WO2025259601A1 - Carbonic anhydrase enzyme inhibitors and methods of use thereof - Google Patents

Carbonic anhydrase enzyme inhibitors and methods of use thereof

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Publication number
WO2025259601A1
WO2025259601A1 PCT/US2025/032875 US2025032875W WO2025259601A1 WO 2025259601 A1 WO2025259601 A1 WO 2025259601A1 US 2025032875 W US2025032875 W US 2025032875W WO 2025259601 A1 WO2025259601 A1 WO 2025259601A1
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optionally substituted
compound
alkyl
pharmaceutically acceptable
acceptable salt
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PCT/US2025/032875
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French (fr)
Inventor
John Piwinski
Mark C. SIRACUSA
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Nemagen Discoveries Inc
Rutgers State University of New Jersey
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Nemagen Discoveries Inc
Rutgers State University of New Jersey
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Publication of WO2025259601A1 publication Critical patent/WO2025259601A1/en
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D497/04—Ortho-condensed systems
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    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • Mast cell-related diseases such as allergies/allergic inflammation, mastocytosis, mast cell activation syndrome and anaphylaxis
  • allergic diseases have risen to epidemic proportions in developed areas of the world, and it is now estimated that 30-40% of the global population suffer from one or more allergic diseases, including atopic dermatitis, asthma and food allergies (Pawankar, et al., WAO White Book on Allergy 2011-2012: Executive Summary. World Allergy Organization (2012)).
  • There are limited treatment options for patients suffering from chronic allergic inflammation and many of them have significant side effects (Bauer, et al., J Allergy Clin Immunol 135, 312-323 (2015)).
  • MZ methazolamide
  • SUMMARY International Application No. PCT/US2023/082927, filed December 7, 2023, discloses certain novel compounds as carbonic anhydrase inhibitors, the content of PCT/US2023/082927 is herein incorporated by reference in its entirety.
  • the invention provides novel compounds that are carbonic anhydrase inhibitors, such as carbonic anhydrase 1 inhibitors, which are useful for treating diseases or conditions mediated by carbonic anhydrase, such as mastocytosis, mast cell-mediated inflammation, allergic diseases, bacterial infections, fungal infections and viral infections.
  • the present disclosure provides a compound according to Formula I, or a pharmaceutically acceptable salt thereof: , Formula I wherein the variables are defined herein.
  • the compound of Formula I can have a structure according to a subformula of Formula I, such as Formula I-A, I-B, I-C, I-D, I-E1, I-E2, I-A1, I-1, or I-1a, as defined herein.
  • the present disclosure provides a compound according to Formula II, or a pharmaceutically acceptable salt thereof: , wherein the variables are defined herein.
  • the present disclosure provides a compound according to Formula III, or a pharmaceutically acceptable salt thereof: , wherein the variables the compound of Formula III can have a structure according to a subformula of Formula III, such as Formula III-A or III-1, as defined herein.
  • the present disclosure provides a compound selected from Table A herein, or a pharmaceutically acceptable salt thereof.
  • the invention also provides a pharmaceutical composition comprising a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Certain embodiments provide a method of inhibiting a carbonic anhydrase enzyme in vitro or in vivo comprising contacting the carbonic anhydrase enzyme with an effective amount of a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, or a pharmaceutically acceptable salt thereof.
  • Certain embodiments provide a method of treating a disease or condition mediated by a carbonic anhydrase enzyme in a mammal (e.g., a human), comprising administering a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, to the mammal.
  • a mammal e.g., a human
  • Certain embodiments provide a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, for the prophylactic or therapeutic treatment of a disease or condition mediated by a carbonic anhydrase enzyme.
  • Certain embodiments provide the use of a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating a disease or condition mediated by a carbonic anhydrase enzyme.
  • the invention also provides a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, for use in medical therapy.
  • the invention also provides a pharmaceutical composition comprising a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of of a disease or condition mediated by a carbonic anhydrase enzyme.
  • the invention also provides processes and intermediates disclosed herein that are useful for preparing a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a salt thereof.
  • processes and intermediates disclosed herein that are useful for preparing a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a salt thereof.
  • PCT/US2023/082927 filed December 7, 2023, discloses that certain novel compounds therein can inhibit carbonic anhydrase in vitro and/or in vivo and in some cases with similar or better efficacy than certain FDA-approved carbonic anhydrase inhibitor such as methazolamide.
  • the present disclosure provides novel compounds that can act as carbonic anhydrase inhibitors, which are useful for treating various diseases or disorders herein, such as mastocytosis, mast cell-mediated inflammation, various allergic diseases, osteoarthritis, ankylosing spondylitis, or neuropathic pain, etc.
  • the novel compounds herein can also have favorable ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles, for example, a good aqueous solubility, metabolic stability, etc., and can be suitable for further pharmaceutical developments for treating the various diseases or disorders herein.
  • ADMET absorption, distribution, metabolism, excretion, and toxicity
  • the novel compounds herein can also have favorable ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles, for example, a good aqueous solubility, metabolic stability, etc., and can be suitable for further pharmaceutical developments for treating the various diseases or disorders herein.
  • ADMET absorption, distribution, metabolism, excretion, and toxicity
  • C1–6 is intended to encompass, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6.
  • halo or halogen is fluoro, chloro, bromo, or iodo.
  • Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e., C1-8 means one to eight carbons). Examples include (C1- C 8 )alkyl, (C 2 -C 8 )alkyl, C 1 -C 6 )alkyl, (C 2 -C 6 )alkyl and (C 3 -C 6 )alkyl.
  • alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n- pentyl, n-hexyl, n-heptyl, n-octyl, and higher homologs and isomers.
  • alkoxy refers to an alkyl groups attached to the remainder of the molecule via an oxygen atom (“oxy”).
  • cycloalkyl refers to a saturated or partially unsaturated (non-aromatic) all carbon ring having 3 to 8 carbon atoms (i.e., (C 3 -C 8 )carbocycle).
  • the term also includes multiple condensed, saturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings).
  • carbocycle includes multicyclic carbocyles such as a bicyclic carbocycles (e.g., bicyclic carbocycles having about 3 to 15 carbon atoms , about 6 to 15 carbon atoms, or 6 to 12 carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g., tricyclic and tetracyclic carbocycles with up to about 20 carbon atoms).
  • the rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements.
  • multicyclic carbocyles can be connected to each other via a single carbon atom to form a spiro connection (e.g., spiropentane, spiro[4,5]decane, etc), via two adjacent carbon atoms to form a fused connection (e.g., carbocycles such as decahydronaphthalene, norsabinane, norcarane) or via two non-adjacent carbon atoms to form a bridged connection (e.g., norbornane, bicyclo[2.2.2]octane, etc.).
  • a spiro connection e.g., spiropentane, spiro[4,5]decane, etc
  • a fused connection e.g., carbocycles such as decahydronaphthalene, norsabinane, norcarane
  • a bridged connection e.g., norbornane, bicyclo[2.2.2]octane
  • Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptane, pinane, and adamantane.
  • aryl refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic.
  • an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms.
  • Aryl includes a phenyl radical.
  • Aryl also includes multiple condensed carbon ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., cycloalkyl).
  • the rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the point of attachment of a multiple condensed ring system, as defined above, can be at any position of the ring system including an aromatic or a carbocycle portion of the ring.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, indanyl, naphthyl, 1, 2, 3, 4- tetrahydronaphthyl, anthracenyl, and the like.
  • heteroaryl refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5–10 membered heteroaryl”). Ring sulfur and nitrogen atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized.
  • heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, and thiadiazolyl.
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl).
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched-chain alkyl group, e.g., having from 2 to 14 carbons, such as 2 to 10 carbons in the chain, one or more of the carbons has been replaced by a heteroatom selected from S, O, P and N, and wherein the nitrogen, phosphine, and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized.
  • the heteroatom(s) S, O, P and N may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
  • the substituent(s) can replace one or more hydrogen atoms attached to the carbon atom(s) and/or the heteroatom(s) of the heteroalkyl.
  • the heteroalkyl is a C1-4 heteroalkyl, which refers to the heteroalkyl defined herein having 1-4 carbon atoms.
  • C1-4 heteroalkyl examples include, but are not limited to, C 4 heteroalkyl such as -CH 2 -CH 2 -N(CH 3 )-CH 3 , C3 heteroalkyl such as -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2- CH 2 -S(O)-CH 3 , -CH 2 -CH 2 -S(O) 2 -CH 3 , C 2 heteroalkyl such as -CH 2 -CH 2 -OH, -CH 2 -CH 2 - NH2, -CH2-NH(CH3), -O-CH2-CH3 and C1 heteroalkyl such as, -CH2-OH, -CH2-NH2, -O- CH 3 .
