-BuLi (25 mL, 60.5 mmol, 1.2 eq) was added dropwise to the reaction mixture in the nitrogen atmosphere, the mixture was stirred for Ih under -70 to -80°C, then sulfur dioxide solution in diethyl ether (100 mL, 5.0 eq, 2.5 M) was added dropwise to the reaction mixture in the nitrogen atmosphere, the reaction was slowly warmed at room temperature for 1 h and then the reaction mixture was concentrated under reduced pressure to obtain the crude product.
  • tetrahydrofuran compound 4- methylthiazole
  • Step 3 To a 100 mL three necked flask was added 24 mL tetrahydrofuran, compound 25B (2.06 g, 10 mmol, 1.0 eq), the mixture was controlled to -70 to -80°C, then n-BuLi (5 mL, 12.0 mmol, 1.2 eq) was added drop wise to the reaction mixture in the nitrogen atmosphere, the mixture was stirred for Ih under -70 to -80°C, then sulfur dioxide solution in diethyl ether (20 mL, 5.0 eq, 2.5 M) was added dropwise to the reaction mixture in the nitrogen atmosphere, the reaction was slowly warmed at room temperature for 1 h and then the reaction mixture was concentrated under reduced pressure to obtain the crude product.
  • n-BuLi 5 mL, 12.0 mmol, 1.2 eq
  • Step 1 To a 100 mL three-necked flask was added 20 mL diethyl ether and Mg (1.64 g, 0.068 mol, 3.3 eq) which was degassed with N2 three times. CH3I (8.80 g, 0.062 mol, 3.0e q) in 10 mL Diethyl ether was dropped into the stirred mixture slowly at 35 °C. Then the mixture was stirred for 0.5 h at 35 °C.
  • Step 2 To a 100 mL three-necked flask was added 10 mL tetrahydrofuran and compound 26A (500 mg, 4.46 mmol, 1.0 eq) which was degassed with N2 three times. n-BuLi (2.5 M) (2.0 mL, 4.91 mmol, 1.1 eq) was dropped into the stirred mixture (T ⁇ -78 °C).
  • Step 3 To a 50 mL round-bottom flask was added 20 mL dichloromethane, compound 26B (812 mg, 4.46 mmol, 1.0 eq) and N-chlorosuccinimide (894 mg, 6.70 mmol, 1.5 eq). The mixture was stirred at room temperature for 30 min with N2 and then filtered. The filtrate was concentrated under vacuum to afford the compound 26C (1.5 g, crude).
  • Step 5 To a 100 mL three-necked flask was added 10 mL tetrahydrofuran and compound 26D (440 mg, 2.0 mmol, 1.0 eq) which was degassed with N2 three times. n-BuLi (2.5 M) (0.88 mL, 2.2 mmol, 1.1 eq) was dropped into the stirred mixture (T ⁇ -78 °C). After stirring for 1 h at -78 °C, sulfur dioxide solution in diethyl ether (220 g/L) (10 mL) was dropped into the stirred mixture (T ⁇ -78 °C). The reaction mixture was warmed to room temperature slowly and then concentrated under vacuum to afford the compound 26E (1.8 g, crude).
  • Step 1 To a 100 mL three necked flask was added 40 mL tetrahydrofuran and diisopropylamino (3.8 g, 37.6 mmol, 1.3 eq), n-BuLi (13.7 mL, 34.2 mmol, 1.2 eq) was added to the reaction mixture drop wise under -78 °C, the reaction mixture was stirred for 1 h, then Mel (4.3 g, 37.6 mmol, 1.3 eq) was added to the reaction mixture and stirred at -78 °C for 1 h, then 3-bromo-4- methylthiophene (5 g, 28.2 mmol, 1.0 eq) in 30 mL tetrahydrofuran was added to the reaction mixture and stirred at -78 °C for 1 h.
  • Step 2 To a 250 mL three necked flask was added 80 mL tetrahydrofuran, compound 27A (2.6 g, 13.7 mmol, 1.0 eq), the mixture was controlled to -70 to -80°C, then n-BuLi (6.7 mL, 16.4 mmol, 1.2 eq) was added dropwise to the reaction mixture in the nitrogen atmosphere, the mixture was stirred for Ih under -70 to -80°C, then sulfur dioxide solution in diethyl ether (30 mL, 5.0 eq, 2.5 M) was added dropwise to the reaction mixture in the nitrogen atmosphere, the reaction was slowly warmed at room temperature for 1 h and then the reaction mixture was concentrated under reduced pressure to obtain the crude product.
  • compound 27A 2.6 g, 13.7 mmol, 1.0 eq
  • Step 4 To a 100 mL three necked flask was added 6 mL tetrahydrofuran and diisopropylamino (300 mg, 2.96 mmol, 1.3 eq), then n-BuLi (1.1 mL, 2.74 mmol, 1.2 eq) was added to the reaction mixture under -78 °C in the nitrogen atmosphere, the reaction mixture was stirred for 1 h, then compound 27C (500 mg, 2.28 mmol, 1.0 eq) in 10 mL tetrahydrofuran was added to the reaction mixture and stirred at -78 °C for 1 h.
  • Step 5 To a 50 mL round-bottom flask was added 10 mL DMF and compound 28D (1.0 g, 3.70 mmol, 1.0 eq). N-bromosuccinimide (659 mg, 3.70 mmol, 1.0 eq) was added to the mixture at 0 °C. The reaction mixture was stirred at room temperature for 16 h. Water (50 mL) was added into the reaction mixture. The water layer was extracted with ethyl acetate (20 mL*4). The organic layer was dried, concentrated under vacuum and purified by column chromatography on silica gel to afford the title compound 28E (1.0 g, HPLC: 84%) as a colorless oil. Yield: 76.9%.
  • Step 6 To a 100 mL round-bottom flask was added 20 mL toluene, compound 28E (1.0 g, 2.86 mmol, 1.0 eq), benzyl mercaptan (356 mg, 2.86 mmol, 1.0 eq), N,N-diisopropylethylamine (741 mg, 5.73 mmol, 2.0 eq), Xantphos (100 mg, 0.17 mmol, 0.06 eq) and Pd(dppf)C12.CHC13 (70 mg, 0.086 mmol, 0.03e q). The reaction was heated to 110 °C for 2 h with nitrogen. The reaction mixture was cooled, concentrated under vacuum and purified by column chromatography on silica gel to afford the compound 28F (770 mg, HPLC: 80%) as a colorless oil. Yield: 70%.
  • Step 7 To a 50 mL round-bottom flask was added 15 mL dichloromethane, 3 mL water, 0.7 mL 12N HC1 and compound 28F (770 mg, 1.96 mmol, 1.0 eq).
  • TCCA (456 mg, 1.96 mmol, 1.0 eq) was added to the mixture with vigorous stirring at 0 - 5 °C.
  • the reaction mixture was stirred at room temperature for 1 h. TLC (PE) showed the reaction was completed.
  • the reaction mixture was filtered and washed with dichloromethane.
  • the water layer was extracted with dichloromethane (5 mL*2).
  • the organic layer was dried and concentrated under vacuum to afford the title compound 28G (0.84 g, crude) as a yellow oil.
  • Step 8 To a 25 mL round-bottom flask was added 5 mL pyridine, compound 28G (724 mg, 1.96 mmol, 1.5 eq) and compound 21B (278 mg, 1.31 mmol, 1.0 eq). The reaction was stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum and purified by column chromatography on silica to afford the compound 28H (110 mg, HPLC: 87%) as a yellow oil. Yield (two steps): 10.3%.
  • Step 1 To a 500 mL three necked flask was added 100 mL dichloromethane and A1CL (40 g, 0.3 mol, 1 eq) at -78 °C, then a solution of thiophene (25.2 g, 0.3 mol, 2.0 eq) and t-butyl bromide (41.1 g, 0.3 mol, 1 eq) were added drop wise to the mixture, the reaction mixture was stirred for 1 h under -78 °C. Then it was allowed to warm to 20 °C. TLC (PE) showed a new point.
  • PE TLC
  • Step 2 To a 100 mL three necked flask was added 25 mL DMF and compound 29A (5 g, 30 mmol, 1.0 eq), then N-chlorosuccinimide (5.7 g, 30 mmol, 1.0 eq) was added to the reaction mixture in portion under 0-5°C, TLC (PE) showed a new point. The mixture was cooled and concentrated under vacuum and the resulting product was purified by column chromatography on silica gel to afford the title compound 29B (6.0 g, HPLC: 95%) as a light oil. Yield: 91.5%.
  • Step 3 To a 100 mL round-bottom flask was added 20 mL toluene, compound 29B (6.0 g, 30 mmol, 1.0 eq), benzyl mercaptan (4.05 g, 28.5 mmol, 0.095 eq), N,N-diisopropylethylamine (7.4 g, 60 mmol, 2.0 eq), Pd(dppf)cl2 (114 mg, 0.13 mmol, 0.025 eq), 4,5-Bis(diphenylphosphino)- 9,9-dimethylxanthene (320 mg, 0.52 mmol, 0.1 eq), the mixture was heat to reflux in the nitrogen atmosphere overnight, TLC (PE) showed the reaction was completed and the mixture was cooled and concentrated under vacuum and the resulting product was purified by column chromatography on silica gel to afford the compound 29C (8.0 g, HPLC: 90%) as an oil. Yield: 90.5%
  • Step 4 To a 100 mL three necked flask was added 40 mL glacial acetic acid, 5 mL water and compound 29C (2.62 g, 0.01 mol, 1.0 eq), then N-chlorosuccinimide (5.3 g, 0.04 mol, 4.0 eq) was added to the reaction mixture in portion under 10-15 °C, then the reaction mixture was stirred for 1 h under 10-15 °C, TLC (PE) showed the reaction was completed. The mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel to afford the compound 29D (350 mg, HPLC: 95%) as an off-white solid. Yield: 46.6%.
  • Example 31 Synthesis of N2,N4,N4-Trimethyl-N2-[2-(l-piperidinyl)phenyl]thiophene-2,4- disulfonamide [00288] Step 1. To a 10 ml single-mouth round bottom flask was added compound 12 (100 mg, 0.2328 mmol, 1.0 eq), 5ml DMF, 96mg K 2 CO 3 (0.6983 mmol, 3.0 eq). The reaction mixture was stirred under 25 °C for 1 h. 0.5 ml Mel was added. The solution was stirred under 25 °C for 2 h. TLC showed the reaction was completed. 20 ml water was added. The solution was extracted by MTBE (30 ml*3).
  • Step 1 To a stirred solution of compound 2 ’-Fluoro acetophenone (30 g, 0.22 mol, 1 eq) and piperidine (19.6 g, 0.23 mol, 1.05 eq) in DMSO (200 mL) was added K 2 CO 3 (45.5 g, 0.33 mol, 1.5 eq). The reaction was stirred at 100 °C for 16 h. TLC showed the reaction was completed. The mixture was cooled to room temperature and poured into water (1 L), extracted with ethyl acetate (400 mL*4).
  • NaBIL 9.4 g, 0.24 mol, 2 eq
  • Step 3 To a mixture of compound 34B (0.5 g, 2.4 mmol, 1 eq) and TEA (320 mg, 3.2 mmol, 1.3e q) in DCM (10 mL) was added MsCl (370 mg, 3.2 mmol, 1.3 eq) drop-wise at 0 °C. The reaction was stirred for another 2 h at the same temperature. TLC showed the reaction was completed. The reaction was concentrated in vacuum at 10 °C and the residue compound 34C (1.1 g) was used directly for the next step without further purification.
  • Step 4 To a stirred solution of compound 12F (290 mg, 1 mmol, 1 eq) in toluene (20 mL) was added PPhs(786 mg, 3 mmol, 3 eq) at 0 °C. The reaction was allowed to warm to room temperature and stirred for another 2 h. TLC showed the reaction was completed. To the reaction was added H 2 O (3 mL) and the reaction was stirred for another 10 min. The resulting mixture was concentrated in vacuum and the residue compound 34D (1.3 g) was used directly for the next step without further purification.
  • Step 5 To a mixture of crude compound 34D (1.3 g, 1 mmol, 1 eq) and crude compound 34C (1.1 g, 2.4 mmol, 2.4 eq) in DMF (15mL) was added Cs 2 CO 3 (l g, 3 mmol, 3 eq). The reaction was heated at 90 °C for 1 h. LCMS showed the reaction was completed. The mixture was cooled to room temperature and poured into water (100 mL), extracted with ethyl acetate (100 mL*2). The combined organic layers were washed with brine (100 mL*3), dried over Na 2 SO 4 , filtered and concentrated in vacuum.
  • Step 6 To a stirred solution of compound 34E (400 mg, 1 mmol, 1 eq) in THF/MeOH (12 mL/8 mL) was added a solution of oxone (860 mg, 1.4 mmol, 1.4 eq) in H 2 O (6 mL) drop-wise at 0 °C. The reaction was allowed to warm to room temperature and stirred for another 3 h. TLC showed the reaction was completed.
  • Step 1 To a stirred solution of compound 4D (290 mg, 1 mmol, 1 eq) in toluene (20 mL) was added PPhs (786 mg, 3 mmol, 3 eq) at 0 °C. The reaction was allowed to warm to room temperature and stirred for another 2 h. TLC showed the reaction was completed. To the reaction was added H 2 O (3 mL) and the reaction was stirred for another 10 min. The resulting mixture was concentrated in vacuum and the residue compound 35A (1.3 g) was used directly for the next step without further purification.
  • Step 3 To a stirred solution of compound 35B (400 mg, 1 mmol, 1 eq) in THF/MeOH (12 mL/8 mL) was added a solution of oxone (860 mg, 1.4 mmol, 1.4 eq) in H 2 O (6 mL) drop-wise at 0 °C. The reaction was allowed to warm to room temperature and stirred for another 3 h. TLC showed the reaction was completed. The mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuum.
  • Step 1 To a 2 L three necked flask was added 500 mL DMSO, 2-Fluorobenzaldehyde (75 g, 0.604 mol, 1.0 eq), piperidine (54.03 g, 0.635 mol, 1.05 eq) and potassium carbonate (125.3 g, 0.906 mol, 1.5 eq). The reaction mixture was stirred overnight at 100 °C. HPLC showed the reaction was completed. The mixture was cooled to room temperature and poured into water (1.5 L), and the reaction mixture was partitioned between ethyl acetate and water. The organic layers were combined, washed with brine, dried over Na 2 SO 4 , filtered and concentrated to afford the title compound 37A (99 g, GC: 97%.) as a yellow liquid. Yield: 87%.