  • C 4 heteroalkyl such as -CH 2 -CH 2 -N(CH 3 )-CH 3
  • C3 heteroalkyl such as -CH2-CH2-O-CH3, -CH2-CH
  • the C 1-4 heteroalkyl (or C 1-4 heteroalkylene) herein contains 1 or 2 heteroatoms, such as one oxygen, one nitrogen, two oxygens, two nitrogens, or one oxygen and one nitrogen.
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -O-CH 2 -CH 2 - and –O-CH 2 -CH 2 -NH-CH 2 -.
  • heteroalkylene groups heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written.
  • heteroalkyl is recited, together with recitations of specific heteroalkyl groups, such as alkoxy or -NR'R '' or the like, it will be understood that the terms heteroalkyl and alkoxy or -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity.
  • heteroalkyl should not be interpreted herein as excluding specific heteroalkyl groups, such as alkoxy or -NR'R '' or the like.
  • heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system, such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • a "ring structure”, “cyclic structure”, or simply “ring”, with a designated number of ring members, such as a “3-10 membered ring structure”, a “3-12 membered ring structure”, or a “5- or 6-membered ring”, should be understood as encompassing any ring structure (e.g., carbocyclic, heterocyclic, aryl, heteroaryl, etc.) having the designated number of ring members, which can be (1) monocyclic or polycyclic (as chemically feasible), such as a monocyclic ring or a bicyclic ring (including fused, spiro, and bridged bicyclic ring, and those ring systems where two monocyclic rings are connected through a single or double bond); (2) aromatic, partially unsaturated, or fully saturated; and in the case of a polycyclic structure, each ring can be independently aromatic, partially unsaturated, or fully saturated; and (3) contain no heteroatom or 1-4 heteroatoms
  • a ring When a ring is said to contain a ring sulfur or nitrogen atom, the sulfur or nitrogen atom can be optionally oxidized.
  • a fully saturated ring refers to a ring in which none of the ring carbon and nitrogen (if present) atoms forms a double bond or triple bond with any other atom.
  • the ring structure can be optionally substituted with one or more substituents described herein.
  • the substituents of a ring structure herein can also have a cyclic structure, and in some cases, two substituents of a ring structure may be said to be joined to form a cyclic structure.
  • alkylene, alkenylene, alkynylene, heteroalkylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene refer to the corresponding divalent radicals of alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, respectively.
  • An “optionally substituted” group such as an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl group, or an optionally substituted ring structure, refers to the respective group that is unsubstituted or substituted.
  • substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent can be the same or different at each position.
  • the optionally substituted groups herein can be substituted with 1-5 substituents.
  • Substituents can be a carbon atom substituent, a nitrogen atom substituent, an oxygen atom substituent or a sulfur atom substituent, as applicable.
  • the permissible substituents herein include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a cycloalkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate,
  • substituents include, but not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl, - alkynylene-heteroaryl, —OH, hydroxyalkyl, haloalkyl, —O-alkyl, —O-haloalkyl, -alkylene- O-alkyl, —O-aryl, —O-alkylene-aryl, acyl, —C(O)-aryl, halo, —NO2, —CN, —SF5, — C(O)OH, —C(O)O-alkyl, —C(O)O-aryl, —C(O)O—alkylene-aryl, —S(O)-alkyl, —S(O)2-
  • substituents include, but not limited to, (C1-C8)alkyl groups, (C 2 -C 8 )alkenyl groups, (C 2 -C 8 )alkynyl groups, (C 3 -C 10 )cycloalkyl groups, halogen (F, Cl, Br or I), halogenated (C1-C8)alkyl groups (for example but not limited to —CF3), — O—(C 1 -C 8 )alkyl groups, —OH, —S—(C 1 -C 8 )alkyl groups, —SH, —NH(C 1 -C 8 )alkyl groups, —N((C1-C8)alkyl)2 groups, —NH2, —C(O)NH2, —C(O)NH(C1-C8)alkyl groups, — C(O)N((C 1 -C8)alkyl groups, —NHC(O)H,
  • Exemplary carbon atom substituents include, but are not limited to, deuterium, halogen, –CN, –NO2, –N3, hydroxyl, alkoxy, cycloalkoxy, aryloxy, amino, monoalkyl amino, dialkyl amino, amide, sulfonamide, thiol, acyl, carboxylic acid, ester, sulfone, sulfoxide, alkyl, haloalkyl, alkenyl, alkynyl, C3–10 carbocyclyl, C6–10 aryl, 3–10 membered heterocyclyl, 5–10 membered heteroaryl, etc.
  • an optionally substituted group herein can be unsubstituted or substituted with 1-5 substituents, as valency permits, wherein, when substituted: (i) each substituent is independently selected from halo, hydroxy, cyano, nitro, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1- C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, and NR e R f , wherein any (C 1 - C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy is optionally substituted with one or more
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
  • Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, acyl groups, esters, sulfone, sulfoxide, C1–10 alkyl, C1–10 haloalkyl, C2–10 alkenyl, C2–10 alkynyl, C3–10 carbocyclyl, 3–14 membered heterocyclyl, C6–14 aryl, and 5–14 membered heteroaryl, or two substituent groups attached to a nitrogen atom are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be further substituted as defined herein.
  • the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group).
  • Nitrogen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated by reference herein.
  • Exemplary nitrogen protecting groups include, but not limited to, those forming carbamates, such as Carbobenzyloxy (Cbz) group, p-Methoxybenzyl carbonyl (Moz or MeOZ) group, tert-Butyloxycarbonyl (BOC) group, Troc, 9-Fluorenylmethyloxycarbonyl (Fmoc) group, etc., those forming an amide, such as acetyl, benzoyl, etc., those forming a benzylic amine, such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, etc., those forming a sulfonamide, such as tosyl, Nosyl, etc., and others such as p-methoxyphenyl.
  • carbamates such as Carbobenzyloxy (Cbz) group, p-Methoxybenzyl carbonyl (Moz or MeOZ) group, ter
  • oxygen atom substituents include, but are not limited to, acyl groups, esters, sulfonates, C 1–10 alkyl, C 1–10 haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl, C 3–10 carbocyclyl, 3–14 membered heterocyclyl, C6–14 aryl, and 5–14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be further substituted as defined herein.
  • the oxygen atom substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group).
  • Oxygen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • oxygen protecting groups include, but are not limited to, those forming alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyls such as 4-methoxybenzyl, methoxymethyl (MOM), benzyloxymethyl (BOM), 2–methoxyethoxymethyl (MEM), etc., those forming silyl ethers, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t- butyldimethylsilyl (TBDMS), etc., those forming acetals or ketals, such as tetrahydropyranyl (THP), those forming esters such as formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, etc., those forming carbonates or sulfonates such as methane
  • a “stable” compound is a compound that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject).
  • protecting group refers to a substituent that is commonly employed to block or protect a particular functional group on a compound.
  • an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound.
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9- fluorenylmethylenoxycarbonyl (Fmoc).
  • a "hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable protecting groups include acetyl and silyl.
  • a “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
  • Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl and the like.
  • protecting groups and their use see P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis 4 th edition, Wiley-Interscience, New York, 2006.
  • a wavy line “ ” that intersects a bond in a chemical structure indicates the point of attachment of the bond that the wavy bond intersects in the chemical structure to the remainder of a molecule.
  • the terms “treat”, “treatment”, or “treating” to the extent it relates to a disease or condition includes inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or disorder, stabilized (i.e., not worsening) state of disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable.
  • Treat”, “treatment”, or “treating,” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease or disorder as well as those prone to have the disease or disorder or those in which the disease or disorder is to be prevented. In one embodiment “treat”, “treatment”, or “treating” does not include preventing or prevention. [0056]
  • the term "therapeutically effective amount” or “effective amount” is an amount sufficient to effect beneficial or desired results such as clinical results. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.
  • mammal refers to any mammalian species such as a human, mouse, rat, dog, cat, hamster, guinea pig, rabbit, livestock, and the like. Accordingly, in certain embodiments, the mammal is a human, mouse, rat, dog, cat, hamster, guinea pig, rabbit or livestock. In certain embodiments, the mammal is a patient (e.g., a human patient). In certain embodiments, the mammal is a pet, such a dog, cat, hamster, guinea pig or rabbit. In certain embodiments, the mammal is a livestock mammal (e.g., a cow, sheep, horse, pig, chicken, etc.).
  • livestock mammal e.g., a cow, sheep, horse, pig, chicken, etc.
  • the term “food” as used herein refers to a substance that can be consumed, e.g., to provide nutritional or therapeutic support to an organism.
  • the term may include, but is not limited to, proteins, carbohydrates, fats, therapeutic agents, such as medicines, etc.
  • the singular form “a”, “an”, and “the”, includes plural references unless it is expressly stated or is unambiguously clear from the context that such is not intended.
  • the term “and/or” as used in a phrase such as “A and/or B” herein is intended to include both A and B; A or B; A (alone); and B (alone).
  • the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).
  • Headings and subheadings are used for convenience and/or formal compliance only, do not limit the subject technology, and are not referred to in connection with the interpretation of the description of the subject technology. Features described under one heading or one subheading of the subject disclosure may be combined, in various embodiments, with features described under other headings or subheadings.
  • the pharmaceutical compositions of the invention can comprise one or more excipients.
  • excipients refers generally to an additional ingredient that is combined with the compound defined herein, or the pharmaceutically acceptable salt thereof to provide a corresponding composition.
  • excipients includes, but is not limited to: carriers, binders, disintegrating agents, lubricants, sweetening agents, flavoring agents, coatings, preservatives, and dyes.
  • the compounds of the invention can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L, or R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
  • the prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • the “enantiomeric purity” of a substance herein can typically be expressed by the enantiomeric excess (“ee”), which can be calculated by subtracting the molar percentage of one enantiomer in the substance from the molar percentage of the other enantiomer, with the total percentages of both enantiomers being 100%.
  • a substance containing 90% of one enantiomer and 10% of the other enantiomer has an enantiomeric purity of 80% ee.
  • Enantiomeric excess can be determined by analytical methods known in the art, such as through chiral HPLC or SFC methods, NMR, or optical rotations.
  • analytical methods known in the art such as through chiral HPLC or SFC methods, NMR, or optical rotations.
  • compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism.
  • the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.
  • optically active forms for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.
  • the compound may be at least 51% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 60% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 80% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95% the absolute stereoisomer depicted.
  • the compound may be at least 99% the absolute stereoisomer depicted.
  • Specific values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. It is to be understood that two or more values may be combined. It is also to be understood that the values listed herein below (or subsets thereof) can be excluded.
  • (C 1 -C 6 )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso- butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;
  • (C3-C6)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • (C 1 -C 6 )alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy;
  • (C1- C 6 )alkanoyl can be acetyl, propanoyl or butanoyl;
  • (C 1 -C 6 )alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, iso
  • the genus of Formula I as defined above, or a subgenus as defined herein excludes any of the specific compounds shown in Table B herein that would otherwise fall within the defined genus.
  • the compound of Formula I can have a stereochemistry according to Formula I-E1: , wherein the variables are ents, with respect to the chiral center to which R 1 is attached, the compound of Formula I-E1 can have an enantiomeric purity of at least 60% enantiomeric excess (“ee”), such as an enantiomeric purity of at least 80% ee, at least 90% ee, at least 95% ee, at least 98% ee, at least 99% ee, or 99.5% ee or higher.
  • ee enantiomeric purity of at least 60% enantiomeric excess
  • the compound of Formula I can have a stereochemistry according to Formula I-E2: , wherein the variables with respect to the chiral center to which R 1 is attached, the compound of Formula I-E2 can have an enantiomeric purity of at least 60% enantiomeric excess (“ee”), such as an enantiomeric purity of at least 80% ee, at least 90% ee, at least 95% ee, at least 98% ee, at least 99% ee, or 99.5% ee or higher.
  • ee enantiomeric excess
  • R 1 is hydroxy.
  • R 1 can also be O-R 1A , wherein R 1A is an optionally substituted alkanoyl.
  • R 1 in a compound is O-R 1A
  • the R 1A can be cleaved in vivo to generate the corresponding compound with R 1 being hydroxy, and thus, such compound can act as a prodrug.
  • Suitable alkanoyl groups are not particularly limited, which can for example be -C(O)-(C1-6 alkyl), such as acetyl, etc.
  • the corresponding acid which can be generated in vivo from cleavage of O-R 1A , is pharmaceutically acceptable.
  • the alkanoyl group can be substituted.
  • R 1A can be an acyl derived from an amino acid, such as a natural amino acid (e.g., a proteinogenic amino acid), for example, R 1A can .
  • R 1A in Formula I, hydrogen.
  • R 2 in Formula I, R 2 is hydrogen.
  • R 2 in a compound can be cleaved in vivo to generate the corresponding compound with R 2 being hydrogen, and thus, such compound can act as a prodrug.
  • Suitable alkanoyl groups are not particularly limited, which can for example be -C(O)-(C1-6 alkyl), such as acetyl, etc.
  • the corresponding acid, R 2 -OH, which can be generated in vivo is pharmaceutically acceptable.
  • n is 0. In some embodiments, n is 1. In some embodiments, n is 2.
  • R 3 at each occurrence is typically independently selected from halogen, C1-4 alkyl optionally substituted with halogen, C1-4 alkoxy optionally substituted with halogen, or N(C 1-4 alkyl)(C 1-4 alkyl).
  • n is not 0, and R 3 at each occurrence can be independently F, Cl, methyl optionally substituted with F, or methoxy optionally substituted with F.
  • R 3 is F, Cl, methyl optionally substituted with F (e.g., CH 3 or CF 3 ), or methoxy optionally substituted with F (e.g., OCF 3 ).
  • the compound of Formula I can have a structure according to Formula I-A: wherein X, R 6 , R 7 , and j are [0086] In some embodiments, the compound of Formula I can have a structure according to Formula I-B: wherein X, R 4 , R 6 , R 7 , and j are defined herein. [0087] In some embodiments, the compound of Formula I can have a structure according to Formula I-C: wherein X, R 6 , R 7 , and j are defined herein.
  • the compound of Formula I can have a structure according to Formula I-D: wherein X, R 3 , R 4 , R 6 , R 7 , are be understood that in Formula I-D, one R 3 is present, which can be at any available position of the phenyl portion of the oxindole ring. Exemplary suitable substitution patterns are shown in the specific examples disclosed herein. [0089] In some embodiments, the compound of Formula I-A, I-B, I-C, or I-D can have a stereochemistry according to Formula I-E1. In some embodiments, the compound of Formula I-A, I-B, I-C, or I-D can have a stereochemistry according to Formula I-E2.
  • the compound of Formula I-A can be characterized as having a structure according to Formula I-A1:
  • the compound of Formula I-A1 can have an enantiomeric purity of at least 60% enantiomeric excess (“ee”), such as an enantiomeric purity of at least 80% ee, at least 90% ee, at least 95% ee, at least 98% ee, at least 99% ee, or 99.5% ee or higher.
  • R 6 is an optionally substituted phenyl.
  • the phenyl is typically substituted with 1-3 substituents, which can for example, be independently selected from halogen (e.g., F), OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl, or 3-6 membered ring, wherein the C1-4 alkyl, C1-4 alkoxy, C1-4 heteroalkyl or 3-6 membered ring is optionally substituted with one or more substituents each independently halogen, CN, OH, C 1-4 alkyl optionally substituted with 1-3 fluorine, C1-4 alkoxy optionally substituted with 1-3 fluorine, or C 3-4 cycloalkyl optionally substituted with 1 or 2 substituents each independently F or m ethyl.
  • substituents can for example, be independently selected from halogen (e.g., F), OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl, or 3-6 membered ring, wherein the C1-4 alky
  • R6 can have a , wherein: k2 is 0, 1, 2, or 3, and G 3 at each occurrence is independently F, Cl, C1-4 alkyl optionally substituted with 1-3 fluorine, C 1-4 alkoxy optionally substituted with 1-3 fluorine, or C 3-4 cycloalkyl optionally substituted with 1 or 2 substituents each independently F or methyl.
  • k2 is 0.
  • k2 is 1 or 2
  • each G 3 is independently F, Cl, or methyl optionally substituted with 1-3 fluorine.
  • R 6 can be 4-trifluoromethylphenyl.
  • R 6 is an optionally substituted 5 or 6-membered heteroaryl, such as pyridyl.
  • the 5 or 6-membered heteroaryl is typically substituted with 1-3 substituents as valency permits, which can for example, be independently selected from halogen (e.g., F), OH, C1-4 alkyl, C1-4 alkoxy, C1-4 heteroalkyl, or 3-6 membered ring, wherein the C1-4 alkyl, C1-4 alkoxy, C1-4 heteroalkyl or 3-6 membered ring is optionally substituted with one or more substituents each independently halogen, CN, OH, C 1-4 alkyl optionally substituted with 1-3 fluorine, C1-4 alkoxy optionally substituted with 1-3 fluorine, or C 3-4 cycloalkyl optionally substituted with 1 or 2 substituents each independently F or methyl.
  • halogen e.g., F
  • OH e.g., F
  • C1-4 alkyl, C1-4 alkoxy, C1-4 heteroalkyl, or 3-6 membered ring is optionally substituted with one or more substituent
  • R 6 in Formula I (such as a subformulae I-E1, I- E2, I-A, I-B, I-C, I-D, or I-A1), R 6 can have a structure of , wherein: k2 is 0, 1, 2, or 3, and G 3 at each occurrence is independently F, Cl, C 1-4 alkyl optionally substituted with 1-3 fluorine, C1-4 alkoxy optionally substituted with 1-3 fluorine, or C3-4 cycloalkyl optionally substituted with 1 or 2 substituents each independently F or methyl. In some embodiments, k2 is 0.