  • Step 2' To a 500 mL three necked flask was added 180 mL methanol and compound 37A (17.4 g, 91.9 mmol, 1.0 eq), which was stirred at 0°C for 10 min. NaBFL (6.95 g, 183.9 mmol, 2.0 eq) was added to the mixture in portions at 0 °C. Then the mixture was stirred at 0 °C for 2 h. TLC showed the reaction was completed. The reaction mixture was poured into water (800 mL). The water layer was extracted with ethyl acetate (400 mL*3). The combined organic layer was dried and concentrated in vacuum to afford the title compound 37B (17.5 g, GC:98%) as a colorless liquid.
  • Step 3 To a 100 mL three necked flask was added 30 mL DCM, compound 37B (318 mg, 1.66 mmol, 1.0 eq) and trimethylamine (252 mg, 2.49 mmol, 1.5 eq). MsCl (286 mg, 2.49 mmol, 1.5 eq) was added to the mixture drop-wise at 0 °C. Then the mixture was stirred at 0 °C for 2 h. TLC showed the reaction was completed. The reaction mixture was concentrated in vacuum at 5 °C and the residue compound 37C (1.3 g, crude, A179-3) was used directly for the next step at once without further purification.
  • Step 4 To a 100 mL three necked flask was added 20 mL toluene and compound 12F ( 200 mg, 0.69 mmol, 1.0 eq. Triphenylphosphine (544.7 mg, 2.08 mmol, 3.0 eq) was added to the mixture in portions at 0 °C. The reaction mixture was allowed to room temperature and stirred for another 2 h. TLC showed the reaction was completed. To the mixture was added water 3 mL) and the mixture was stirred for another 10 min. The solution was concentrated in vacuum and the residue compound 37D (1.3 g, crude, Al 80-2) was used directly for the next step at once without further purification.
  • Triphenylphosphine 544.7 mg, 2.08 mmol, 3.0 eq
  • Step 5 To a 100 mL three necked flask was added 15 mL DMF, compound 37D (1.3 g, 0.69 mmol, 1.0 eq), compound 37C (1.3 g, 1.66 mmol, 2.4 eq) and CS 2 CO 3 (675 mg, 2.07 mmol, 3.0 eq). The reaction mixture was stirred overnight at 90 °C. LC-MS showed the reaction was completed. The mixture was cooled to room temperature and poured into water (100 mL), extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuum. And the residue was purified by column chromatography on silica gel to afford the title compound 37E (180 mg) as an oil. Yield: 51% (two steps).
  • Step 6 To a 100 mL three necked flask was added 9 mL THF, 6 mL MeOH and compound 37E (180 mg, 0.45 mmol, 1.0 eq), which was stirred at 0 °C for 10 min. Oxone (419 mg, 0.68 mmol, 1.5 eq) in water (4 mL) was dropped into the mixture at 0 °C. The reaction mixture was allowed to room temperature and stirred for another 3 h . TLC showed the reaction was completed. The reaction mixture was poured into water. The water layer was extracted with ethyl acetate (50mL*2). The combined organic layer was dried and concentrated in vacuum.
  • Step 1 To a 100 mL three necked flask was added 15 mL DMF, compound 35A (1.3 g, 0.69 mmol, 1.0 eq), compound 37C (1.4 g, 0.83 mmol, 1.2 eq) and CS 2 CO 3 (674 mg, 2.07 mmol, 3.0 eq). The reaction mixture was stirred overnight at 90 °C. LC-MS showed the reaction was completed. The mixture was cooled to room temperature and poured into water (100 mL), extracted with ethyl acetate (40 mL*3). The organic layers were combined, washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuum. And the residue was purified by column chromatography on silica gel to afford the title compound 38A (160 mg) as an oil. Yield: 45%.
  • Step 2 To a 100 mL three necked flask was added 9 mL THF, 6 mL MeOH and compound 38A (160 mg, 0.4 mmol, 1.0 eq), which was stirred at 0 °C for 10 min. Oxone (372 mg, 0.6 mmol, 1.5 eq) in water (4 mL) was dropped into the mixture at 0 °C. The reaction mixture was allowed to room temperature and stirred for another 3 h. TLC showed the reaction was completed. The reaction mixture was poured into water. The water layer was extracted with ethyl acetate (50 mL*2). The combined organic layer was dried and concentrated in vacuum.
  • Step 1 To a 50 mL round-bottom flask was added 10 mL DMSO, 2-Fluorobenzaldehyde (1.19 g, 9.6 mmol, 1.0 eq), compound 11A (1.5 g, 0.01 mol, 1.05 eq) and Potassium carbonate (3.30 g, 0.024 mol, 2.5 eq) which was degassed with N2 three times. The reaction was stirred at 100 °C for 16 h. TLC (PE) showed the reaction was completed. The reaction mixture was cooled, added 50mL water and extracted with EA (20 mL*2). The organic layer was washed with brine (20 mL*3), dried and concentrated in vacuum to afford the title compound 39A (2.0 g, LCMS: 94%) as an orange oil. Yield: 96.6%.
  • 2-Fluorobenzaldehyde (1.19 g, 9.6 mmol, 1.0 eq)
  • compound 11A 1.5 g, 0.01
  • Step 2' To a 50 mL round-bottom flask was added 20 mL MeOH, compound 39A (2.0 g, 9.2 mmol, 1.0 eq). NaBEE (697 mg, 0.018 mol, 2.0 eq) was added to the stirred mixture at 0 °C. After stirring for 2 h at 0 °C, the reaction mixture was added 100 mL water and extracted with EA (50 mL*2). The organic layer was washed with brine (50 mL*l), dried and concentrated in vacuum to afford the title compound 39B (1.9 g, LCMS: 93%) as a yellow solid. Yield: 94.0%.
  • Step 3 To a 10 OmL three-necked flask was added 10 mL DCM, compound 39B (363 mg, 1.65 mmol, 1.0 eq) and TEA (218 mg, 2.16 mmol, 1.3 eq). MsCl (247 mg, 2.16 mmol, 1.3 eq) was added to the stirred mixture at 0 °C. After stirring for 2 h at 0 °C, the reaction mixture was concentrated in vacuum at 5 °C to afford the title compound 39C (crude) as a solid.
  • Step 1 To a 50 ml single-mouth flask bottom was added 1.5 g compound 11A (10.0227 mmol, 1.0 eq), 20ml DMSO, 1.24g 2 ’-Fluoroacetophenone (9.0205 mmol, 0.9 eq), 4.15 g K 2 CO 3 (30.0682 mmol, 3.0 eq). The reaction mixture was heated to 100°C overnight. TLC showed little SY002282 was left but all the A181-1 was finished. The mixture was poured into 100ml water, extracted by MTBE (50 ml*2).
  • Step 3 To a 25 ml single-mouth flask bottom was added 10 ml DCM, 386 mg compound 40B (1.6565 mmol, 1.0 eq), 268 mg TEA (2.6504mmol, 1.6 eq). The reaction mixture was cooled to 0°C and 28 5mg (2.4848 mmol, 1.5e q). Methanesulfonyl chloride was added as drop. The reaction mixture was stirred at 0°C for 2 h. TLC showed little Al 81-3 was left. 20ml water was added to the solution and the water phase was extracted by DCM (10 ml*2). The organic phase was dried over Na 2 SO 4 and concentrated under vacuum at 10 °C. The obtained liquid compound 40C was used to Step6 without purification.
  • Step 4 To a 50 ml single-mouth flask bottom was added compound 35A (0.6902 mmol, 1.0 eq), compound 40C (1.6565 mmol, 2.4 eq), 15ml DMF, 674 mg CS 2 CO 3 (2.0706 mmol, 3.0 eq). The reaction mixture was heated to 90°C for 1 h. LC-MS showed the reaction was complete. The solution was poured into 30 ml water and extracted by MTBE (30 ml*2).
  • Step 1 To a 50 ml single-mouth flask bottom was added compound 37D (0.5177 mmol, 1.0 eq), compound 40C (1.2942 mmol, 2.5 eq), 15 ml DMF, 506 mg CS 2 CO 3 (1.5531 mmol, 3.0 eq). The reaction mixture was heated to 90°C for 1 h. LC-MS showed the reaction was complete. The solution was poured into 30ml water and extracted by MTBE (30 ml*2).
  • Step 1 To a 50 ml single-mouth flask bottom was added compound 37D (0.5177 mmol, 1.0 eq), compound 39C (0.6212 mmol, 1.2 eq), 15 ml DMF, 506 mg CS 2 CO 3 (1.5531 mmol, 3.0 eq). The reaction mixture was heated to 90°C for 1 h. LC-MS showed the reaction was complete. The solution was poured into 30ml water and extracted by MTBE (30 ml*2).
  • Step 1 To a stirred solution of 3'-chloro-2'-fluoroacetophenone (1 g, 5.8 mmol, 1 eq) and compound 11A (912 mg, 6.1 mmol, 1.05 eq) in DMSO (20 mL) was added K 2 CO 3 (2.0 g, 14.5 mol, 2.5 eq). The reaction was stirred at 90°C for 16 h. TLC showed the reaction was completed. The mixture was cooled to room temperature and poured into water (100 mL), extracted with ethyl acetate (150 mL*3).
  • Step 6 To a stirred solution of compound 43D (220 mg, 0.47 mmol, 1 eq) in THF/MeOH (6 mL/4 mL) was added a solution of oxone (372 mg, 0.61 mmol, 1.3 eq) in H 2 O (3 mL) drop-wise at 0°C. The reaction was allowed to warm to room temperature and stirred for 16 h. TLC showed the reaction was completed. The mixture was poured into water (100mL), extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuum.
  • Step 1 To a 100 mL three necked flask was added 15 mL DMSO, 3-chloro-2- fluorobenzaldehyde (1.44 g, 9.1 mmol, 1.0 eq), 11A (1.5 g, 10.0 mmol, l.le q) and potassium carbonate (3.78 g, 27.3 mmol, 3.0 eq). The reaction mixture was stirred overnight at 100°C. TLC showed the reaction was completed. The mixture was cooled to room temperature and poured into water (200 mL), and the reaction mixture was partitioned between ethyl acetate and water. The organic layers were combined, washed with brine, dried over Na 2 SO 4 , filtered concentrated and purified by column chromatography on silica gel to afford the compound 44A (1.5 g) as a yellow liquid. Yield: 66%.
  • Step 2 To a 100 mL three necked flask was added 15mL methanol and 44A (1.5 g, 6.0 mmol, 1.0 eq), which was stirred at 0°C for 10 min. NaBIL (0.45 g, 11.9 mmol, 2.0 eq) was added to the mixture in portions at 0°C. Then the mixture was stirred at 0°C for 2 h. TLC showed the reaction was completed. The reaction mixture was poured into water (100 mL). The water layer was extracted with ethyl acetate (50 mL*3). The combined organic layer was dried and concentrated in vacuum to afford the compound 44B (1.5 g) as a colorless liquid. Yield: 99%.
  • Step 3 To a 100 mL three necked flask was added 50 mL dichloromethane, compound 44B (630 mg, 2.48 mmol, 1.0 eq) and triethylamine (503 mg, 4.97 mmol, 2.0 eq). Methanesulfonyl chloride (569 mg, 4.97 mmol, 2.0 eq) was added to the mixture drop-wise at 0 °C. Then the mixture was stirred at 0 °C for 3 h. TLC showed the reaction was completed. The reaction mixture was concentrated in vacuum at 5 °C and the residue 44C (1.2 g, crude) was used directly for the next step at once without further purification. [00335] Step 4.
  • Step 5 To a 100 mL three necked flask was added 20 mL DMF, 35A (1.8 g, 1.04 mmol, 1.0 eq), 44C (1.4 g, 2.48 mmol, 2.4 eq) and CsCO3 (1.02 g, 3.12 mmol, 3.0 eq). The reaction mixture was stirred overnight at 90°C. LC-MS showed the reaction was completed. The mixture was cooled to room temperature and poured into water (100 mL), extracted with ethyl acetate (40 mL*3). The organic layers were combined, washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuum. And the residue was purified by column chromatography on silica gel to afford the compound 44D (395 mg) as a yellow solid. Yield: 83% (two steps).
  • Step 8 To a 100 mL three necked flask was added 18 mL THF, 12 mL MeOH and 44D (395 mg, 0.86 mmol, 1.0 eq), which was stirred at 0°C for 10 min. Oxone (793 mg, 1.29 mmol, 1.5 eq) in water (8 mL) was dropped into the mixture at 0°C. The reaction mixture was allowed to room temperature and stirred for another 3 h. LC-MS showed the reaction was completed. The reaction mixture was poured into water. The water layer was extracted with ethyl acetate (50 mL*2). The combined organic layer was dried and concentrated in vacuum.
  • Step 1 To a 100 mL three necked flask was added 40 mL di chloromethane, compound 44B (422 mg, 1.66 mmol, 1.0 eq) and triethylamine (336 mg, 3.32 mmol, 2.0 eq). Methanesulfonyl chloride (381 mg, 114.56 mmol, 2.0 eq) was added to the mixture drop-wise at 0°C. Then the mixture was stirred at 0°C for 3 hours. TLC showed the reaction was completed. The reaction mixture was concentrated in vacuum at 5 °C and the residue 44C (1.2 g, crude) was used directly for the next step at once without further purification.
  • Step 2 ⁇ To a 100 mL three necked flask was added 20 mL toluene and compound 12F (200 mg, 0.69 mmol, 1.0 eq). Triphenylphosphine (545 mg, 2.08 mmol, 3.0 eq) was added to the mixture in portions at 0°C. The reaction mixture was allowed to room temperature and stirred for another 2 h. TLC showed the reaction was completed. To the mixture was added water (3 mL) and the mixture was stirred for another 10 min. The solution was concentrated in vacuum and the residue 34D (1 g, crude) was used directly for the next step at once without further purification.
  • Step 3 To a 100 mL three necked flask was added 15 mL DMF, 34D (1 g, 0.69 mmol, 1.0 eq), 44C (1.2 g, 1.66 mmol, 2.4 eq) and CsCO3 (675 mg, 2.07 mmol, 3.0 eq). The reaction mixture was stirred overnight at 90°C. LC-MS showed the reaction was completed. The mixture was cooled to room temperature and poured into water (100 mL), extracted with ethyl acetate (40 mL*3). The organic layers were combined, washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuum.
  • Step 4 To a 100 mL three necked flask was added 9 mL THF, 6 mL MeOH and 45A (175 mg, 0.38 mmol, 1.0 eq), which was stirred at 0°C for 10 min. Oxone (352 mg, 0.57 mmol, 1.5 eq) in water (4 mL) was dropped into the mixture at 0°C. The reaction mixture was allowed to room temperature and stirred for another 3 h. LC-MS showed the reaction was completed. The reaction mixture was poured into water.
  • Step 1 To a 50 ml single-mouth flask bottom was added 20 ml toluene, compound 12F (200 mg, 0.69 mmol, 1.0 eq). PPhs (542 mg, 2.07 mmol, 3.0 eq) was added under 5°C. The reaction mixture was stirred at 0°C for 2 h. TLC showed the reaction was complete. 2ml water was added and stirred for another 10 min. Then the solution was concentrated under vacuum. The obtained compound 34D (crude) was used to Step 3 without purification.