  • k2 is 1 or 2, and each G 3 is independently F, Cl, or methyl optionally substituted with 1-3 fluorine.
  • R 6 can .
  • R 6 can be .
  • R 6 can be .
  • R 6 in Formula I (such as a subformulae I-E1, I-E2, I-A, I-B, I-C, I-D, or I-A1), R 6 can be pyrrolyl, which is optionally substituted, for example, with substituents independently selected from halogen (e.g., F), C1-4 alkyl optionally substituted with 1-3 fluorine, or a 3-6 membered ring optionally substituted with one or more substituents each independently halogen, CN, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, C 1-4 alkoxy optionally substituted with 1-3 fluorine, or C 3-4 cycloalkyl optionally substituted with 1 or 2 substituents each independently F or methyl.
  • halogen e.g., F
  • C1-4 alkyl optionally substituted with 1-3 fluorine
  • C 1-4 alkoxy optionally substituted with 1-3 fluorine
  • C 3-4 cycloalkyl optionally substitute
  • R 6 can be difluoropyrrolyl, e.g., .
  • R 6 in Formula I (such as a subformulae I-E1, I-E2, I-A, I-B, I-C, I-D, or I-A1), R 6 is an optionally substituted 5-10 membered heterocyclic ring.
  • the 5-10 membered heterocyclic ring has one or two ring heteroatoms, which can be independently N, O, or S.
  • the 5-10 membered heterocyclic ring can be a monocyclic 5 or 6 membered ring having one or two ring heteroatoms, such as one or two ring nitrogen atoms.
  • the 5-10 membered heterocyclic ring can be a bicyclic ring having one or two ring heteroatoms, such as one or two ring nitrogen atoms.
  • the 5-10 membered heterocyclic ring can be substituted with 1-5 independently selected substituents, such as 1-5 independently selected R A as defined herein.
  • the compound of Formula I (such as a subformulae I-E1, I-E2, I-A, I-B, I-C, I-D, or I-A1) can be characterized as having a structure according to Formula I-1: , wherein: X, R 1 , R 2 , R 3 , n, R 4 , R 5 , R 7 , and j are defined herein, k is 0, 1, 2, 3, or 4; and R A at each occurrence is independently F, OH, NH2, COOH, CONH2, G A , C(O)-G A , O-G A , NH-G A , N(C1-4 alkyl)-G A , C(O)-O-G A , C(O)-NH-G A , or C(O)-N(C1-4 alkyl)-G A ; wherein G A at each occurrence is independently C1-4 alkyl or a 3-10 membered ring (more preferably,
  • k in Formula I-1 is 0. [0098] In some embodiments, k in Formula I-1 is 1. [0099] In some embodiments, k in Formula I-1 is 2. [0100] In some embodiments, R A at each occurrence is independently F, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, or C1-4 alkoxy optionally substituted with 1-3 fluorine.
  • one R A is an optionally substituted 3-8 membered ring, such as an optionally substituted phenyl, and any remaining R A at each occurrence is independently F, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, or C1-4 alkoxy optionally substituted with 1-3 fluorine.
  • the compound of Formula I (such as a subformulae I-E1, I-E2, I-A, I-B, I-C, I-D, or I-A1) or I-1 can be characterized as having a structure according to Formula I-1a: , wherein: X, R 1 , R 2 , R 3 , n, R 4 , R 5 , R 7 , and j are defined herein, k1 is 0, 1, 2, 3, or 4; and G 2 at each occurrence is independently halogen, CN, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, C1-4 alkoxy optionally substituted with 1-3 fluorine, or C3-4 cycloalkyl optionally substituted with 1 or 2 substituents each independently F or methyl.
  • Formula I-1a wherein: X, R 1 , R 2 , R 3 , n, R 4 , R 5 , R 7 , and j are defined herein, k1 is 0, 1, 2, 3, or 4;
  • R 6 can be a fused, spiro, or bridged 6-10 membered bicyclic heterocyclic ring having 1-3 ring heteroatoms each independently N, S, or O, preferably, the 6-10 membered bicyclic heterocyclic ring has only one ring heteroatom, wherein the bicyclic heterocyclic ring is optionally substituted, for example, with 1-3 substituents each independently a halogen, CN, OH, C 1-4 alkyl optionally substituted with 1-3 fluorine, C 1-4 alkoxy optionally substituted with 1-3 fluorine, or a 3-5 membered ring optionally substituted with 1-3
  • R 6 can be selected from the following: , . I (such as a subformulae I-E1, I-E2, I-A, I-B, I-C, I-D, I-A1, I-1, or I- 1a), X is typically CH or CR 7 , wherein R 7 is defined herein, e.g., R 7 can be F.
  • R 7 is defined herein, e.g., R 7 can be F.
  • X is CH.
  • X in Formula I (such as a subformulae I-E1, I-E2, I-A, I-B, I-C, I-D, I-A1, I-1, or I-1a)
  • X can also be N.
  • the integer j in Formula I (such as a subformulae I-E1, I-E2, I-A, I-B, I-C, I-D, I- A1, I-1, or I-1a) is typically 0 or 1. In some preferred embodiments, j is 0. In some embodiments, j is 1. In some embodiments, R 7 at each occurrence is independently F, Cl, C1-4 alkyl optionally substituted with F, or C1-4 alkoxy optionally substituted with F.
  • R 1 is hydrogen, OH, or O-R 1A , wherein R 1A is an optionally substituted alkanoyl;
  • R 2 is hydrogen or an optionally substituted alkanoyl;
  • n is 0, 1, 2, 3, or 4, preferably, 0 or 1,
  • R 3 at each occurrence is independently halogen, C1-4 alkyl optionally substituted with halogen, C 1-4 alkoxy optionally substituted with halogen, NH 2 , NH(C 1-4 alkyl), or N(C 1-4 alkyl)(C1-4 alkyl);
  • R 10 and R 11 are each independently hydrogen, halogen, OH, NH 2 , G A , O-G A , NH-G A , or N(C1-4 alkyl)-G A ; wherein G A at each occurrence is independently C1-4 alkyl or a 3-10 membered ring, wherein the
  • Suitable further definitions of R 1 , R 2 , R 3 , and n for Formula II can include any of those described herein in connection with Formula I or its subformulae, in any combinations.
  • R 10 is hydrogen.
  • R 10 is halogen.
  • R 10 is G A , wherein G A is defined herein.
  • R 10 is G A , wherein G A is C 1-4 alkyl which is optionally substituted as described herein.
  • R 10 is G A , wherein G A is a 3-10 membered ring, such as a 5 or 6 membered heterocyclic ring having one or two ring heteroatoms, such as one or two ring nitrogen atoms or one ring nitrogen and one ring oxygen atom, or a 5 or 6 membered heteroaryl, e.g., pyridyl, which can be optionally substituted as described herein.
  • R 10 can be .
  • R 10 can be [0114] In some embodiments, R 10 is O-G A , wherein G A is defined herein. In some embodiments, R 10 is O-G A , wherein G A is C 1-4 alkyl which is optionally substituted as described herein. For example, in some embodiments, R 10 can be O-CF3. [0115] In some embodiments, R 11 is hydrogen. [0116] In some embodiments, R 11 is halogen. [0117] In some embodiments, R 11 is G A , wherein G A is defined herein.
  • R 11 is G A , wherein G A is a 3-10 membered ring, such as a 5 or 6 membered heterocyclic ring having one or two ring heteroatoms, such as one or two ring nitrogen atoms or one ring nitrogen and one ring oxygen atom, or a 5 or 6 membered heteroaryl, e.g., pyridyl, which can be optionally substituted as described herein.
  • R 11 is G A , wherein G A is defined herein.
  • R 11 is G A , wherein G A is C1-4 alkyl which is optionally substituted as described herein.
  • R 11 is O-G A , wherein G A is defined herein. In some embodiments, R 11 is O-G A , wherein G A is C1-4 alkyl which is optionally substituted as described herein. For example, in some embodiments, R 11 can be O-CF3. [0119] Typically, R 10 and R 11 are different. For example, in some embodiments, one of R 10 and R 11 is hydrogen or halogen, and the other of R 10 and R 11 is G A or O-G A as defined herein. [0120] Typically, m in Formula II is 0.
  • m is 1 and R 12 is halogen, C1-4 alkyl optionally substituted with F, or C1-4 alkoxy optionally substituted with F.
  • Suitable further definitions of R 1 , R 2 , R 3 , R 4 , R 5 , and n for Formula III can include any of those described herein in connection with Formula I or its subformulae, in any combinations.
  • the compound of Formula III can be characterized as having a structure according to Formula III-A: , Formula III-A, wherein Ring E, j2, and R 20 are defined herein.
  • the compound of Formula III can be characterized as having a structure according to Formula III-B: O S NH 2 O j 2 , wherein Ring E, j2, R 3 , and R 20 are defined herein.
  • Ring E in Formula III can be a monocyclic 5 or 6 membered heteroaryl, for example, an oxazole, thiazole, pyridine, pyrazine, pyrimidine ring, etc.
  • Ring E, together with the optional substituent(s) (R 20 )j2 are selected , 1-3 ring heteroatoms.
  • the bicyclic heteroaryl can be a fused ring from two rings, with one ring being a pyridine, pyridone, pyrimidine, thiazole, imidazole, or oxazole, and another ring being a phenyl or pyridine ring, wherein the fusion can occur at any two available ring atoms.
  • Ring E together with the optional substituent(s) (R 20 ) j2 , are selected from the , N (R 20 ) j2 .
  • Ring E in Formula III can be a 5-14 membered heterocyclic ring, such as piperidine, tetrahydropyran ring, etc.
  • Ring E, together with the optional substituent(s) (R 20 )j2 can , wherein j2 and R 20 are defined herein.
  • j2 can be 1.
  • j2 can be 2.
  • R 20 at each occurrence is typically independently halogen, G B , O- G B , NH-G B , or N(C 1-4 alkyl)-G B , wherein G B is defined herein.
  • one or more R 20 is G B , wherein G B is defined herein. In some embodiments, one or more R 20 is G B , wherein G B is C 1-4 alkyl which is optionally substituted as described herein.
  • one or more R 20 is G B , wherein G B is a 3-10 membered ring, such as (i) a phenyl ring, (ii) a 5 or 6 membered heterocyclic ring having one or two ring heteroatoms, such as one or two ring nitrogen atoms or one ring nitrogen and one ring oxygen atom, or (iii) a 5 or 6 membered heteroaryl, e.g., pyridyl, each of (i)-(iii) can be optionally substituted as described herein.
  • one R 20 can .
  • one R 20 can be phenyl.
  • the compound of Formua III can be characterized as having a structure according to Formula III-1: , wherein: 1 2 3 4 R , R , R , R , R 5 , and n are R 21 is hydrogen or R 20 as defined herein.
  • R 21 is hydrogen.
  • R 21 can have any of the definition defined for R 20 herein.
  • R 21 is an optionally substituted phenyl.
  • R 21 is an optionally substituted 5 or 6 membered heteroaryl.
  • the phenyl, or 5 or 6 membered heteroaryl can be typically substituted with 1-3 substituents each independently F, Cl, C1-4 alkyl optionally substituted with 1-3 fluorine, or C 1-4 alkoxy optionally substituted with 1-3 fluorine.
  • the present disclosure also provides novel specific compounds as described in the Examples section herein, including any new synthetic intermediate or target compound, as well as a stereoisomer thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound selected from the following Table A: Table A.
  • the present disclosure provides an enantiomerically enriched compound selected from the following: O O S N H O O S N H 2 HO ee, at least 95% ee, at least 98% ee, at least 99% ee, or 99.5% ee or higher.
  • the present disclosure provides a compound of: , wherein the compound has an enantiomeric purity of at least 80% ee, preferably, at least 90% ee, at least 95% ee, at least 98% ee, at least 99% ee, or 99.5% ee or higher.
  • the S-enantiomer, NEM-23AS has a better aqueous solubility, and less CYP inhibition, compared to the R-enantiomer, NEM-23AR.
  • the S-enantiomer, NEM-23AS was also found to be more active in inhibiting carbonic anhydrase enzyme compared to the R-enantiomer, NEM-23AR.
  • the S-enantiomer is the preferred enantiomer.
  • the present disclosure provides a compound of: , wherein the compound has an least 80% ee, preferably, at least 90% ee, at least 95% ee, at least 98% ee, at least 99% ee, or 99.5% ee or higher.
  • the present disclosure provides a compound of: , wherein the compound has an enant at least 80% ee, preferably, at least 90% ee, at least 95% ee, at least 98% ee, at least 99% ee, or 99.5% ee or higher.
  • the present disclosure provides a compound of: , wherein the compound has an enantiomeric purity of at least 80% ee, preferably, at least 90% ee, at least 95% ee, at least 98% ee, at least 99% ee, or 99.5% ee or higher.
  • the present disclosure provides a compound of: O O S N H 2 , wherein the compound has an enantiomeric purity of at least 80% ee, preferably, at least 90% ee, at least 95% ee, at least 98% ee, at least 99% ee, or 99.5% ee or higher.
  • the present disclosure provides a compound of: O O S N , wherein the compound has an enantiomeric purity of at least 80% ee, preferably, at least 90% ee, at least 95% ee, at least 98% ee, at least 99% ee, or 99.5% ee or higher.
  • the present disclosure provides a salt of a compound selected from Table A.
  • the present disclosure provides a pharmaceutically acceptable salt of a compound selected from Table A.
  • the present disclosure provides a stereoisomer of a compound selected from Table A, or a salt thereof.
  • the present disclosure provides a stereoisomer of a compound selected from Table A, or a pharmaceutically acceptable salt thereof. [0151] In some embodiments, the present disclosure provides a deuterated analog of a compound selected from Table A, or a salt thereof. [0152] In some embodiments, the present disclosure provides a deuterated analog of a compound selected from Table A, or a pharmaceutically acceptable salt thereof. [0153] The present disclosure also lists the following compounds:
  • Table B List of Compounds
  • the genus of compounds described herein can exclude any of the specific compounds in Table B in racemic forms. Compounds of Table B are also described in PCT/US2023/082927.
  • a salt of a compound of Formula I, II, or III herein can be useful as an intermediate for isolating or purifying a compound of Formula I, II, or III. Additionally, administration of a compound of Formula I, II, or III as a pharmaceutically acceptable acid or base salt may be appropriate.
  • Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, ⁇ -ketoglutarate, and ⁇ - glycerophosphate.
  • Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
  • Salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • the compounds of the present disclosure can be readily synthesized by those skilled in the art in view of the present disclosure. Exemplified syntheses are also shown in the Examples section. Certain Methods of Use [0158] As described herein, compounds of Formula I, II, or III may be used as carbonic anhydrase inhibitors. Carbonic anhydrases (Car) are a family of metabolic enzymes that regulate pH and CO2 homeostasis (Supuran, C.T.2008. Nat Rev Drug Discov 7:168-181, which is hereby incorporated by reference herein).
  • Car enzymes found in mammals are divided into four broad subgroups, which, in turn consist of several isoforms: cytosolic Car (Car1, Car2, Car3, Car7, Car13), mitochondrial Car (Car5A, Car5B), secreted Car (Car6), and membrane-associated Car (Car4, Car9, Car12, Car14). Additionally, there are three additional “acatalytic" Car isoforms (Car8, Car10, Car11) whose functions remain unclear.
  • certain embodiments of the invention provide a method of inhibiting a carbonic anhydrase enzyme (e.g., the enzyme’s activity or function) in vitro or in vivo, the method comprising contacting the carbonic anhydrase enzyme with an effective amount of a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof).
  • a method comprises contacting a cell comprising the carbonic anhydrase enzyme.
  • the cell is in a mammal.
  • the cell is contacted by administering the compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, a salt thereof (e.g., a pharmaceutically acceptable salt thereof) to the mammal.
  • a salt thereof e.g., a pharmaceutically acceptable salt thereof
  • the activity or function of the carbonic anhydrase is inhibited by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% (e.g., as compared to a control, such as a cell or a mammal not contacted with the compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein).
  • a control such as a cell or a mammal not contacted with the compound of Formula I
  • compounds of Formula I, II, or III, or salts thereof for the methods or uses herein are those selected from Table A which have a POI as tested in the in vitro mast cell development assay equal or higher than that of MZ, for example, those showing a POI at 10 uM (or below) of 80% or above, preferably, 90% or above, more preferably, 95% or above.
  • Certain embodiments also provide a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a salt thereof, for use in inhibiting a carbonic anhydrase enzyme in vitro or in vivo.
  • Certain embodiments provide the use of a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a salt thereof, for the manufacture of a medicament for inhibiting a carbonic anhydrase enzyme in vitro or in vivo.
  • the carbonic anhydrase enzyme is carbonic anhydrase (Car) 1 (see, UniProKB No P00915).
  • Certain embodiments also provide a method of inhibiting mast cell development and/or mast cell function (e.g., mast cell activation) in a mammal, comprising administering a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, to the mammal.
  • a compound of Formula I, II, or III e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, for use in the inhibition of mast cell development and/or mast cell function (e.g., mast cell activation).
  • Certain embodiments also provide the use of a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, to prepare a medicament for inhibiting mast cell development and/or mast cell function (e.g., mast cell activation).
  • a compound of Formula I, II, or III e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, to prepare a medicament for inhibiting mast cell development and/or mast cell function (e.g., mast cell activation).
  • Certain embodiments also provide a method of treating a disease or condition mediated by a carbonic anhydrase enzyme in a mammal (e.g., a human), comprising administering a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, to the mammal.
  • a mammal e.g., a human
  • Certain embodiments provide a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, for the prophylactic or therapeutic treatment of a disease or condition mediated by a carbonic anhydrase enzyme.