  • Step 2 ⁇ To a 25 ml single-mouth flask bottom was added 10 ml dichloromethane, compound 43B (444 mg, 1.66 mmol, 1.0 eq), triethylamine (268 mg, 2.65 mmol, 1.6 eq). The reaction mixture was cooled to 0°C and methanesulfonyl chloride (285 mg, 2.48 mmol, 1.5 eq) was added as drop. The reaction mixture was stirred at 0°C for 2 h. TLC showed little compound 43B was left. 20 ml water was added to the solution and the water phase was extracted by dichloromethane (10 ml*2). The organic phase was dried over Na 2 SO 4 and concentrated under vacuum at 10°C. The residue compound 43C was used to step3 without purification.
  • Step 3 To a 50 ml single-mouth flask bottom was added compound 34D (0.69 mmol, 1.0 eq), compound 43C (1.66 mmol, 2.4 eq), 15 ml DMF, CS 2 CO 3 (674 mg, 2.0706 mmol, 3.0 eq). The reaction mixture was heated to 90°C overnight. LC-MS showed the reaction was complete. The solution was poured into 30ml water and extracted by methyl tert-butyl ether (30 ml*2).
  • Step 1 2-bromothiophene (4.9 g, 30 mmol, 1 eq), ferrocene (1.9 g, 10 mmol, 0.3 eq), DMSO (60 mL), a DMSO solution of H 2 SO 4 (0.5 M, 60 ml) and a DMSO solution of CF 3 I (3 M, 30 mL, 3 eq) were charged in a 3 -necked flask. A 30% H2O2 (6 mL) was added drop- wise at the rate of 0.5 mL/min. The temperature of the mixture was thus obtained rose up to 40°C -50°C. The mixture was stirred at this temperature for 20 min. GC showed the reaction was mainly completed.
  • Step 2 To a stirred solution of compound 48A (2 g, 7.7 mmol, 1 eq), benzyl mercaptan (1.1 g, 8.7 mmol, 1 eq) and N,N-diisopropylethylamine (2.2 g, 17.4 mmol, 2 eq) in toluene (30 mL) was added PdC ⁇ dppffCI Cb (212 mg, 0.26 mmol, 0.03 eq) and Xantphos (301 mg, 0.52 mol, 0.06 eq). The reaction was degassed with nitrogen and heated at 100°C for 3 h. TLC showed the reaction was completed. The mixture was cooled to room temperature and concentrated in vacuum.
  • Step 3 To a stirred solution of compound 48B (2 g, 1.56 mmol, 1 eq) in acetic acid/ dichloromethane/H 2 O (60 mL/12 mL/20 mL) was added N-chlorosuccinimide (4.6 g, 34.8 mmol, 4.7 eq) at 0°C. The reaction was allowed to warm to room temperature and stirred for another 2hrs. TLC showed the reaction was completed.
  • Step 1 To a 50 ml single-mouth flask bottom was added 20 ml DMSO, 2-fluoro-3- nitrotoluene (2.5 g, 16.13 mmol, 1.0 eq), piperidine (1.65 g, 19.35 mmol, 1.2 eq), K 2 CO 3 (4.45 g, 32.26 mmol, 2.0 eq). The reaction mixture was stirred at 110°C overnight. TLC showed the reaction was complete. The solution was poured into 100 ml water and extracted by methyl tert-butyl ether (30 ml*3).
  • Step 1 To a 100 mL round-bottom flask was added dioxane 60 mL, l-fluoro-2- nitrobenzene (5.92 g, 42 mmol, 1.0 eq), potassium carbonate (14.5 g, 105 mmol, 2.5 eq) and 4- methylpiperidine (5 g, 50 mmol, 1.2 eq) was dropped into the stirred mixture and refluxed overnight. LC-MS showed the reaction was completed. This reaction was added water 100mL and extracted with EA (40 mL*3). The organic solution was dried over sodium sulfate, filtered and concentrated to afford the compound 52A (8 g). Yield: 86.6 %.
  • Step 2 To a 250 mL round-bottom flask was added methanol 80 mL, compound 52A (8 g, 36.3 mmol, 1.0 eq), Raney -Nickel catalyst (0.8 g) was dropped into the stirred mixture at room temperature for overnight. TLC showed the reaction was complete. The solution was filtered and concentrated to afford the title compound 52B (2 g). Yield: 29 %.
  • Step 3 To a mixture of compound 53B (140 mg, 0.72 mmol, 1.05 eq) in 1 mL of pyridine was added compound 4D (200 mg, 0.69 mmol, 1 eq) at 25°C. The reaction was stirred for another 2 h at the same temperature. TLC showed the reaction was completed. The reaction mixture was diluted with ethyl acetate (100 mL) and 0.5M HC1 (100 mL), brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuum.
  • Step 1 To a 100 mL round-bottom flask was added dioxane 30 mL, l-Fluoro-2- nitrobenzene (2.01 g, 14.3 mmol, 1.0 eq), potassium carbonate (4.93 g, 35.7 mmol, 2.5 eq) and 4- benzylpiperidine (3 g, 17.1 mmol, 1.2 eq) was dropped into the stirred mixture and refluxed overnight. LC-MS showed the reaction was completed. This reaction was added water 100m aLnd extracted with ethyl acetate (40 mL*3). The organic solution was dried over sodium sulfate, filtered and concentrated to afford the title compound 55A (4.2 g). Yield: 99 %.
  • Step 2 ⁇ To a 100mL round-bottom flask was added methanol 40 mL, compound 55A (4.2 g, 14.2 mmol, 1.0 eq), Raney-Nickel catalyst (0.5 g) was dropped into the stirred mixture at room temperature for overnight. TLC showed the reaction was complete. The solution was filtered and concentrated to afford the compound 55B (1.5 g). Yield: 40 %.
  • Example 56 Synthesis of N2-[2-(4,4-Dimethyl-l-piperidinyl)-3-fluorophenyl]-N5,N5- dimethylthiophene-2,5-disulfonamide [00367] Step 1. To a 25 ml single-mouth flask bottom was added 10ml acetonitrile, compound 11A (1 g, 6.68 mmol, 1.2 eq), 2,3 -difluoronitrobenzene (886 mg, 5.57 mmol, 1.0 eq), triethylamine (1.13 g, 11.14 mmol, 2.0 eq). The reaction mixture was stirred at 90°C overnight. TLC showed the reaction was complete. The solution was concentrated under vacuum.
  • Step 1 To a 100 mL round-bottom flask was added DMSO 30 mL, 2-fluoro-3- nitrotoluene (2.5 g, 16.1 mmol, 1.0 eq) , potassium carbonate (6.7 g, 48.3 mmol, 3.0 eq) and 11A (2.9 g, 19.3 mmol, 1.2 eq) was dropped into the stirred mixture, then the mixture was stirred at 120°C overnight. LC-MS showed the reaction was completed. This reaction was added water 100m aLnd extracted with ethyl acetate (50 mL*3).
  • Step 2 To a 100 mL round-bottom flask was added methanol 50 mL, compound 58A (2.5 g, 10.1 mmol, 1.0 eq), Pd/C (0.5 g) was dropped into the stirred mixture at room temperature under H2 for overnight. TLC showed the reaction was completed. The solution was filtered and concentrated to afford compound 58B (1.5g) as a light-yellow solid. Yield: 68.2%.
  • Step 1 To a 2 L round-bottom flask was added acetic acid 800 mL and 2-ethylaniline (200 g, 1.65 mol, 1.0 eq). Then acetic anhydride (253 g, 2.48 mol, 1.5 eq) was dropped into the stirred mixture at 10°C-20°C. Then the mixture was stirred at 30°C for 0.5 hours. TLC showed the reaction was completed. This reaction was added water 2 L and extracted with di chloromethane (2 L*l). The organic solution was washed with brine (500 mL*3), dried over sodium sulfate, filtered and concentrated to afford compound 59A (220 g) as a white solid. Yield: 81.5%.
  • Step 2 To a 100 mL round-bottom flask was added acetic acid 800 mL, compound 59A(110 g, 0.67 mol, 1.0 eq). Fuming nitric acid (340 g, 5.40 mol, 8.0 eq) was added dropwise into the mixture at a temperature of 50°C-55°C. Then the mixture was stirred at 50°C-55°C for 0.5 h. LC- MS showed the reaction was completed. The mixture was poured into ice, and extracted with dichloromethane (1 L*2). The organic layer was washed with brine (500 mL*3), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel to afford compound 59B (50 g, crude) as a yellow solid.
  • Fuming nitric acid 340 g, 5.40 mol, 8.0 eq
  • Step 3 To a 1 L round-bottom flask was added 420 mL water, compound 59B (50 g, 0.24 mol, 1.0 eq) and H2SO4 (141 g, 1.44 mol, 6.0 eq), the reaction was refluxed for overnight. LC-MS showed the reaction was completed; the pH of the mixture was adjusted to 9-10 with 2 N NaOH, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, concentrated in vacuum and the residue was purified by column chromatography on silica gel to afford compound 59C (10 g, GC: 90%) as a yellow liquid. Yield: 10.0% (two steps).
  • Step 4 To a 100 mL round-bottom flask was added 35 mL water, aqueous HBr ( 18.3 g, 90.3 mmol, 2.5 eq) and 59C ( 6 g, 36.1 mmol, 1.0 eq). The mixture was refluxed for 1 h and then cooled to 0°C. A solution of NaNCL (2.5 g, 36.1 mmol, 1.0 eq) in water (14 mL) was added dropwise at a temperature of 0°C-10°C.
  • Step 5 To a 100 mL round-bottom flask was added DMSO 30 mL, 59D (3.70 g, 16.1 mmol, 1.0 eq) , potassium carbonate (5.56 g, 40.2 mmol, 2.5 eq) and piperidine (1.64 g, 19.3 mmol, 1.2 eq), then the mixture was stirred at 120°C overnight. LC-MS showed the reaction was completed. This reaction was added water 100 mL and extracted with ethyl acetate (50 mL*3). The organic solution was dried over sodium sulfate, filtered and concentrated to afford compound 59E (190 mg) as a yellow liquid. Yield: 5.0%.
  • Step 6 To a 100 mL round-bottom flask was added methanol 20 mL, compound 59E (190 mg, 0.8 mmol, 1.0 eq), Pd/C (0.1 g) was dropped into the stirred mixture at room temperature under H2 for overnight. TLC showed the reaction was completed. The solution was filtered and concentrated to afford compound 59F (95 mg) as a yellow liquid. Yield: 57.6%.
  • Step 1 To a 500 ml three-neck flask bottom was added 200 ml toluene, 3-pentanone (20 g, 232 mmol, 1.0 eq), ethyl cyanoacetate (36.79 g, 325 mmol, 1.4 eq), ammonium acetate (4.78 g, 58 mmol, 0.25 eq), acetic acid (16.74 g, 279 mmol, 1.2 eq). The flask was equipped with a Dean-Stark tube. The solution was refluxed under N2 overnight. GC showed the solution was nearly complete. The solution was cooled and 300 ml MTBE was added.
  • Step 2' To a 100 ml three-neck flask bottom was added 50 ml ethanol. Sodium (1.39 g, 61 mmol, 2.0 eq) was added with water bath. After the sodium had reacted, cyanoacetamide (5.1 g, 61 mmol, 2.0 eq) was added and the reaction mixture was heated to reflux for 15 min. The mixture was cooled and a solution of 60A (5 g, 30 mmol, 1.0 eq) in 5 ml ethanol was added as a thin stream. The reaction mixture, which was very thick, turned yellow-orange and was mildly exothermic.
  • Step 3 To a 250 ml three-neck flask was added 47 ml H2SO4, 60B (20 g, 91 mmol, 1.0 eq). The flask was equipped with a magnetic stir bar and a constant pressure dropping funnel. With stirring, 15.15 ml of water was added dropwise over a 45-min period. Sometimes solids emerged and then redissolved during this procedure. The solution was heated to reflux. After 1 h this moderated, and a clear yellow-brown solution with little foam was evident. Heating was discontinued, and after 10 min, 18.18 ml of water was added dropwise over a 35-min period to the still hot solution. Then heating was resumed, and the reaction mixture was brought to reflux overnight.
  • Step 5 To a 100 ml three-neck flask bottom was added 20 ml THF. LiAlHi (1.01 g, 26.63 mmol, 3.0 eq) was added at 0°C. A solution of 60D (1.5 g, 8.88 mmol, 1.0 eq) in 15 ml THF was added to the reaction mixture at 0-5°C. The solution was stirred at 25°C for 1 h and then refluxed for 3 h. The solution was cooled and 1 ml water, 2 ml 10% NaOH, 1ml water was dropped to the solution under 5°C. The mixture was filtered and the solid was washed with dichloromethane.
  • Step 6 To a 50 ml single-mouth flask bottom was added 20 ml DMSO, 2-fluoro-3- nitrotoluene (0.92 g, 5.92 mmol, 1.0 eq), 60E (1.5 g, 8.88 mmol, 1.5 eq), K 2 CO 3 (2.45 g, 17.75 mmol, 3.0 eq). The reaction mixture was stirred at 120°C overnight. TLC showed the reaction was complete.
  • Step 1 To a 25 ml single-mouth flask bottom was added 10 ml dioxane, 2,3- difluoronitrobenzene (1 g, 6.28 mmol, 1.0 eq), hexamethyleneimine (1.65 g, 7.54 mmol, 1.2 eq), K 2 CO 3 (1.73 g, 12.57 mmol, 2.0 eq). The reaction mixture was stirred at 105°C for 1 h. TLC showed the reaction was complete. The solution was poured into 40 ml water and extracted by MTBE (30 ml*3). The MTBE phase was dried over Na 2 SO 4 and concentrated under vacuum to afford compound 64A (1.4 g, crude) as a red oil. It was used to next step without purification.
  • Step 1 To a 100 mL round-bottom flask was added 1,4-dioxane 10 mL, l-chloro-2- fluoro-3 -nitrobenzene (2 g, 11.4 mmol, 1.0 eq) , potassium carbonate(3.94 g, 28.5 mmol, 2.5 eq) and hexamethyleneimine (1.24 g, 12.5 mmol, 1.1 eq) was dropped into the stirred mixture, then the mixture was refluxed overnight. TLC showed the reaction was completed. This reaction was added water 50 mL and extracted with ethyl acetate (20 mL*3). The organic solution was dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel to afford the title compound 65A (2.5 g) as a yellow liquid. Yield: 86.2%.
  • Step 2 ⁇ To a 100 mL round-bottom flask was added methanol 25 mL, compound 65A (2.5 g, 9.8 mmol, 1.0 eq), Raney Ni (0.25 g) was dropped into the stirred mixture at room temperature under H2 for overnight. LC-MS showed the reaction was completed. The solution was filtered and concentrated to afford the compound 65B (1.9 g) as a yellow liquid. Yield: 86.4%.
  • Step 1 To a 100 mL round-bottom flask was added 1,4-dioxane 50 mL, l-chloro-2- fluoro-3 -nitrobenzene (5 g, 28.5 mmol, 1.0 eq), potassium carbonate (9.8 g, 71.2 mmol, 2.5 eq) and 4-piperidinol_(3.17 g, 31.3 mmol, 1.1 eq) was dropped into the stirred mixture, then the mixture was refluxed overnight. LC-MS showed the reaction was completed. This reaction was added water 200 mL and extracted with ethyl acetate (50 mL*3). The organic solution was dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel to afford 67A (6 g) as a yellow solid. Yield: 82.1%.
  • Step 2' To a 100 mL three necked flask was added 60 mL dichloromethane and oxalyl chloride (5.93 g, 46.7 mmol, 2.0 eq). The mixture was cooled to -80°C and treated drop wise with a solution of DMSO (9.13 g, 116.9 mmol, 5.0 eq) in di chloromethane (25 mL). The mixture was stirred at -80°C for 15 min. Then the mixture was treated dropwise with a solution of 67A (6 g, 23.4 mmol, 1.0 eq) in di chloromethane (25 mL). The mixture was stirred at -70°C for 1.5 h.
  • DMSO 9.13 g, 116.9 mmol, 5.0 eq
  • Step 4 To a 100 mL round-bottom flask was added methanol 50mL, compound 67C (1.7 g, 5.5 mmol, 1.0 eq), Raney Ni (0.2 g) was dropped into the stirred mixture at room temperature under H2 for 1 h. TLC showed the reaction was completed. The solution was filtered and concentrated to afford the compound 67D (1.1 g) as ayellow solid. Yield: 73.3%.
  • Step 2' To a 100 mL round-bottom flask was added methanol 20 mL, compound 68A (1.2 g, 4.4 mmol, 1.0 eq), Raney Ni (0.2 g) was dropped into the stirred mixture at room temperature under H2 for 1 h. TLC showed the reaction was completed. The solution was filtered, concentrated and purified on silica gel to afford the compound 68B (0.7 g) as a yellow liquid. Yield: 65.4%.
  • Step 1 To a 250 ml three-necked flask bottom was added 70 ml THF, LiAlIL (3.68 g, 96.77 mmol, 3.0 eq). A solution of 4-ethyl-4-methylpiperidine-2, 6-dione (5 g, 32.26 mmol, 1.0 eq) in 80 ml THF was added to the bottom under 10°C. The reaction mixture was stirred for 1 h at 15°C and then reflux for 3 h. TLC showed the reaction was complete. The solution was cooled to 0°C and 3.68 ml water, 7.36 ml 10% NaOH, 3.68 ml water was added as turn at 0°C.
  • Step 1 To a 100 mL round-bottom flask was added DMSO 20 mL, 2-fluoro-3- nitrotoluene (0.73 g, 4.7 mmol, 1.0 eq), potassium carbonate (1.95 g, 14.1 mmol, 3 eq) and 71A (1.00 g, 6.1 mmol, 1.3 eq) was dropped into the stirred mixture, then the mixture was stirred at 125°C for 60 hours. LC-MS showed the reaction was completed. This reaction was added water 50 mL and extracted with ethyl acetate (20 mL*3). The organic solution was dried over sodium sulfate, fdtered and concentrated.
  • Step 2 ⁇ To a 100 mL round-bottom flask was added methanol 20 mL, compound 72A (0.8 g, 3.1 mmol, 1.0 eq), Pd/C (0.2 g) was dropped into the stirred mixture at room temperature under H2 for overnight. LC-MS showed the reaction was completed. The solution was filtered and concentrated, the residue was purified by column chromatography on silica gel to afford the compound 72B (215 mg). Yield: 31.0%.
  • Step 1 To a 500 ml three-neck flask bottom was added 200 ml toluene, 3-pentanone (62 g, 721 mmol, 1.0 eq), ethyl cyanoacetate (114 g, 1.01 mol, 1.4 eq), ammonium acetate (14.82 g, 192 mmol, 0.25 eq), acetic acid (51.89 g, 865 mmol, 1.2 eq). The flask was equipped with a Dean-Stark tube. The solution was refluxed under N2 overnight. GC showed the solution was nearly complete. The solution was cooled and poured into 1 L water.
  • the water phase was extracted by 500ml methyl tert-butyl ether.
  • Step 2' To a 500 ml three-neck flask bottom was added 200 ml ethanol. Sodium (5.58 g, 242 mmol, 2.0 eq) was added with water bath. After the sodium had reacted, cyanoacetamide (20.38 g, 242 mmol, 2.0 eq) was added and the reaction mixture was heated to reflux for 15 min. The mixture was cooled and a solution of 60A (20 g, 121 mmol, 1.0 eq) in 20 ml ethanol was added as a thin stream. The reaction mixture, which was very thick, turned yellow-orange and was mildly exothermic.
  • Step 3 To a 500 ml three-neck flask was added 141 ml H2SO4, 60B (60 g, 274 mmol, 1.0 eq). The flask was equipped with a magnetic stir bar and a constant pressure dropping funnel. With stirring, 45.45 ml of water was added dropwise over a 45 min period. Sometimes solids emerged and then redissolved during this procedure. The solution was heated to reflux. After 1 h this moderated, and a clear yellow-brown solution with little foam was evident. Heating was discontinued, and after 10 min, 54.54 ml of water was added dropwise over a 35-min period to the still hot solution. Then heating was resumed, and the reaction mixture was brought to reflux overnight.
  • Step 1 To a solution of 1, 2-difluoro-3 -nitro-benzene (500 mg, 3.14 mmol, 1 eq) and 6- azaspiro [2.5]octane (557 mg, 3.77 mmol, 1.2 eq, HC1) in ACN (5 mL) was added TEA (636 mg, 6.29 mmol, 875 ⁇ L, 2 eq). The mixture was stirred at 80 °C for 12 hours. LC-MS showed 1, 2- difluoro-3 -nitro-benzene was consumed completely and desired mass was detected. The solution was concentrated under vacuum. The obtained oil was added water (40 mL) and extracted by EtOAc (60 mL).
  • Step 2 To a solution of 6-(2-fluoro-6-nitro-phenyl)-6-azaspiro [2.5] octane (590 mg, 2.36 mmol, 1 eq) in EtOH (5 mL) and H 2 O (0.5 mL) was added Fe (658 mg, 11.8 mmol, 5 eq) and NH4CI (1.26 g, 23.6 mmol, 10 eq). The mixture was stirred at 80 °C for 12 hours. LC-MS showed 6-(2-fluoro-6-nitro-phenyl)-6-azaspiro [2.5] octane was consumed completely and desired mass was detected.
  • Step 3 To a solution of 2-(6-azaspiro[2.5]octan-6-yl)-3-fluoro-aniline (100 mg, 454 pmol, 1 eq) in Py (2 mL) was added 5-(dimethylsulfamoyl)thiophene-2-sulfonyl chloride (197 mg, 681 pmol, 1.5 eq). The mixture was stirred at 20 °C for 12 hours. LC-MS showed 2-(6-azaspiro [2.5] octan-6-yl)-3 -fluoro-aniline remained and desired compound was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue.
  • Step 1 To a solution of 2-(6-azaspiro [2.5]octan-6-yl)-3-fluoro-aniline (100 mg, 454 pmol, 1 eq) in Py (2 mL) was added 5-pyrrolidin-l-ylsulfonylthiophene-2-sulfonyl chloride (215 mg, 681 pmol, 1.5 eq). The mixture was stirred at 20 °C for 12 hours. LC-MS showed 2-(6-azaspiro [2.5] octan-6-yl)-3 -fluoro-aniline remained and desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue.
  • Example 77 N-[2-(4, 4-dimethyl-l-piperidyl)-3-methyl-phenyl]-5-pyrrolidin-l-ylsulfonyl- thiophene-2-sulfonamide
  • Step 1 To a solution of 5-bromothiophene-2-si/lfonyl chloride (10 g, 38.2 mmol, 1 eq) in DCM (100 mL) was added pyrrolidine (13.6 g, 191 mmol, 16.0 mL, 5 eq) at 0 °C. The mixture was stirred at 20 °C for 3 hours. LC-MS showed 5-bromothiophene-2-sulfonyl chloride was consumed completely and one main peak with desired mass was detected. The reaction mixture was partitioned between HC1 (IM, 40 mL) and DCM (150 mL).
  • Step 2' To a solution of l-[(5-bromo-2-thienyl) sulfonyl] pyrrolidine (5 g, 16.9 mmol, 1 eq) and phenylmethanethiol (2.31 g, 18.6 mmol, 2.18 mL, 1.1 eq) and DIEA (4.36 g, 33.8 mmol, 5.88 mL, 2 eq) in Tol.
  • Step 3 To a solution of l-[(5-benzylsulfanyl-2-thienyl) sulfonyl] pyrrolidine (2 g, 5.89 mmol, 1 eq) in AcOH (48 mL) and H 2 O (12 mL) was added NCS (2.36 g, 17.7 mmol, 3 eq). The mixture was stirred at 20 °C for 4 hours. TLC showed l-[(5-benzylsulfanyl-2-thienyl) sulfonyl] pyrrolidine was consumed completely and one major new spot with larger polarity was detected.
  • the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (450 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na 2 SO 4 , 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/petrolewm ether gradient @ 40 mL/min) to give desired 5-pyrrolidin-l-ylsulfonylthiophene-2- sulfonyl chloride (1.6 g, 5.07 mmol, 86.0% yield) as a white solid.
  • Step 4 To a solution of 5-pyrrolidin-l-ylsulfonylthiophene-2-sulfonyl chloride (174 mg, 549 pmol, 1.2 eq) in Py. (2 mL) was added 2-(4, 4-dimethyl-l-piperidyl)-3-methyl-aniline (100 mg, 458 pmol, 1 eq). The mixture was stirred at 20 °C for 12 hours. LC-MS showed 2-(4, 4-dimethyl-l- piperidyl)-3-methyl-aniline was consumed completely and desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue.
  • Example 78 N5-[2-(7-azaspiro [3.5] nonan-7-yl)-3-chloro-phenyl]-N2, N2-dimethyl-thiophene- 2, 5-disulfonamide.
  • Step 1 To a solution of 1 -chloro-2-fluoro-3 -nitro-benzene (452 mg, 2.58 mmol, 1 eq) and 7-azaspiro [3.5] nonane (500 mg, 3.09 mmol, 1.2 eq, HC1) in ACN (3 mL) was added TEA (521 mg, 5.15 mmol, 2 eq). The mixture was stirred at 80 °C for 2 hours. LC-MS showed l-chloro-2- fluoro-3 -nitro-benzene was consumed completely and desired mass was detected. The solution was concentrated under vacuum. The obtained oil was added water (40 mL) and extracted by EtOAc (60 mL).
  • Step 2 ⁇ To a solution of 7-(2-chloro-6-nitro-phenyl)-7-azaspiro [3.5] nonane (700 mg, 2.49 mmol, 1 eq) in EtOH (5 mL) and H 2 O (0.5 mL) was added Fe (696 mg, 12.5 mmol, 5 eq) and NH 4 CI (1.33 g, 24.9 mmol, 10 eq). The mixture was stirred at 80 °C for 2 hours. LC-MS showed 7- (2-chloro-6-nitro-phenyl)-7-azaspiro [3.5] nonane 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.
  • Step 3 To a solution of 2-(7-azaspiro [3.5] nonan-7-yl)-3 -chloro-aniline (100 mg, 399 pmol, 1 eq) in Py (2 mL) was added 5 -(dimethylsulfamoyl) thiophene-2-sulfonyl chloride (173 mg, 598 pmol, 1.5 eq). The mixture was stirred at 20 °C for 12 hours. LC-MS showed 2-(7-azaspiro [3.5] nonan-7-yl)-3 -chloro-aniline 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.
  • Step 1 To a solution of 1, 2-difluoro-3 -nitro-benzene (410 mg, 2.58 mmol, 1 eq) and 7- azaspiro [3.5] nonane (500 mg, 3.09 mmol, 1.2 eq, HC1) in ACN (3 mL) was added TEA (522 mg, 5.15 mmol, 2 eq). The mixture was stirred at 80 °C for 2 hours. LC-MS showed 2-difluoro-3 -nitrobenzene was consumed completely and desired mass was detected. The solution was concentrated under vacuum. The obtained oil was added H 2 O (40 mL) and extracted by EtOAc (20 mL * 3).
  • Step 2 ⁇ To a solution of 7-(2-fluoro-6-nitro-phenyl)-7-azaspiro [3.5] nonane (650 mg, 2.46 mmol, 1 eq) in EtOH (5 mL) and H 2 O (0.5 mL) was added Fe (687 mg, 12.3 mmol, 5 eq) and NH 4 CI (1.32 g, 24.6 mmol, 10 eq). The mixture was stirred at 80 °C for 2 hours. LC-MS showed 7- (2-fluoro-6-nitro-phenyl)-7-azaspiro [3.5] nonane 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.
  • Step 3 To a solution of 2-(7-azaspiro [3.5] nonan-7-yl)-3 -fluoro-aniline (100 mg, 427 pmol, 1 eq) in Py (2 mL) was added 5 -(dimethylsulfamoyl) thiophene-2-sulfonyl chloride (186 mg, 640 pmol, 1.5 eq). The mixture was stirred at 20 °C for 12 hours. LC-MS showed Reactant 1 was consumed completely and desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue.
  • Example 80 N-[2-(6- azaspiro [2.5] octan-6-yl)-3-chloro-phenyl]-5-pyrrolidin-l-ylsulfonyl- thiophene-2-sulfonamide
  • Step 1 The mixture of 1 -chloro-2-fluoro-3 -nitro-benzene (200 mg, 1.14 mmol, 1 eq) and 6-azaspiro [2.5] octane (185 mg, 1.25 mmol, 1.1 eq, HC1) and K 2 CO 3 (472 mg, 3.42 mmol, 3 eq) in DMSO (2 mL) was heated to 120 °C and stirred for 12 hours under N2 atmosphere. LC-MS showed no l-chloro-2-fluoro-3 -nitro-benzene remained and desired compound was detected. The mixture was diluted with water (20 mL) and EtOAc (20 mL).
  • Step 2 To a solution of 6-(2-chloro-6-nitro-phenyl)-6-azaspiro[2.5]octane (200 mg, 749 pmol, 1 eq) and NH4CI (401 mg, 7.50 mmol, 10 eq) in EtOH (3 mL) and H 2 O (1 mL) was added Fe (209 mg, 3.75 mmol, 5 eq) at 80 °C under N2. The mixture was stirred at 80 °C for 36 hours. LC- MS showed 6-(2-chloro-6-nitro-phenyl)-6-azaspiro [2.5] octane was consumed completely and one main peak with desired mass was detected.