  • Certain embodiments also provide the use of a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating a disease or condition mediated by a carbonic anhydrase enzyme.
  • diseases or conditions mediated by a carbonic anhydrase enzyme are known in the art, and include, e.g., mast cell-mediated diseases.
  • diseases associated with carbonic anhydrase enzymes and/or mast cells include, but are not limited to, e.g., allergic diseases, bacterial infections, fungal infections, viral infections, mastocytosis and mast cell-mediated inflammation.
  • the disease or condition mediated by a carbonic anhydrase enzyme is an allergic disease.
  • allergic disease refers to a condition caused by hypersensitivity of the immune system in response to an environmental exposure.
  • the allergic diseases include, but are not limited to, asthma (e.g. fungal asthma), atopic dermatitis, contact dermatitis, chronic itch (pruritus), urticaria, hay fever, allergic conjunctivitis, allergic rhinitis, anaphylaxis, eosinophilic esophagitis, food allergies, and allergen-induced mastocytosis.
  • asthma e.g. fungal asthma
  • atopic dermatitis e.g., contact dermatitis, chronic itch (pruritus)
  • urticaria hay fever
  • allergic conjunctivitis allergic rhinitis
  • anaphylaxis eosinophilic esophagitis
  • food allergies eosinophilic esophagitis
  • allergen-induced mastocytosis e.g., asthma, e.g. fungal asthma
  • atopic dermatitis e.g., contact dermatitis,
  • the bacterial infection is a gram-negative bacterial infection.
  • fungal infections include infections caused by Aspergillus fumigates, or other Aspergiullus species, as well as Candida species, Cryptococcus species, Histoplasma capsulatum, Pneumocystis jirovecii, and Stachybotrys chartarum.
  • Non-limiting examples of viral infections include HIV, SARS-CoV-2, and Dengue.
  • the disease or condition mediated by a carbonic anhydrase enzyme is mastocytosis.
  • mastocytosis refers to a disease characterized by the presence of too many mast cells in various organs and tissues, including but not limited to, infection- or allergen-induced mastocytosis, cutaneous mastocytosis, indolent systemic mastocytosis, systemic mastocytosis with associated clonal hematologic non-mast cell lineage diseases (such as myelodysplastic syndrome, myeloproliferative syndrome, acute myeloid leukemia, non-Hodgkin’s lymphoma), aggressive systemic mastocytosis, mast cell leukemia, mast cell activation syndrome, and localized mast cell proliferations (such as mast cell sarcoma and extracutaneous mastocytoma).
  • infection- or allergen-induced mastocytosis such as myelodysplastic syndrome, myeloproliferative syndrome, acute myeloid leukemia, non-Hodgkin’s lymphoma
  • aggressive systemic mastocytosis such as mast cell leukemia, mast cell activ
  • the mastocytosis is mast cell activation syndrome.
  • the disease or condition mediated by a carbonic anhydrase enzyme is mast cell-mediated inflammation.
  • the term “mast cell-mediated inflammation” refers to any inflammatory response and/or pathology that is promoted or supported by mast cell development and/or activation. This includes mast cell responses promoted by exposure to allergens, infectious agents, or unknown stimuli.
  • the mast cell- mediated inflammation is caused by mastocytosis, an infection (e.g., a parasite infection, such as a helminth parasite (e.g., a Trichinella spiralis infection)), or an allergy (e.g., a food allergy or food allergy-like disease).
  • the mast cell-mediated inflammation is mast cell-mediated intestinal inflammation.
  • the mast cell-mediated inflammation is mast cell-mediated airway inflammation (e.g., eosinophilic airway inflammation).
  • the disease or condition mediated by a carbonic anhydrase enzyme is osteoarthritis.
  • the disease or condition mediated by a carbonic anhydrase enzyme is ankylosing spondylitis.
  • Carbonic anhydrase has been shown to be associated with osteoarthritis, and carbonic anhydrase inhibitors have been shown to be antiarthritic, for example, methazolamide was previously shown to have an effect in treating ankylosing spondylitis. See e.g., Sun et. al. Sci Rep 13:15370 (2023); Nolan et al. Pharmacol Res.24(4):377-83(1991); Chang et al. Arthritis Res Ther. 14(4):R176 (2012); Kenny, Calcif Tissue Int.40(4):212-8 (1987); and Chang et al.
  • the disease or condition mediated by a carbonic anhydrase enzyme is neuropathic pain.
  • Neuropathic pain has also been shown to be associated with carbonic anhydrase inhibition. See e.g., Expert Rev Neurother.16(8):961-8 (2016).
  • the present disclosure provides a method of treating osteoarthritis, the method comprising administering a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or any of the compounds in Table A or Table B herein, or any of the compounds disclosed in PCT/US2023/082927, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • a compound of Formula I, II, or III e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or any of the compounds in Table A or Table B herein, or any of the compounds disclosed in PCT/US2023/082927, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the present disclosure provides a method of treating ankylosing spondylitis, the method comprising administering a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or any of the compounds in Table A or Table B herein, or any of the compounds disclosed in PCT/US2023/082927, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • a compound of Formula I, II, or III e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or any of the compounds in Table A or Table B herein, or any of the compounds disclosed in PCT/US2023/082927, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the present disclosure provides a method of treating neuropathic pain, the method comprising administering a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or any of the compounds in Table A or Table B herein, or any of the compounds disclosed in PCT/US2023/082927, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • a compound of Formula I, II, or III e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or any of the compounds in Table A or Table B herein, or any of the compounds disclosed in PCT/US2023/082927, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • a mast cell response such as mast cell-mediated inflammation (e.g., mast cell-mediated intestinal inflammation; or mast cell-mediated airway inflammation).
  • the mast cell response e.g., mast cell-mediated inflammation
  • an allergy such as a food allergy.
  • a mast cell response e.g., mast cell activation and/or mast-cell mediated inflammation causes airway constriction.
  • a method described herein may further comprise administering one or more additional therapeutic agent(s).
  • additional therapeutic agent(s) such as an agent may be useful for treating a disease or condition mediated by a carbonic anhydrase enzyme (e.g., for treating allergic diseases, bacterial infections, fungal infections, viral infections, mastocytosis and/or mast cell-mediated inflammation).
  • the one or more additional therapeutic agent(s) is/are administered simultaneously or sequentially with a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof.
  • the one or more additional therapeutic agent(s) is/are administered simultaneously with a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition/formulation comprising a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, and the one or more additional therapeutic agent(s) is administered.
  • a compound of Formula I, II, or III e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, and the one or more additional therapeutic agent(s) are administered sequentially.
  • the compound of Formula I, II, or III e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, is administered first and the one or more additional therapeutic agent(s) is administered second.
  • the one or more additional therapeutic agent(s) is administered first and the compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, is administered second.
  • the one or more additional therapeutic agent(s) is an anti-histamine, a steroid, immunotherapy (e.g., an allergy shot, oral tolerance therapy, etc.), a decongestant, a bronchodilator, a mast cell stabilizer, a prostaglandin antagonist, a blocking/neutralizing antibody (e.g. an anti-IgE therapy, an anti-IL-4R alpha therapy, or an anti-SIGLEC8 therapy), and/or a leukotriene modifier. In certain embodiments, a combination of such agents is administered. [0190] In certain embodiments, the one or more additional therapeutic agent(s) is an anti-histamine.
  • a histamine antagonist commonly called an antihistamine, is a pharmaceutical drug class that includes two types of drugs: histamine H1-receptor antagonists and histamine H2-receptor antagonists.
  • Antagonists of the histamine H1-receptor are used to treat allergic reactions in the nose (e.g., itching, runny nose, and sneezing) and which are used off-label for insomnia. They are sometimes also used to treat motion sickness or vertigo caused by problems with the inner ear.
  • Antagonists of the histamine H2-receptor are used to treat gastric acid conditions (e.g., peptic ulcers and acid reflux).
  • Non-limiting examples of antihistamines that may be used in the present invention include: acrivastine, azelastine, bilastine, brompheniramine, buclizine, bromodiphenhydramine, carbinoxamine, cetirizine (Zyrtec; metabolite of hydroxyzine, its prodrug), chlorpromazine, cimetidine, cyclizine, chlorphenamine, chlorodiphenhydramine, clemastine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimetindene, diphenhydramine (Benadryl), ebastine, embramine, famotidine, fexofenad
  • the one or more additional therapeutic agent(s) is a blocking and/or neutralizing antibody (e.g., an antibody useful for treating inflammation).
  • an antibody may target IgE, IL-4R alpha or SIGLEC8.
  • the one or more additional therapeutic agent(s) is an anti-IgE therapy.
  • Anti-IgE therapies that may be used in the present invention include anti-IgE therapeutic antibodies, such as a monoclonal antibody.
  • a non-limiting example of a suitable monoclonal antibody is Omalizumab (Xolair).