  • Step 3 To a solution of 5-pyrrolidin-l-ylsulfonylthiophene-2-sulfonyl chloride (140 mg, 444 pmol, 1.5 eq) in PYRIDINE (2 mL) was added 2-(6-azaspiro [2.5] octan-6-yl)-3 -chloro- aniline (70 mg, 296 pmol, 1 eq). The mixture was stirred at 15 °C for 12 hours. LC-MS showed 5- pyrrolidin-l-ylsulfonylthiophene-2-sulfonyl chloride was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue.
  • Step 1 To a solution of 4-(trifluoromethyl) piperidine (480 mg, 3.13 mmol, 1.1 eq) and 1 -chloro-2-fluoro-3 -nitro-benzene (500 mg, 2.85 mmol, 1 eq) in dioxane (5 mL) was added K 2 CO 3 (787 mg, 5.70 mmol, 2 eq). The mixture was stirred at 100 °C for 12 hours. LC-MS showed 4- (trifluoromethyl) piperidine remained and desired compound was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue.
  • Step 2 To a solution of l-(2-chloro-6-nitro-phenyl)-4-(trifluoromethyl) piperidine (490 mg, 1.59 mmol, 1 eq) in H 2 O (5 mL) and EtOH (0.5 mL) was added Fe (443 mg, 7.94 mmol, 5 eq) and NH4CI (849 mg, 15.9 mmol, 10 eq). The mixture was stirred at 80 °C for 12 hours. LC-MS showed l-(2-chloro-6-nitro-phenyl)-4-(trifluoromethyl) piperidin 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.
  • Step 3 To a solution of 3 -chloro-2-[4-(trifluoromethyl)-l -piperidyl] aniline (100 mg, 359 pmol, 1 eq) in Py (2 mL) was added 5-(dimethylsulfamoyl) thiophene-2-sulfonyl chloride (156 mg, 538 pmol, 1.5 eq). The mixture was stirred at 20 °C for 12 hours. LC-MS showed 3-chloro-2- [4-(trifluoromethyl)-l -piperidyl] aniline remained and desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue.
  • Example 82 N5-[2-(3, 3-dimethylpyrrolidin-l-yl)-3-methyl-phenyl]-N2, N2-dimethyl- thiophene-2, 5-disulfonamide
  • Step 1 To a solution of 2-fluoro-l-methyl-3 -nitro-benzene (1 g, 6.45 mmol, 1 eq) and 3, 3-dimethylpyrrolidine (918 mg, 6.77 mmol, 1.05 eq, HC1) in DMSO (10 mL) was added CS 2 CO 3 (5.25 g, 16.1 mmol, 2.5 eq). The mixture was stirred at 100 °C for 12 hours. LC-MS showed 2- fluoro-l-methyl-3 -nitro-benzene was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (150 mL).
  • Step 2' To a solution of 3, 3 -dimethyl- l-(2-methyl-6-nitro-phenyl) pyrrolidine (500 mg, 2.13 mmol, 1 eq) in EtOH (5 mL) and H 2 O (1 mL) was added Fe (596 mg, 10.7 mmol, 5 eq) and NH4CI (1.14 g, 21.3 mmol, 10 eq). The mixture was stirred at 80 °C for 12 hours. LC-MS showed 3, 3 -dimethyl- l-(2-methyl-6-nitro-phenyl) pyrrolidine was consumed completely and one main peak with desired mass was detected.
  • Step 3 To a solution of 5-(dimethylsulfamoyl)thiophene-2-sulfonyl chloride (374 mg, 1.29 mmol, 1.2 eq) in pyridine (2 mL) was added 2-(3, 3-dimethylpyrrolidin-l-yl)-3-methyl-aniline (220 mg, 1.08 mmol, 1 eq). The mixture was stirred at 20 °C for 12 hours. LC-MS showed 5- (dimethylsulfamoyl) thiophene-2-sulfonyl chloride 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 pre p-HPLC (neutral condition: column: Phenomenex Gemini-NX 80*40mm*3um; mobile phase: [water (10mM NELHCO 3 -ACN]; B%: 45%-75%, 8min) to give desired N5-[2-(3, 3-dimethylpyrrohdin-l-yl)-3-methyl-phenyl]-N2, N2-dimethyl-thiophene- 2, 5 -disulfonamide (118 mg, 258 pmol, 24.0% yield) as a yellow solid.
  • Example 83 5-[4-chloro-3-(4,4-dimethyl-l-piperidyl) indazol-l-yl] sulfonyl-N,N-dimethyl- thiophene-2-sulfonamide
  • Step 1 To a solution of 3, 3 -dimethylazetidine (823 mg, 6.77 mmol, 1.05 eq, HC1) in DMSO (10 mL) was added 2-fluoro-l-methyl-3 -nitro-benzene (1 g, 6.45 mmol, 1 eq) and CS 2 CO 3 (5.25 g, 16.1 mmol, 2.5 eq). The mixture was stirred at 100 °C for 12 hours. LC-MS showed 2- fluoro-l-methyl-3 -nitro-benzene was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (150 mL).
  • Step 2 To a solution of 3, 3 -dimethyl- l-(2-methyl-6-nitro-phenyl) azetidine (500 mg, 2.27 mmol, 1 eq) in EtOH (5 mL) and H 2 O (1 mL) was added Fe (634 mg, 11.4 mmol, 5 eq) and NH4CI (1.21 g, 22.7 mmol, 10 eq). The mixture was stirred at 80 °C for 12 hours. LC-MS showed 3, 3 -dimethyl- l-(2-methyl-6-nitro-phenyl) azetidine was consumed completely and one main peak with desired mass was detected.
  • Step 3 To a solution of 5-(dimethylsulfamoyl)thiophene-2-sulfonyl chloride (365 mg, 1.26 mmol, 1.2 eq) in pyridine (2 mL) was added 2-(3,3-dimethylazetidin-l-yl)-3-methyl-aniline (200 mg, 1.05 mmol, 1 eq). The mixture was stirred at 20 °C for 12 hours. LC-MS showed 2-(3, 3- dimethylazetidin-l-yl)-3-methyl-aniline was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue.
  • Example 84 N-(2-(4, 4-dimethylpiperidin-l-yl)-3-methylphenyl)-5-(isopropylsulfonyl) thiophene-2-sulfonamide
  • Step 1 To a solution of 2-(4, 4-dimethylpiperidin-l-yl)-3 -methylaniline (0.5 g, 2.29 mmol, 1 eq) in DCM (5 mL) was added 5-bromothiophene-2-sulfonyl chloride (659 mg, 2.52 mmol, 1.1 eq), TEA (463 mg, 4.58 mmol, 637 ⁇ L, 2 eq). The mixture was stirred at 20 °C for 12 hours.
  • Step 2 To a solution of 5-bromo-N-(2-(4, 4-dimethylpiperidin-l-yl)-3 -methylphenyl) thiophene-2-sulfonamide (200 mg, 451 pmol, 1 eq) and 2-(isopropyldisulfanyl)propane (142 mg, 947 pmol, 151 ⁇ L, 2.1 eq) in THF (2 mL) was added dropwise w-BuLi (2.5 M, 235 ⁇ L, 1.3 eq) at -70 °C. The resulting mixture was stirred at -70 °C for 0.5 hour.
  • Step 3 To a solution of N-(2-(4, 4-dimethylpiperidin-l-yl)-3-methylphenyl)-5- (isopropylthio) thiophene-2-sulfonamide (90 mg, 205 pmol, 1 eq) in DCM (1 mL) was added m- CPBA (125 mg, 616 pmol, 85% purity, 3 eq) at 0 °C. The mixture was stirred at 20 °C for 12 hours.
  • Example 85 N2-(3-chloro-2-(4, 4-difluoropiperidin-l-yl) phenyl)-N5, N5-dimethylthiophene-2, 5-disulfonamide
  • the reaction mixture was diluted with H 2 O (20 mL) and extracted with (EtOAc). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-20% EtOAc/petroleum ether gradient @ 40 mL/min) to give desired l-(2-chloro-6-nitrophenyl)-4, 4-difluoropiperidine (230 mg, 831 pmol, 26.2% yield) as a yellow oil.
  • Step 2 To a solution of l-(2-chloro-6-nitro-phenyl)-4, 4-difluoro-piperidine (230 mg, 831 pmol, 1 eq) in EtOH (3 mL) and H 2 O (0.6 mL) was added Fe (232 mg, 4.16 mmol, 5 eq) and NH4CI (445 mg, 8.31 mmol, 10 eq). The mixture was stirred at 80 °C for 3 hours. LC-MS showed 1- (2-chloro-6-nitro-phenyl)-4, 4-difluoro-piperidine was consumed completely and one main peak with desired mass was detected.
  • Step 3 To a solution of 3-chloro-2-(4, 4-difluoro-l -piperidyl) aniline (140 mg, 568 pmol, 1 eq) in PYRIDINE (2 mL) was added 5 -(dimethylsulfamoyl) thiophene-2-sulfonyl chloride (197 mg, 681 pmol, 1.2 eq). The mixture was stirred at 15 °C for 3 hours. LC-MS showed 3-chloro- 2-(4, 4-difluoro-l -piperidyl) aniline was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue.
  • Step 2' To a solution of 2-(2-methyl-6-nitro-phenyl)-2-azaspiro[3.3]heptanes (200 mg, 861 pmol, 1 eq) in MeOH (10 mL) was added Pd/C (10 mg, 50% purity) and H2 (861 pmol). The mixture was stirred at 20 °C for 1 hour. LC-MS showed 2-(2-methyl-6-nitro-phenyl)-2-azaspiro [3.3] heptanes was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and washed with EtOAc (90 mL), then the filtrate was concentrated under reduced pressure to give a residue.
  • Step 3 To a solution of 5-(dimethylsulfamoyl)thiophene-2-sulfonyl chloride (236 mg, 816 pmol, 1.1 eq) in pyridine (2 mL) was added 2-(2-azaspiro[3.3]heptan-2-yl)-3-methyl-aniline (150 mg, 741 pmol, 1 eq). The mixture was stirred at 20 °C for 12 hours. LC-MS showed 2-(2- azaspiro[3.3]heptan-2-yl)-3-methyl-aniline was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue.
  • Step 1 To a solution of 2-fluoro-l-methyl-3 -nitro-benzene (500 mg, 3.22 mmol, 1 eq) and 1, 2, 3, 3a, 4, 5, 6, 6a-octahydrocyclopenta[c]pyrrole (571 mg, 3.87 mmol, 1.2 eq, HC1) in dioxane (4 mL) was added K 2 CO 3 (891 mg, 6.45 mmol, 2 eq). The mixture was stirred at 100 °C for 12 hours. LC-MS showed 2-fluoro-l-methyl-3 -nitro-benzene was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue.
  • Step 2. A mixture of 2-(2-methyl-6-nitro-phenyl)-3, 3a, 4, 5, 6, 6a-hexahydro-lH- cyclopenta[c]pyrrole (400 mg, 1.62 mmol, 1 eq), Pd/C (50 mg, 10% purity, 1 eq) in MeOH (10 mL) was degassed and purged with H2 (15 PSI) for 3 times, and then the mixture was stirred at 20 °C for 12 hours under H2 atmosphere.
  • LC-MS showed 2-(2-methyl-6-nitro-phenyl)-3, 3a, 4, 5, 6, 6a- hexahydro-lH-cyclopenta[c]pyrrole was consumed completely and desired mass was detected.
  • Step 3 To a solution of 2-(3, 3a, 4, 5, 6, 6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl)-3- methyl-aniline (160 mg, 740 pmol, 1 eq) in Py (1 mL) was added 5-(dimethylsulfamoyl)thiophene-2- sulfonyl chloride (322 mg, 1.11 mmol, 1.5 eq). The mixture was stirred at 20 °C for 2 hours. LC- MS showed 2-(3, 3a, 4, 5, 6, 6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl)-3-methyl-aniline was consumed completely and desired mass was detected.
  • the reaction mixture was concentrated to give a residue.
  • the residue was purified by pre p-HPLC (neutral condition; column: Phenomenex Gemini- NX 80*40mm*3um; mobile phase: [water (10mM NELHCO3)-ACN]; B%: 45%-75%, 8min) to give desired N5-[2-(3, 3a, 4, 5, 6, 6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl)-3-methyl-phenyl]-N2, N2- dimethyl-thiophene-2, 5 -disulfonamide (142 mg, 301 pmol, 40.7% yield, 100% purity) as a yellow solid.
  • Example 88 5-[[2-(4, 4-dimethyl-l-piperidyl)-3-methyl-phenyl] sulfamoyl] -N, N-dimethyl- thiophene-2-carboxamide
  • Step 1 To a solution of 5-bromo-N-[2-(4,4-dimethyl-l-piperidyl)-3-methyl-phenyl] thiophene-2-sulfonamide (0.3 g, 677 pmol, 1 eq), N-methylmethanamine (110 mg, 1.35 mmol, 124 ⁇ L, 2 eq, HC1) and TEA (205 mg, 2.03 mmol, 283 ⁇ L, 3 eq) in MeOH (10 mL) was added Pd(dppf)C12 (49.5 mg, 67.7 pmol, 0.1 eq) under CO atmosphere. The suspension was degassed and purged with CO for 3 times.
  • Example 89 N-[3-chloro-2-(4, 4-dimethyl-l-piperidyl) phenyl] -5-isopro pylsulfonyl- thiophene- 2-sulfonamide [00465] Step 1. To a solution of 1 -chloro-2-fluoro-3 -nitro-benzene (1 g, 5.70 mmol, 1 eq) and 4,4-dimethylpiperidine (938 mg, 6.27 mmol, 1.1 eq, HC1) in dioxane (10 mL) was added K 2 CO 3 (2.36 g, 17.1 mmol, 3 eq). The mixture was stirred at 100 °C for 12 hours.
  • Step 2 To a solution of l-(2-chloro-6-nitro-phenyl)-4, 4-dimethyl-piperidine (1.5 g, 5.58 mmol, 1 eq) and NH4CI (2.99 g, 55.8 mmol, 10 eq) in H 2 O (2 mL) and EtOH (20 mL) was added Fe (1.56 g, 27.9 mmol, 5 eq). The mixture was stirred at 80 °C for 12 hours. LC-MS showed l-(2- chloro-6-nitro-phenyl)-4, 4-dimethyl-piperidine was consumed completely and one main peak with desired mass was detected.
  • Step 3 To a solution of 3-chloro-2-(4, 4-dimethyl-l -piperidyl) aniline (400 mg, 1.68 mmol, 1 eq) and 5-bromothiophene-2-sulfonyl chloride (876 mg, 3.35 mmol, 2 eq) in DCM (4 mL) was added TEA (339 mg, 3.35 mmol, 466 ⁇ L, 2 eq). The mixture was stirred at 20 °C for 12 hours. LC-MS showed 3-chloro-2-(4, 4-dimethyl-l -piperidyl) aniline was consumed completely and one main peak with desired mass was detected.
  • Step 4 To a solution of 5-bromo-N-[3-chloro-2-(4,4-dimethyl-l- piperidyl)phenyl]thiophene-2-sulfonamide (0.5 g, 1.08 mmol, 1 eq) and 1 ,2-diisopropyldisulfane (340 mg, 2.26 mmol, 361 ⁇ L, 2.1 eq) in THF (5 mL) was added dropwise n-BuLi (2.5 M, 561 ⁇ L, 1.3 eq) at -70 °C. The resulting mixture was stirred at -70 °C for 0.5 hour.
  • Step 5 To a solution of N-[3-chloro-2-(4, 4-dimethyl-l-piperidyl)phenyl]-5- isopropylsulfanyl-thiophene-2-sulfonamide (220 mg, 479 pmol, 1 eq) in DCM (3 mL) was added m- CPBA (292 mg, 1.44 mmol, 85% purity, 3 eq) at 0 °C. The mixture was stirred at 20 °C for 12 hours.
  • Step 1 To a solution of tert-butyl 0 -oxopyrrolidine- 1 -carboxylate (10 g, 54.0 mmol, 1 eq) in THF (100 mL) was added t-BuOK (14.5 g, 130 mmol, 2.4 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. Then bromo-(4-bromobutyl)-triphenyl-X5-phosphane (31.0 g, 64.8 mmol, 1.2 eq) in THF (100 mL) was added dropwise to the mixture at 0 °C. Then the mixture was stirred at 20 °C for 12 hours.
  • Step 2' A mixture of tert-butyl 3 -cyclobutylidenepyrrolidine-1 -carboxylate (1.25 g, 5.60 mmol, 1 eq), Pd/C (200 mg, 10% purity) in MeOH (30 mL) was degassed and purged with H2 for 3 times, and then the mixture was stirred at 20 °C for 12 hours under H2(15PSI) atmosphere. LC-MS showed tert-butyl 3 -cyclobutylidenepyrrolidine-1 -carboxylate was consumed completely and desired mass was detected.
  • Step 3 The mixture of tert-butyl 3 -cyclobutylpyrrolidine-1 -carboxylate (1.1 g, 4.88 mmol, 1 eq) in HCl/MeOH (10 mL) was stirred at 20 °C for 1 hour. LC-MS showed tert-butyl 3- cyclobutylpyrrolidine-1 -carboxylate was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give desired 3-cyclobutylpyrrolidine (750 mg, crude, HC1) as an orange oil. MS (ESI): mass calcd. For CsHisN 125.12, m/z found 126.3 [M+H] + .
  • Step 4 To a solution of 2-fluoro-l-methyl-3 -nitro-benzene (100 mg, 645 pmol, 1 eq) and 3-cyclobutylpyrrolidine (156 mg, 967 pmol, 1.5 eq, HC1) in dioxane (2 mL) was added K 2 CO 3 (267 mg, 1.93 mmol, 3 eq). The mixture was stirred at 100 °C for 12 hours. LC-MS showed 2- fluoro-l-methyl-3 -nitro-benzene desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue.
  • Step 5 A mixture of 3 -cyclobutyl- l-(2-methyl-6-nitro-phenyl) pyrrolidine (180 mg, 691 pmol, 1 eq), Pd/C (50 mg, 320 pmol, 10% purity) in MeOH (5 mL) was degassed and purged with EEQ 5 PSI) for 3 times, and then the mixture was stirred at 20 °C for 1 hour under H2 atmosphere.
  • LC-MS showed 3 -cyclobutyl- l-(2-methyl-6-nitro-phenyl) pyrrolidine was consumed completely and desired mass was detected.
  • Step 6 To a solution of 2-(3-cyclobutylpyrrolidin-l-yl)-3-methyl-aniline (90 mg, 391 pmol, 1 eq) in Py (1 mL) was added 5 -(dimethylsulfamoyl) thiophene-2-sulfonyl chloride (170 mg, 586 pmol, 1.5 eq). The mixture was stirred at 20 °C for 2 hours. LC-MS showed 2-(3- cyclobutylpyrrolidin-l-yl)-3-methyl-aniline was consumed completely and desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue.
  • Example 91 5-(azetidin-l-ylsulfonyl)-N-(3-chloro-2-(4, 4-dimethylpiperidin-l-yl) phenyl) thiophene-2-sulfonamide
  • Step 1 To a solution of 5-bromothiophene-2-sulfonyl chloride (1 g, 3.82 mmol, 1 eq) in DCM (10 mL) was added TEA (967 mg, 9.55 mmol, 1.33 mL, 2.5 eq) and azetidine (429 mg, 4.58 mmol, 507 ⁇ L, 1.2 eq, HC1). The mixture was stirred at 20 °C for 12 hours. LC-MS showed 5- bromothiophene-2-sulfonyl chloride was consumed completely and desired mass was detected. The reaction mixture was quenched by water 30 mL, and then extracted with DCM 60 mL (20 mL * 3).
  • Step 2 A mixture of l-[(5-bromo-2-thienyl) sulfonyl] azetidine (1 g, 3.54 mmol, 1 eq), phenylmethanethiol (484 mg, 3.89 mmol, 456 ⁇ L, 1.1 eq), DIEA (915 mg, 7.08 mmol, 1.23 mL, 2 eq), Pd(dppf)C12 (64.8 mg, 88.5 pmol, 0.025 eq) and (5-diphenylphosphanyl-9, 9-dimethyl-xanthen- 4-yl)-diphenyl-phosphane (205 mg, 354 pmol, 0.1 eq) in Tol.
  • Step 4 To a solution of 3-chloro-2-(4, 4-dimethyl-l -piperidyl) aniline (200 mg, 838 pmol, 1 eq) in Py (2 mL) was added 5-(azetidin-l-ylsulfonyl) thiophene-2-sulfonyl chloride (379 mg, 1.26 mmol, 1.5 eq). The mixture was stirred at 20 °C for 12 hours. LC-MS showed 3-chloro-2-(4, 4- dimethyl-1 -piperidyl) aniline was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue.
  • Step 1 To a solution of 1 -chloro-2-fluoro-3 -nitro-benzene (1 g, 5.70 mmol, 1 eq) and 2- methylpiperidine (927 mg, 6.84 mmol, 1.11 mL, 1.2 eq, HC1) in dioxane (10 mL) was added K 2 CO 3 (1.97 g, 14.2 mmol, 2.5 eq). The mixture was stirred at 100 °C for 12 hours. LC-MS showed 1- chloro-2-fluoro-3 -nitro-benzene 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.
  • Step 2 To a solution of l-(2-chloro-6-nitro-phenyl)-2-methyl-piperidine (500 mg, 1.96 mmol, 1 eq) in EtOH (10 mL) and H 2 O (1 mL) was added Fe (548 mg, 9.82 mmol, 5 eq) and NH4CI (1.05 g, 19.6 mmol, 10 eq). The mixture was stirred at 80 °C for 12 hours. LC-MS showed l-(2- chloro-6-nitro-phenyl)-2-methyl-piperidine was consumed completely and desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue.
  • Step 3 To a solution of 3 -chloro-2-(2-methyl-l -piperidyl) aniline (150 mg, 667 pmol, 1 eq) in Py (2 mL) was added 5 -(dimethylsulfamoyl) thiophene-2-sulfonyl chloride (290 mg, 1.00 mmol, 1.5 eq). The mixture was stirred at 15 °C for 12 hours. LC-MS showed 3-chloro-2-(2- methyl-1 -piperidyl) aniline was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue.
  • Example 93 N-[3-chloro-2-(4, 4-dimethyl-l-piperidyl) phenyl] -5-cyclopen tylsulfonyl- thiophene-2-sulfonamide [00483] Step 1.
  • Step 2 To a solution of N-[3-chloro-2-(4,4-dimethyl-l-piperidyl)phenyl]-5- cyclopentylsulfanyl-thiophene-2-sulfonamide (0.2 g, 412 pmol, 1 eq) in DCM (3 mL) was added m- CPBA (251 mg, 1.24 mmol, 85% purity, 3 eq )at 0 °C. The mixture was stirred at 20 °C for 12 hours.
  • Step 1 To a solution of 2-fluoro-l-methyl-3 -nitro-benzene (400 mg, 2.58 mmol, 1 eq) and 3-phenylpyrrolidine (569 mg, 3.87 mmol, 1.5 eq) in dioxane (6 mL) was added K 2 CO 3 (713 mg, 5.16 mmol, 2 eq). The mixture was stirred at 100 °C for 12 hours. LC-MS showed 2-fluoro-l- methyl-3 -nitro-benzene was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue.
  • Step 2 A mixture of l-(2-methyl-6-nitro-phenyl)-3-phenyl-pyrrolidine (495 mg, 1.75 mmol, 1 eq), Pd/C (50 mg, 320 pmol, 10% purity) in MeOH (5 mL) was degassed and purged with H2 (15 PSI) for 3 times, and then the mixture was stirred at 20 °C for 1 hour under H2 atmosphere.
  • LC-MS showed l-(2-methyl-6-nitro-phenyl)-3-phenyl-pyrrolidine was consumed completely and desired mass was detected.
  • the reaction mixture was filtered and concentrated under reduced pressure to give a residue.
  • Step 3 To a solution of 3-methyl-2-(3-phenylpyrrolidin-l-yl) aniline (120 mg, 476 pmol, 1 eq) in Py (1 mL) was added 5 -(dimethylsulfamoyl) thiophene-2-sulfonyl chloride (207 mg, 713 pmol, 1.5 eq). The mixture was stirred at 20 °C for 2 hours. LC-MS showed 3-methyl-2-(3- phenylpyrrolidin-l-yl) aniline was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue.
  • Step 1 To a solution of (2R, 6S)-2, 6-dimethylmorpholine (722 mg, 6.27 mmol, 1.1 eq) in DMSO (5 mL) was added CS 2 CO 3 (4.64 g, 14.2 mmol, 2.5 eq) and 1 -chloro-2-fluoro-3 -nitrobenzene (1 g, 5.70 mmol, 1 eq). The mixture was stirred at 100 °C for 12 hours. LC-MS showed (2R, 6S)-2, 6-dimethylmorpholine was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with water 50 mL and extracted with EtOAc (300 mL).
  • Step 2 To a solution of (2S, 6R)-4-(2-chloro-6-nitro-phenyl)-2, 6-dimethyl-morpholine (300 mg, 1.11 mmol, 1 eq) in EtOH (3 mL) and H 2 O (0.6 mL) was added Fe (619 mg, 11.1 mmol, 10 eq) andNH 4 C1 (593 mg, 11.1 mmol, 10 eq). The mixture was stirred at 80 °C for 12 hours. LC-MS showed (2S, 6R)-4-(2-chloro-6-nitro-phenyl)-2, 6-dimethyl-morpholine was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent.
  • Step 3 To a solution of 3-chloro-2-[(2S, 6R)-2, 6-dimethylmorpholin-4-yl] aniline (180 mg, 748 pmol, 1 eq) in pyridine (2 mL) was added 5 -(dimethylsulfamoyl) thiophene-2-sulfonyl chloride (260 mg, 898 pmol, 1.2 eq). The mixture was stirred at 20 °C for 3 hours.
  • Step 1 To a solution of 2-fluoro-l-methyl-3 -nitro- benzene (500 mg, 3.22 mmol, 1 eq) in DMSO (3 mL) was added CS 2 CO 3 (2.63 g, 8.06 mmol, 2.5 eq) and 3,4-dimethylpyrrolidine (481 mg, 3.55 mmol, 1.1 eq, HC1). The mixture was stirred at 100 °C for 12 hours. LC-MS showed 2- fluoro-l-methyl-3 -nitro- benzene was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL * 3).
  • Step 2 To a solution of 3, 4-dimethyl-l-(2-methyl-6-nitro-phenyl) pyrrolidine (400.00 mg, 1.71 mmol, 1 eq) in MeOH (20 mL) was added Pd/C (10%, 50 mg) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi or atm.) at 15°C for 1 hour. LC-MS showed 3, 4-dimethyl-l-(2-methyl-6-nitro-phenyl) pyrrolidine was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and washed 3 times with EtOAc and concentrated under reduced pressure to give a residue.
  • Step 3 To a solution of 2-(3, 4-dimethylpyrrolidin-l-yl)-3-methyl-aniline (280 mg, 1.37 mmol, 1 eq) in pyridine (3 mL) was added 5 -(dimethylsulfamoyl) thioph ene-2-sulfonyl chloride (437 mg, 1.51 mmol, 1.1 eq). The mixture was stirred at 15 °C for 3 hours. LC-MS showed 2-(3, 4- dimethylpyrrolidin-l-yl)-3-methyl-aniline was consumed completely and two main peaks with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent to give a residue (420 mg, crude) as a yellow oil. MS (ESI): mass calcd. For C19H27N3O4S3 457.12, m/z found 458.3 [M+H] + .
  • Step 4 N5-[2-(3,4-dimethylpyrrolidin-l-yl) -3-methyl-phenyl]-N2, N2-dimethyl- thiophene-2, 5 -disulfonamide (420 mg, 918 pmol, 1 eq) was purified by prep-WY,C ( HC1 condition, column: Phenomen ex luna Cl 8 80*40mm*3 um; mobile phase: [water(0.04%HCl)-ACN];B%: 58%- 73%,7min) to give desired compound which was diluted with 10 mL of water and basified with half saturated solution of NaHCCE to pH 8, and then it was extracted with EtOAc (10 mL), the organic layer was separated and washed with 10 mL of brine, dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under reduced pressure to give desired N2-(2-((3S, 4S)-3, 4- dimethylpyrrolidin-l-yl)-3-
  • Step 1 N5-[2-(3, 4-dimethylpyrrolidin-l-yl)-3-methyl-phenyl]-N2, N2-dimethyl- thiophene-2, 5-disulfonamide 5 (420 mg, 918 pmol, 1 eq) was purified by prep-HPLC ( HC1 condition : column: Phenomenex luna Cl 8 80*40mm*3 um; mobile phase: [water(0.04%HCl)- ACN]; B%: 58%-73%, 7min) to give desired N2-(2-((3R, 4S)-3, 4-dimethylpyrrolidin-l-yl)-3- methylphenyl)-N5, N5 -dimethylthiophene-2, 5-disulfonamide which had few impurity, then purified by second prep-HPLC (neutral condition: column: Waters Xbridge BEH Cl 8 100*25mm*5um;mobile phase: [water(10mM NH 4 HCO 3 )-
  • Example 98 N2-(3-chloro-2-(4-methoxy-4-methylpiperidin-l-yl) phenyl)-N5, N5- dimethylthiophene-2, 5-disulfonamide [00496]
  • Step 1 To a solution of 1 -chloro-2-fluoro-3 -nitro-benzene (233 mg, 1.33 mmol, 1.1 eq) and 4-methoxy-4-methyl-piperidine; hydrochloride (200 mg, 1.21 mmol, 1 eq) in DCM (5 mL) was added TEA (366 mg, 3.62 mmol, 504 ⁇ L, 3 eq). The mixture was stirred at 40 °C for 12 hours.