  • the one or more additional therapeutic agent(s) is an anti-IL-4R alpha therapy.
  • Anti-IL-4R therapies that may be used in the present invention include anti-IL-4R alpha therapeutic antibodies, such as a monoclonal antibody.
  • a non- limiting example of a suitable antibody is dupilumab.
  • the one or more additional therapeutic agent(s) is an anti-SIGLEC8 alpha therapy.
  • Anti- SIGLEC8 therapies that may be used in the present invention include anti-SIGLEC8 alpha therapeutic antibodies, such as a monoclonal antibody.
  • a non-limiting example of a suitable antibody is bubblentelimab.
  • the one or more additional therapeutic agent(s) is a prostaglandin antagonist.
  • a prostaglandin antagonist is a hormone antagonist acting upon one or more prostaglandins, a subclass of eicosanoid compounds, which function as signaling molecules in numerous types of animal tissues.
  • prostaglandin antagonists that may be used in the present invention include NSAIDs and seratrodast.
  • the one or more additional therapeutic agent(s) a steroid.
  • a steroid is an organic compound, typically containing four rings arranged in a specific configuration. Steroids have two principal biological functions: certain steroids (such as cholesterol) are important components of cell membranes which alter membrane fluidity, and many steroids are signaling molecules which activate steroid hormone receptors.
  • the steroid core structure is composed of seventeen carbon atoms, bonded in four "fused" rings: three six-member cyclohexane rings (rings A, B and C in the first illustration) and one five-member cyclopentane ring (the D ring).
  • Steroids vary by the functional groups attached to this four-ring core and by the oxidation state of the rings.
  • Sterols are forms of steroids with a hydroxyl group at position three and a skeleton derived from cholestane. Steroids can also vary more markedly by changes to the ring structure (for example, ring scissions which produce secosteroids, such as vitamin D3).
  • Non-limiting examples of steroids that may be used in the present invention include: beclomethasone, ciclesonide, fluticasone proprionate, fluticasone furoate, mometasone, budesonide, triamcinolone, dexamethasone, deltasone, and prednisone.
  • the one or more additional therapeutic agent(s) is an immunotherapy.
  • Immunotherapy is the treatment of a disease or condition by inducing, enhancing, or suppressing an immune response. Immunotherapies that are designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies.
  • Non-limiting examples of immunotherapies that may be used in the present invention include, allergy shots and oral tolerance therapies.
  • the one or more additional therapeutic agent(s) is a decongestant. Decongestants are a type of agent that is used to relieve nasal congestion in the upper respiratory tract. Non-limiting examples of decongestants that may be used in the present invention include pseudoephedrine, phenylephrine, and oxymetazoline.
  • the one or more additional therapeutic agent(s) is a bronchodilator. Bronchodilators are a type of agent that dilates the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lungs.
  • Non- limiting examples of bronchodilators that may be used in the present invention include albuterol and levalbuterol.
  • the one or more additional therapeutic agent(s) is a mast cell stabilizer.
  • Mast cell stabilizers are generally cromone medications that are used to prevent or control certain allergic disorders. They block a calcium channel essential for mast cell degranulation, stabilizing the cell and thereby preventing the release of histamine and related mediators.
  • Non-limiting examples of mast cell stabilizers that may be used in the present invention include cromolyn sodium, lodoxamide, and nedocromil.
  • the one or more additional therapeutic agent(s) is a leukotriene modifier.
  • Leukotriene modifiers are a type of agent that functions as a leukotriene-related enzyme inhibitor (arachidonate 5-lipoxygenase) or leukotriene receptor antagonist (cysteinyl leukotriene receptors), and consequently, opposes the function of these inflammatory mediators.
  • leukotriene modifiers include monteleukast, zafirlukast, and zyflo.
  • the one or more additional therapeutic agent(s) is a tyrosine kinase inhibitor (TKIs), such as KIT inhibitors.
  • Tyrosine kinases are enzymes that activate signal transduction cascades by phosphorylating proteins involved in those signaling processes. TKIs inhibit tyrosine kinase phosphorylation.
  • Non-limiting examples of TKIs that may be used in the present invention include imatinib, sunitinib, dasatinib, nilotinib, avapritinib, and bezuclatinib.
  • the compounds of Formula I, II, or III e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or salts thereof, can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • the oral formulation can be a suspension of a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or salts thereof, in an aqueous methylcellulose solution, such as a 0.5% methylcellulose solution having a viscosity of 400-4000 cPs.
  • aqueous methylcellulose solution such as a 0.5% methylcellulose solution having a viscosity of 400-4000 cPs.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, buffers or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • an injectable formulation can be a solution/suspension of a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a salt thereof, in an aqueous vehicle.
  • such injectable formulation can include one or more solubilizer to increase the solubility of the active compound in the aqueous vehicle.
  • solubilizers are not particularly limited and can include any of those conventionally used in formulation science, for example, cyclodextrins, etc.
  • a formulation of compounds herein can be formulated together with beta-cyclodextrin, in particular, sulfobutylether beta-cyclodextrin (SBE- ⁇ -CD) in an aqueous vehicle.
  • SBE- ⁇ -CD sulfobutylether beta-cyclodextrin
  • NEM-24A can be formulated at 6 mg/mL with 20% SBE- ⁇ -CD in water, which can be suitable for injection.
  • SBE- ⁇ -CD is commercially available, for example, under the tradename Captisol for SBE6.5- ⁇ -CD.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • a dermatologically acceptable carrier which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Examples of useful dermatological compositions which can be used to deliver the compounds of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No.4,608,392), Geria (U.S. Pat.
  • Useful dosages of the compounds of Formula I, II, or III can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No.4,938,949.
  • the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub- doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • Compounds of the invention can also be administered in combination with other therapeutic agents.
  • agents include anti-histamines, steroids, immunotherapies (e.g., allergy shots, oral tolerance therapies, etc.), decongestants, bronchodilators, mast cell stabilizers, leukotriene modifiers, prostaglandin antagonists, and blocking/neutralizing antibodies (e.g., anti-IgE therapies, anti-IL-4R alpha therapies, and anti-SIGLEC8 therapies).
  • immunotherapies e.g., allergy shots, oral tolerance therapies, etc.
  • decongestants e.g., bronchodilators, mast cell stabilizers, leukotriene modifiers, prostaglandin antagonists, and blocking/neutralizing antibodies (e.g., anti-IgE therapies, anti-IL-4R alpha therapies, and anti-SIGLEC8 therapies).
  • the invention also provides a composition
  • a composition comprising a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent (e.g., an additional agent described herein), and a pharmaceutically acceptable diluent or carrier.
  • a compound of Formula I, II, or III e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent (e.g., an additional agent described herein), and a pharmaceutically acceptable diluent or carrier.
  • the invention also provides a kit comprising a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein or the pharmaceutically acceptable salt thereof and the other therapeutic agent or agents to an animal to treat a disease or condition that is mediated by carbonic anhydrase.
  • a kit comprising a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of Formula I, II, or III, e.g., any of the subformul
  • mast cells are potent innate immune cells that activate in response to diverse stimuli, including cytokines and antigen-antibody complexes. Upon activation, mast cells release numerous effector molecules that are well described for their ability to promote detrimental inflammation in the context of allergies, asthma, mastocytosis and mast cell activation syndrome. Despite the clinical need, therapeutic strategies to target mast cell responses and reduce mast cell activation remain limited.
  • Mast cell progenitors that express high levels of the enzyme Carbonic anhydrase (Car)1 were recently identified. Using these cells, it was demonstrated that targeting Car1 with the inhibitor methazolamide (MZ) was sufficient to prevent mast cell development and mast cell-mediated inflammation.
  • Car Carbonic anhydrase
  • PCT/US2023/082927 discloses more potent Car1 inhibitors, such as those shown in Table B of the present disclosure or (4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3- yl)benzenesulfonamide (CAR0037)), which can more efficiently inhibits mast cell responses as compared to MZ.
  • Compounds of Formula I, II, or III herein can have similar or better efficacy in inhibiting carbonic anhydrase than MZ and can be used for the treatment of mast cell- mediated inflammation and other mast-cell mediated diseases or conditions.
  • the reaction mixture was cooled to room temperature and diluted by water (40 mL), extracted with ethyl acetate (40 mL * 2). The combined organics were washed with brine (40 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash column (ISCO 20 g silica, 20-70 % ethyl acetate in petroleum ether, gradient over 20 min).
  • the reaction mixture was cooled to room temperature.50 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (50 mL*2) and the combined extracts was dried with anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure to give a residue.
  • the reaction mixture was cooled to room temperature.10 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (20 mL*2) and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue.
  • the residue was purified by flash column (ISCO 4 g silica, 0- 20 % ethyl acetate in petroleum ether, gradient over 20 min).