  • Step 2 To a solution of l-(2-chloro-6-nitro-phenyl)-4-methoxy-4-methyl-piperidine (225 mg, 790 pmol, 1 eq) in EtOH (3 mL) and H 2 O (0.3 mL) was added Fe (353 mg, 6.32 mmol, 8 eq) and NH4CI (634 mg, 11.9 mmol, 15 eq). The mixture was stirred at 80 °C for 12 hours. LCMS showed l-(2-chloro-6-nitro-phenyl)-4-methoxy-4-methyl-piperidine was consumed and desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude oil.
  • Step 3 To a solution of 3 -chloro-2-(4-methoxy-4-methyl-l -piperidyl) aniline (130 mg, 510 pmol, 1 eq) in Py (2 mL) was added 5-(dimethylsulfamoyl) thiophene-2-sulfonyl chloride (177.45 mg, 612.35 pmol, 1.2 eq). The mixture was stirred at 15 °C for 12 hours. LCMS showed 3- chloro-2-(4-methoxy-4-methyl-l -piperidyl) aniline was consumed and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a crude oil.
  • Step 1 To a solution of 1 -chloro-2-fluoro-3 -nitro-benzene (2.34 g, 13.3 mmol, 1.05 eq) and 3, 3 -difluoropiperidine; hydrochloride (2 g, 12.7 mmol, 1 eq) in dioxane (40 mL) was added K 2 CO 3 (5.26 g, 38.1 mmol, 3 eq). The mixture was stirred at 100 °C for 60 hours. LCMS showed 1- chloro-2-fluoro-3 -nitro-benzene was consumed and desired mass was detected. The crude was added H 2 O (60 mL), and extracted with EtOAc (150 mL).
  • Step 2 To a solution of l-(2-chloro-6-nitro-phenyl)-3, 3 -difluoro-piperidine (0.9 g, 3.25 mmol, 1 eq) in EtOH (10 mL) and H 2 O (1 mL) was added Fe (1.45 g, 26.0 mmol, 8 eq) and NH4CI (2.61 g, 48.8 mmol, 15 eq). The mixture was stirred at 80 °C for 12 hours. LCMS showed l-(2- chloro-6-nitro-phenyl)-3, 3 -difluoro-piperidine was consumed and desired mass was detected.
  • Step 3 To a solution of 5 -(dimethylsulfamoyl) thiophene-2-sulfonyl chloride (200 mg, 690 pmol, 1 eq) in Py (2 mL) was added 3-chloro-2-(3, 3 -difluoro- 1 -piperidyl) aniline (170 mg, 690 pmol, 1 eq). The mixture was stirred at 15 °C for 12 hours. LCMS showed 5 -(dimethylsulfamoyl) thiophene-2-sulfonyl chloride was consumed and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a crude oil.
  • Example 100 N5-[3-chloro-2-(2, 6-dimethylmorpholin-4-yl) phenyl] -N2, N2-dimethyl- thiophene-2, 5-disulfonamide
  • Step 1 To a solution of 1 -chloro-2-fluoro-3 -nitro-benzene (480 mg, 2.74 mmol, 1.05 eq) and 2, 6-dimethylmorpholine (300 mg, 2.60 mmol, 321 ⁇ L, 1 eq) in dioxane (10 mL) was added K 2 CO 3 (1.08 g, 7.81 mmol, 3 eq). The mixture was stirred at 100 °C for 12 hours. LCMS showed 1- chloro-2-fluoro-3 -nitro-benzene was consumed and desired mass was detected. The crude was added H 2 O (20 mL), and extracted with EtOAc (45 mL).
  • Step 2 To a solution of 4-(2-chloro-6-nitro-phenyl)-2, 6-dimethyl-morpholine (300 mg, 1.11 mmol, 1 eq) in EtOH (3 mL) and H 2 O (0.3 mL) was added Fe (495 mg, 8.87 mmol, 8 eq) and NH4CI (889 mg, 16.6 mmol, 15 eq). The mixture was stirred at 80 °C for 12 hours. LCMS showed 4-(2-chloro-6-nitro-phenyl)-2, 6-dimethyl-morpholine was consumed and desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude oil.
  • Step 3 To a solution of 3-chloro-2-(2, 6-dimethylmorpholin-4-yl) aniline (200 mg, 831 pmol, 1 eq) in Py (5 mL) was added 5 -(dimethylsulfamoyl) thiophene -2-sulfonyl chloride (265 mg, 914 pmol, 1.1 eq). The mixture was stirred at 15 °C for 12 hours. LCMS showed 3-chloro-2-(2, 6- dimethylmorpholin-4-yl) aniline was consumed and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a crude oil.
  • Step 1 To a solution of 2-fluoro-l-methyl-3 -nitro-benzene (356 mg, 2.30 mmol, 1 eq) and pyrrolidin-3-ol (200 mg, 2.30 mmol, 185 ⁇ L, 1 eq) in dioxane (5 mL) was added K 2 CO 3 (635 mg, 4.59 mmol, 2 eq). The mixture was stirred at 100 °C for 12 hours. LCMS showed 2-fluoro-l- methyl-3 -nitro-benzene was consumed and desired mass was detected. The crude was added H2O (10 mL), and extracted with EtOAc 45 mL (15 mL * 3).
  • Step 2 To a solution of l-(2-methyl-6-nitro-phenyl) pyrrolidin -3-ol (300 mg, 1.35 mmol, eq) in MeOH (5 mL) was added H2 and Pd/C (30 mg, 10% purity). The mixture was stirred at 15 °C for 2 hours. LCMS showed 1 -(2-methyl-6-nitro-phenyl) pyrrolidin -3-ol was consumed and desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give desired l-(2-amino-6-methyl-phenyl) pyrrolidin-3-ol (250 mg, crude) as a brown oil. MS (ESI): mass calcd. For C11H16N2O 192.13, m/z found 193.4 [M+H] + .
  • Step 3 To a solution of 1 -(2-amino-6-methyl-phenyl) pyrrolidin-3-ol (250 mg, 1.30 mmol, 1 eq) in Py (5 mL) was added 5 -(dimethylsulfamoyl) thiophene-2-sulfonyl chloride (377 mg, 1.30 mmol, 1 eq). The mixture was stirred at 15 °C for 12 hours. LCMS showed l-(2-amino-6- methyl-phenyl) pyrrolidin-3-ol was consumed and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a crude oil.
  • the residue was purified by prep- HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (lOmM NH 4 HCO 3 )-ACN]; B%: 35%-65%, 8 min).
  • the purified product was dissolved in 20 mL of water, and then the solution was lyophilized to give desired N2-(2-(3-hydroxypyrrolidin-l-yl)-3- methylphenyl)-N5, N5 -dimethylthiophene-2, 5 -disulfonamide (39.1 mg, 87.5 pmol, 6.73% yield, 99.7 % purity) as a white solid.
  • Example 102 5-(tert-butylthio)-N-(3-chloro-2-(4, 4-dimethylpiperidin-l-yl) phenyl) thiophene- 2-sulfonamide
  • Step 1 To a solution of 5-bromo-N-(3-chloro-2-(4, 4-dimethylpiperidin-l-yl) phenyl) thiophene-2-sulfonamide (200 mg, 431 pmol, 1 eq), 2-methylpropane-2-thiol (50.6 mg, 561 pmol, 63.1 ⁇ L, 1.3 eq), BINAP (268 mg, 431 pmol, 1 eq) and CS 2 CO 3 (351 mg, 1.08 mmol, 2.5 eq) in Tol. (2 mL) was added Pd2(dba)3 (197 mg, 216 pmol, 0.5 eq).
  • Step 2' To a solution of 5-(tert-butylthio)-N-(3-chloro-2-(4, 4-dimethylpiperidin-l-yl) phenyl) thiophene-2-sulfonamide (140 mg, 296 pmol, 1 eq ⁇ in DCM (3 mL) was added m-CPBA (180 mg, 888 pmol, 85% purity, 3 eq ⁇ at 0 °C. The mixture was stirred at 20 °C for 12 hours.
  • Step 1 To a solution of 1 -chloro-2-fluoro-3 -nitro-benzene (1 g, 5.70 mmol, 1 eq ⁇ and 1- (4-piperidyl)piperidine (1.52 g, 7.41 mmol, 1.3 eq, HC1) in dioxane (15 mL) was added K 2 CO 3 (2.36 g, 17.1 mmol, 3 eq ⁇ . The mixture was stirred at 100 °C for 12 hours. LC-MS showed l-chloro-2- fluoro-3 -nitro-benzene 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.
  • Step 3 To a solution of 3 -chloro-2-[4-(l -piperidyl)-! -piperidyl] aniline (140 mg, 476 pmol, 1 eq ⁇ in Py (1.5 mL) was added 5 -(dimethylsulfamoyl) thiophene-2-sulfonyl chloride (207 mg, 715 pmol, 1.5 eq ⁇ . The mixture was stirred at 15 °C for 2 hours. LC-MS showed 3-chloro-2-[4-(l- piperidyl)-! -piperidyl] aniline was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue.
  • Example 104 N2, N2-dimethyl-N5-(3-methyl-2-(3-phenylazetidin-l-yl) phenyl) thiophene-2, 5- disulfonamide
  • Step 1 To a solution of Zn (6.41 g, 98.0 mmol, 4 eq) in DMA (15 mL) was added 1, 2- dibromoethane (691 mg, 3.68 mmol, 277 ⁇ L, 0.15 eq) and TMSC1 (799 mg, 7.35 mmol, 933 ⁇ L, 0.3 eq) at 25 °C. After addition, the mixture was stirred at this temperature for 25 mins, and then tertbutyl 3 -iodoazetidine- 1 -carboxylate (17.4 g, 61.3 mmol, 2.5 eq) in DMA (15 mL) was added dropwise at below 65 °C.
  • Step 3 A mixture of 3 -phenylazetidine (2.2 g, 13.0 mmol, 1 eq, HC1), 2-fluoro-l-methyl- 3 -nitro-benzene (2.41 g, 15.6 mmol, 1.2 eq) and CS 2 CO 3 (10.6 g, 32.4 mmol, 2.5 eq) in DMSO (25 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. LC-MS showed 3 -phenylazetidine was consumed completely and one main peak with desired mass was detected.
  • Step 4 A mixture of l-(2-methyl-6-nitrophenyl)-3 -phenylazetidine (0.9 g, 3.35 mmol, 1 eq), Fe (937 mg, 16.8 mmol, 5 eq) and NH4CI (897 mg, 16.8 mmol, 5 eq) in H 2 O (2 mL) and EtOH (9 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 70 °C for 12 hours under N2 atmosphere.
  • LC-MS showed l-(2-methyl-6-nitrophenyl)-3 -phenylazetidine was consumed completely and one main peak with desired mass was detected.
  • the reaction mixture was concentrated under reduced pressure to remove MeOH.
  • Step 5 A mixture of 3-methyl-2-(3-phenylazetidin-l-yl) aniline (0.3 g, 1.26 mmol, 1 eq), 5-(N, N-dimethylsulfamoyl)thiophene-2-sulfonyl chloride (365 mg, 1.26 mmol, 1 eq) and TEA (318 mg, 3.15 mmol, 438 ⁇ L, 2.5 eq) in DCM (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 12 hours under N2 atmosphere.
  • the residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*40mm*3um; mobile phase: [water (lOmM NILHCOsj-ACN]; B%: 30%-60%,8 min) to give desired N2, N2-dimethyl-N5-(3-methyl-2-(3- phenylazetidin-l-yl) phenyl)thiophene-2, 5-disulfonamide (58.4 mg, 116 pmol, 9.25% yield, 98.0% purity) as a yellow solid.
  • Example 105 N2-(3-chloro-2-(3-isopropylpyrrolidin-l-yl) phenyl)-N5, N5-dimethylthiophene- 2, 5-disulfonamide
  • Step 1 A mixture of potassium;2-methylpropan-2-olate (3.20 g, 28.5 mmol, 2.5 eq), isopropyl(triphenyl)phosphonium;iodide (12.3 g, 28.5 mmol, 2.5 eq) in tetrahydrofuran (30 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 1 hour under N2 atmosphere. Then l-benzylpyrrolidin-3-one (2 g, 11.4 mmol, 1.87 mL, 1 eq) in tetrahydrofuran (10 mL) was added and the mixture was 35 °C for 4.5 hours.
  • Step 2' To a solution of l-benzyl-3-isopropylidene-pyrrolidine (600 mg, 2.98 mmol, 1 eq) in formic acid (1 mL) and MeOH (5 mL) was added Pd/C(10%, 0.1 g) and Pd(OH)2/C (10%, 0.1 g) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 Psi or atm.) at 30 °C for 48 hours. LC-MS indicated l-benzyl-3- isopropylidene-pyrrolidine was consumed completely.
  • Step 3 To a solution of l-chloro-2-fluoro-3 -nitro-benzene (200 mg, 1.14 mmol, 1 eq) in DMSO (3 mL) was added CS 2 CO 3 (928 mg, 2.85 mmol, 2.5 eq) and 3-isopropylpyrrolidine (193 mg, 1.71 mmol, 1.5 eq). The mixture was stirred at 100 °C for 12 hours. LC-MS showed l-chloro-2- fluoro-3 -nitro-benzene was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with H 2 O 10 mL and extracted with EtOAc 60 mL (20 mL * 3).
  • Step 4 To a solution of l-(2-chloro-6-nitro-phenyl)-3-isopropyl-pyrrolidine (140 mg, 521 pmol, 1 eq) in EtOH (3 mL) and H 2 O (0.6 mL) was added Fe (291 mg, 5.21 mmol, 10 eq) and NH4CI (279 mg, 5.21 mmol, 10 eq). The mixture was stirred at 80 °C for 12 hours. LC-MS showed l-(2-chloro-6-nitro-phenyl)-3-isopropyl-pyrrolidine was consumed completely and one main peak with desired mass was detected.
  • Step 5 To a solution of 3-chloro-2-(3-isopropylpyrrolidin-l-yl) aniline (80 mg, 335 pmol, 1 eq) in pyridine (2 mL) was added 5 -(dimethylsulfamoyl) thiophene-2-sulfonyl chloride (117 mg, 402 pmol, 1.2 eq). The mixture was stirred at 20 °C for 3 hours. LC-MS showed 3-chloro-2-(3- isopropylpyrrolidin-l-yl) aniline was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue.
  • Example 106 N-(3-chloro-2-(4, 4-dimethylpiperidin-l-yl) phenyl) -5-isobutyrylthiophene-2- sulfonamide
  • Step 1 To a solution of 5-bromo-N-[3-chloro-2-(4, 4-dimethyl-l- piperidyl)phenyl]thiophene-2-sulfonamide (110 mg, 237 pmol, 1 eq) and N-methoxy-N, 2-dimethyl- propanamide (65.3 mg, 498 pmol, 2.1 eq) in THF (2 mL) was added w-BuLi (2.5 M, 94.9 ⁇ L, 1 eq) at -70 °C. The mixture was stirred at -70 °C for 0.5 hour.
  • Example 107 5-[[3-chloro-2-(4, 4-dimethyl-l-piperidyl) phenyl] methylsulfonyl] -N, N- dimethyl-thiophene-2-sulfonamide
  • Step 1 To a solution of 5-(N, N-dimethylsulfamoyl) thiophene-2-sulfonyl chloride (290 mg, 1.00 mmol, 1 eq) in Tol. (20 mL) was added PPhs (787 mg, 3.00 mmol, 3 eq) at 0 °C. The mixture was allowed to warm to 20 °C and stirred for 2 hours. To the above solution was added H2O (3 mL) and the mixture was stirred for another 0.17 hours. LC-MS showed 5-(N, N- dimethylsulfamoyl) thiophene-2-sulfonyl chloride was consumed completely and one main peak with desired mass was detected.
  • Step 3 To a solution of 3-chloro-2-(4, 4-dimethyl-l -piperidyl) benzaldehyde (630 mg, 2.50 mmol, 1 eq) in MeOH (7 mL) was added NaBEL (189 mg, 5.00 mmol, 2 eq) in 20 portions at 0 °C. After addition, the mixture was stirred at 20 °C for 1 hour. LC-MS showed 3-chloro-2-(4, 4- dimethyl-1 -piperidyl) benzaldehyde was consumed completely and one main peak with desired mass was detected. The reaction mixture was partitioned between 20 mL of HC1 (IM) and ethyl acetate (60 mL).
  • IM HC1
  • ethyl acetate 60 mL
  • Step 4 To a solution of [3-chloro-2-(4, 4-dimethyl-l -piperidyl) phenyl] methanol (100 mg, 394 pmol, 1 eq) and TEA (59.8 mg, 591 pmol, 82.3 ⁇ L, 1.5 eq) in DCM (1 mL) was added MsCl (67.7 mg, 591 pmol, 45.8 ⁇ L, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hour.
  • Step 5 To a solution of [3-chloro-2-(4, 4-dimethyl-l -piperidyl) phenyl] methyl methanesulfonate (150 mg, 452 pmol, 1 eq) in DMF (2 mL) was added 5-mercapto-N, N- dimethylthiophene-2-sulfonamide (202 mg, 904 pmol, 2 eq) and CS 2 CO 3 (442 mg, 1.36 mmol, 3 eq). The mixture was stirred at 90 °C for 1 hour.
  • Step 6 To a solution of 5-((3-chloro-2-(4, 4-dimethylpiperidin-l-yl) benzyl) thio)-N, N- dimethylthiophene-2-sulfonamide (150 mg, 327 pmol, 1 eq) in DCM (2 mL) was added m-CPBA (99.5 mg, 490 pmol, 85% purity, 1.5 eq) at 0 °C. The mixture was stirred at 20 °C for 12 hours.
  • Example 108 5-[[3-chloro-2-(4, 4-dimethyl-l-piperidyl) phenyl] -fluoro-methyl] sulfonyl-N, N- dimethyl-thiophene-2-sulfonamide [00530] Step 1. To a solution of 5-[[3-chloro-2-(4, 4-dimethyl-l -piperidyl) phenyl] methylsulfonyl] -N, N-dimethyl-thiophene-2-sulfonamide (50 mg, 102 pmol, 1 eq) in Tol. (1 mL) was added dropwise LDA (2 M, 66.2 ⁇ L, 1.3 eq) at -70 °C.
  • Step 1 To a solution of 1 -chloro-2-fluoro-3 -nitro-benzene (500 mg, 2.85 mmol, 1 eq) in DMSO (4 mL) was added CS 2 CO 3 (1.86 g, 5.70 mmol, 2 eq) and 2-(methoxymethyl) piperidine (566 mg, 3.42 mmol, 1.2 eq, HC1). The mixture was stirred at 100 °C for 12 hours. LC-MS showed desired mass was detected. The reaction mixture was added to water (300 mL), the aqueous phase was extracted with EtOAc (150 mL). The organic layer was dried over Na 2 SO 4 , filtered and the filtrate was concentrated to give a residue.
  • Step 2 ⁇ To a solution of l-(2-chloro-6-nitro-phenyl)-2-(methoxymethyl) piperidine (220 mg, 773 pmol, 1 eq) in H 2 O (0.1 mL) and EtOH (0.5 mL) was added Fe (345 mg, 6.18 mmol, 8 eq) and NH4CI (413 mg, 7.73 mmol, 10 eq). The mixture was stirred at 80 °C for 12 hours. LCMS showed l-(2-chloro-6-nitro-phenyl)-2-(methoxymethyl) piperidine was consumed completely and desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue.
  • Example 110 N5-[2-(9-azabicyclo [3.3.1] nonan-9-yl)-3-chloro-phenyl]-N2, N2-dimethyl- thiophene-2, 5-disulfonamide [00534] Step 1.
  • Step 2' To a solution of 9-(2-chloro-6-nitro-phenyl)-9-azabicyclo [3.3.1] nonane (300 mg, 1.07 mmol, 1 eq) in H 2 O (0.5 mL) and EtOH (3 mL) was added Fe (477mg, 8.55 mmol, 8 eq) and NH4CI (857 mg, 16.0 mmol, 15 eq). The mixture was stirred at 80°C for 3 hours. LC-MS showed 9-(2-chloro-6-nitro-phenyl)-9-azabicyclo [3.3.1] nonane was consumed completely and one main peak with desired mass was detected.
  • Step 3 To a solution of 2-(9-azabicyclo [3.3.1] nonan-9-yl)-3 -chloro-aniline (200 mg, 798 pmol, 1 eq) in Py (1 mL) was added 5-(dimethylsulfamoyl) thiophene-2-sulfonyl chloride (347 mg, 1.20 mmol, 1.5 eq). The mixture was stirred at 15 °C for 1.5 hours. LC-MS showed 2-(9- azabicyclo [3.3.1] nonan-9-yl)-3 -chloro-aniline was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue.
  • Example 111 N2-[3-chloro-2-(4, 4-dimethyl-l-piperidyl) phenyl] -N5-methyl- thiophene-2, 5- disulfonamide
  • Step 1 To a solution of 5-bromothiophene-2-sulfonyl chloride (2 g, 7.65 mmol, 1 eq) in DCM (20 mL) was added methanamine; hydrochloride (568 mg, 8.41 mmol, 1.1 eq) and TEA (1.93 g, 19.12 mmol, 2.66 mL, 2.5 eq). The mixture was stirred at 15 °C for 2 hours. LCMS showed 5- bromothiophene-2-sulfonyl chloride was consumed and desired mass was detected.
  • Step 2 A mixture of 5-bromo-N-methyl-thiophene-2-sulfonamide (1.6 g, 6.25 mmol, 1 eq), phenylmethanethiol (853 mg, 6.87 mmol, 805 ⁇ L, 1.1 eq), DIEA (1.61 g, 12.5 mmol, 2.18 mL, 2 eq), Pd(dppf)C12 (114 mg, 156 pmol, 0.025 eq) and (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4- yl)-diphenyl- phosphane (361 mg, 625 pmol, 0.1 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 N2 atmosphere.
  • Step 3 To a solution of 5-benzylsulfanyl-N-methyl-thiophene-2-sulfonamide (1.5 g, 5.01 mmol, 1 eq) in AcOH (16 mL) and H 2 O (4 mL) was added NCS (2.01 g, 15.0 mmol, 3 eq). The mixture was stirred at 0 °C for 3 hours. LCMS showed 5-benzylsulfanyl-N-methyl-thiophene-2- sulfonamide was consumed and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a crude oil.
  • Step 4 To a solution of 5 -(methylsulfamoyl) thiophene-2-sulfonyl chloride (300 mg, 1.09 mmol, 1 eq) in Py (5 mL) was added 3 -chloro-2-(4,4-dimethyl-l -piperidyl) aniline (312 mg, 1.31 mmol, 1.2 eq). The mixture was stirred at 15 °C for 3 hours. LCMS showed 5- (methylsulfamoyl) thiophene-2-sulfonyl chloride was consumed and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a crude oil.
  • Example 112 N2-[3-chloro-2-(4, 4-dimethyl-l-piperidyl) phenyl] thiophene-2, 5-disulfonamide
  • Step 2' A mixture of 5-bromothiophene-2-sulfonamide (1.5 g, 6.20 mmol, 1 eq), phenylmethanethiol (1.33 g, 10.7 mmol, 1.25 mL, 1.73 eq), DIEA (1.60 g, 12.4 mmol, 2.16 mL, 2 eq), Pd(dppf)C12 (113 mg, 155 pmol, 0.025 eq) and (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4- yl)-diphenyl-phosphane (358 mg, 620 pmol, 0.1 eq) in Tol.
  • Step 3 To a solution of 5-benzylsulfanylthiophene-2-sulfonamide (1.5 g, 5.26 mmol, 1 eq) in AcOH (16 mL) and H 2 O (4 mL) was added NCS (2.11 g, 15.8 mmol, 3 eq). The mixture was stirred at 10 °C for 3 hours. LC-MS showed 5-benzylsulfanylthiophene-2-sulfonamide was consumed completely and desired mass was detected. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (400 mL).
  • Step 4 To a solution of 5-sulfamoylthiophene-2-sulfonyl chloride (200 mg, 764 pmol, 1 eq) in Py (0.5 mL) was added 3-chloro-2-(4, 4-dimethyl-l -piperidyl) aniline (274 mg, 1.15 mmol, 1.5 eq). The mixture was stirred at 15 °C for 1 hour. LC-MS showed 5-sulfamoylthiophene-2-sulfonyl chloride was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue.
  • Step 1 To a solution of 1 -chloro-2-fluoro-3 -nitro-benzene (10 g, 57.0 mmol, 1 eq) in DCM (100 mL) was added DIEA (14.7 g, 114 mmol, 19.8 mL, 2 eq) and tert-butyl piperazine-1- carboxylate (11.7 g, 62.7 mmol, 1.1 eq). The mixture was stirred at 20 °C for 2 hours. LC-MS showed no l-chloro-2-fluoro-3 -nitro-benzene remained. Several new peaks were shown on LC-MS and desired compound was detected.
  • Step 2 To a solution of tert-butyl 4-(2-chloro-6-nitro-phenyl) piperazine- 1 -carboxylate (6.1 g, 17.9 mmol, 1 eq) in EtOH (50 mL) and H 2 O (10 mL) was added Fe (9.97 g, 178 mmol, 10 eq) and NH4CI (9.55 g, 178 mmol, 10 eq). The mixture was stirred at 80 °C for 12 hours. LC-MS showed tert-butyl 4-(2-chloro-6-nitro-phenyl) piperazine- 1 -carboxylate was consumed completely and one main peak with desired mass was detected.
  • the reaction mixture was diluted with H 2 O (300 mL) and extracted with EtOAc (600 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-35% EtOAc /petroleum ether gradient @ 85 mL/min) to give desired tert-butyl 4-(2-amino-6-chloro-phenyl) piperazine- 1 -carboxylate (4.16 g, 13.3 mmol, 74.8% yield) as a white solid.
  • Step 3 To a solution of tert-butyl 4-(2-amino-6-chloro-phenyl) piperazine- 1 -carboxylate (3 g, 9.62 mmol, 1 eq) in Py (10 mL) was added 5 -(dimethylsulfamoyl) thiophene-2-sulfonyl chloride (3.07 g, 10.6 mmol, 1.1 eq). The mixture was stirred at 20 °C for 2 hours.

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Abstract

L'invention concerne de nouveaux dérivés de sulfonanilide et de benzylsulfonyle, ainsi que des compositions et des procédés de préparation et d'utilisation de ceux-ci, qui sont utiles dans le traitement de maladies et troubles divers liés à des activités TRPML telles que les maladies de stockage lysosomal, la dystrophie musculaire, les maladies neurodégénératives communes liées à l'âge, les maladies associées au stress oxydatif ou aux espèces réactives de l'oxygène (ERO), ainsi que le vieillissement.
PCT/US2021/053533 2020-10-06 2021-10-05 Dérivés de sulfonanilide et benzylsulfonyle, et compositions et procédés associés WO2022076383A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024011155A1 (fr) * 2022-07-07 2024-01-11 Libra Therapeutics, Inc. Agonistes de trpml1 oxazolique et leurs utilisations
WO2024026540A1 (fr) * 2022-08-05 2024-02-08 Macquarie University Inhibiteurs et leurs utilisations
WO2023235305A3 (fr) * 2022-05-31 2024-02-08 Lysoway Therapeutics, Inc. Dérivés cycliques de sulfonyle, compositions et procédés associés

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Publication number Priority date Publication date Assignee Title
US20070049594A1 (en) * 2000-12-22 2007-03-01 Aventis Pharmaceuticals Inc. Novel compounds and compositions as cathepsin inhibitors
US20070141059A1 (en) * 2003-12-11 2007-06-21 Axys Pharmaceuticals, Inc. Use of cathepsin s inhibitors for treating an immune response caused by administration of a small molecule therapeutic or biologic
US20200016146A1 (en) * 2016-04-06 2020-01-16 The Hospital For Sick Children Compositions and methods for treating helicobacter pylori infection

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Publication number Priority date Publication date Assignee Title
US20070049594A1 (en) * 2000-12-22 2007-03-01 Aventis Pharmaceuticals Inc. Novel compounds and compositions as cathepsin inhibitors
US20070141059A1 (en) * 2003-12-11 2007-06-21 Axys Pharmaceuticals, Inc. Use of cathepsin s inhibitors for treating an immune response caused by administration of a small molecule therapeutic or biologic
US20200016146A1 (en) * 2016-04-06 2020-01-16 The Hospital For Sick Children Compositions and methods for treating helicobacter pylori infection

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023235305A3 (fr) * 2022-05-31 2024-02-08 Lysoway Therapeutics, Inc. Dérivés cycliques de sulfonyle, compositions et procédés associés
WO2024011155A1 (fr) * 2022-07-07 2024-01-11 Libra Therapeutics, Inc. Agonistes de trpml1 oxazolique et leurs utilisations
WO2024026540A1 (fr) * 2022-08-05 2024-02-08 Macquarie University Inhibiteurs et leurs utilisations

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