  • Example 6 Synthesis of Compound NEM-33A and NEM-40A (2) [0244] AT - 75 °C, precooled N-isopropylpropan-2-amine (2.52 g, 24.90 mmol, 3.52 mL, 2 eq) in THF (20 mL), furan (20 mL) and 1-bromo-4-(trifluoromethoxy)benzene (3 g, 12.45 mmol, 1.85 mL, 1 eq) were consecutively added dropwise to n-BuLi (2.5 M, 9.96 mL, 2 eq) in 20 min. The mixture was allowed to warm up to 20°C. The mixture was quenched with 1 N HCl aq.10 mL.
  • Example 8 Synthesis of Compound NEM-43A [0254] To a solution of 4-bromo-3,5-difluoro-benzoic acid (2 g, 8.44 mmol, 1 eq) in THF (20 mL) was added dropwise BH3.THF (1 M, 25.32 mL, 3 eq) at 0°C over 15 min. After addition, the mixture was stirred at this temperature for 30 min then stirred at 20°C for 5 hr. The mixture was cooled to 0°C and quenched with MeOH (5 mL), then diluted with H 2 O 30 mL and extracted with ethyl acetate 90 mL (30mL * 3).
  • the reaction mixture was concentrated under reduced pressure to remove 2-methylbutan-2-ol.
  • the residue was diluted with water (5 mL) and extracted with ethyl acetate (5 mL*3). The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash column (ISCO 8 g silica, 0-50 % ethyl acetate in petroleum ether, gradient over 20 min).
  • the mixture was stirred at 80°C for 12 h.20 mL of water was added to the mixture.
  • the mixture was extracted with dichloromethane (10 mL*2) and the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue.
  • the crude product was purified by flash column (ISCO 10 g silica, 0 ⁇ 60% ethyl acetate in petroleum ether, gradient over 30 min).
  • reaction mixture was bubbled with N 2 for a while and heated to 90°C, stirred for 12 h under N 2 atmosphere.3 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (5 mL*2) and the combined extracts was dried with anhydrous Na 2 SO 4 and filtered, the filtrate was concentrated under reduced pressure to give a residue.
  • the residue was purified by flash column (ISCO 4 g silica, 0-45% ethyl acetate in petroleum ether, gradient over 20 min).
  • the resulting mixture was stirred at -70 °C for 1 hr.
  • the reaction was poured into ice NH 4 Cl aq.10 ml at 0 °C.
  • the mixture was extracted with ethyl acetate (30 mL*2), the combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash column (ISCO 20 g silica, 0-20 % ethyl acetate in petroleum ether, gradient over 20 min).
  • Example 24 Synthesis of Compound NEM-69A benzenesulfonamide (2) [0310] To a solution of 4-bromo-N-tert-butyl-benzenesulfonamide (1.29 g, 4.42 mmol, 2 eq) in THF (5 mL) was added dropwise n-BuLi (2.5 M, 3.54 mL, 4 eq) at -70 °C over 10 min. After addition, the mixture was stirred at this temperature for 20 min, and then 5- bromoindoline-2,3-dione (500 mg, 2.21 mmol, 1 eq) in THF (5 mL) was added dropwise at - 70 °C.
  • the resulting mixture was stirred at -70 °C for 3 hr.
  • the reaction was poured into ice NH4Cl aq.50 ml at 0 °C.
  • the mixture was extracted with ethyl acetate (45 mL*2), the combined extracts were washed with brine (50 mL), dried with anhydrous Na 2 SO 4 and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash column (ISCO 20 g silica, 0-60 % ethyl acetate in petroleum ether, gradient over 20 min).
  • Example 25 Synthesis of Compound NEM-70A Synthesis of 4-[4-(chloromethyl)phenyl]pyridine (2) [0316] To a solution of [4-(4-pyridyl)phenyl]methanol (1 g, 5.40 mmol, 1 eq) in DCM (10 mL) was added dropwise SOCl 2 (3.21 g, 26.99 mmol, 1.96 mL, 5 eq) at 0°C. The resulting mixture was stirred at 25°C for 2 hr. The product fraction was evaporated under reduced pressure. Compound 4-[4-(chloromethyl)phenyl]pyridine (1 g, crude) was obtained as a white solid which was used in next step without purification.
  • the mixture was stirred at 60°C for 12 hr.20 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (10 mL*2), and the combined extracts were washed with brine (20 mL), dried with anhydrous Na 2 SO 4 and filtered, the filtrate was concentrated under reduced pressure to give a residue.
  • the crude product was purified by flash column (ISCO 5 g silica, 0 ⁇ 50% ethyl acetate in petroleum ether, gradient over 30 min).
  • Example 26 Synthesis of Compound NEM-71A pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (2) [0319] To a solution of N-tert-butyl-4-(5-chloro-3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (200 mg, 506.49 ⁇ mol, 1 eq) in DMF (3 mL) was added K 2 CO 3 (210.00 mg, 1.52 mmol, 3 eq) and 4-[4-(chloromethyl)phenyl]pyridine (123.79 mg, 607.79 ⁇ mol, 1.2 eq). The mixture was stirred at 60°C for 2 h.
  • Example 33 Synthesis of Compound NEM-80A O O O O S S O O S Cl N O N H H N HO N N yl]benzenesulfonamide (2) [0342] To a solution of 4-bromo-N-tert-butyl-benzenesulfonamide (1.26 g, 4.33 mmol, 2 eq) in THF (10 mL) was added dropwise n-BuLi (2.5 M, 3.46 mL, 4 eq) at -70°C under N 2 atmosphere.
  • Example 34 Synthesis of Compound NEM-81A [0345] To a solution of (5-bromothiazol-2-yl)methanol (1 g, 5.15 mmol, 1 eq) in DCM (10 mL) was added SOCl2 (1.23 g, 10.31 mmol, 748.58 ⁇ L, 2 eq) at 0°C, the reaction was stirred at 25°C for 2 h. The reaction was concentrated under reduce pressure.5-bromo-2- (chloromethyl) thiazole (1 g, crude) was obtained as a red solid which was used directly without purification.
  • the reaction mixture was cooled to room temperature.20 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (40 mL*2). The combined extracts were dried with anhydrous Na 2 SO 4 and concentrated under reduced pressure to give a residue.
  • reaction mixture was bubbled with N2 for a while and heated to 90°C and stirred for 12 h under N 2 atmosphere.
  • the reaction mixture was cooled to room temperature.10 mL of water was added to the mixture and the mixture was extracted with ethyl acetate (20 mL*2).
  • the combined extracts were dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash column (ISCO 4 g silica, 0- 35 % ethyl acetate in petroleum ether, gradient over 20 min).
  • N-tert-butyl-4-[3-hydroxy-2- oxo-1-[[5-(4-pyridyl)thiazol-2-yl]methyl]indolin-3-yl]benzenesulfonamide (240 mg, 425.19 ⁇ mol, 38.02% yield, 94.72% purity) was obtained as a yellow solid.
  • Example 36 Synthesis of Compound NEM-84A [0356] A mixture of (2-chloropyrimidin-5-yl)methanol (1 g, 6.92 mmol, 1 eq), 4- pyridylboronic acid (1.28 g, 10.38 mmol, 1.5 eq), Pd(dppf)Cl2 (506.16 mg, 691.76 ⁇ mol, 0.1 eq), Na2CO3 (1.47 g, 13.84 mmol, 2 eq) in dioxane (10 mL) and H2O (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 5 hr under N2 atmosphere.20 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (20 mL*2).
  • Example 40 Synthesis of Compound NEM-89A tert-butyl-benzenesulfonamide (3)
  • N-tert-butyl-4-(6-chloro-3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide 150 mg, 379.87 ⁇ mol, 1 eq
  • 1-bromo-4-(bromomethyl)benzene 113.93 mg, 455.84 ⁇ mol, 1.2 eq
  • K 2 CO 3 131.25 mg, 949.68 ⁇ mol, 2.5 eq
  • the reaction was stirred at 60°C for 3 h.3 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (10 mL*3) and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue.
  • Example 41 Synthesis of Compound NEM-91A a g, g, 36.58 mmol, 3.05 mL, 3 eq) in dioxane (30 mL) were added SPhos Pd G3 (951.40 mg, 1.22 mmol, 0.1 eq) and NaOtBu (2 M, 12.19 mL, 2 eq). The reaction mixture was degassed with N2 for three times.
  • the reaction mixture was cooled to room temperature.
  • N-tert-butyl-4-(6-chloro-3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (550 mg, 988.93 ⁇ mol, 17.96% yield) was obtained as a yellow solid.
  • the mixture was stirred at 60°C for 12 h.5 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (5 mL*2) and the combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated to give a residue.
  • the crude product was purified by flash column (ISCO 2 g silica, 0 ⁇ 50% ethyl acetate in petroleum ether, gradient over 30 min).
  • the mixture was stirred at 60°C for 5 hr.20 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (10 mL*2) and the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated to give a residue.
  • the crude product was purified by flash column (ISCO 4 g silica, 0 ⁇ 50% ethyl acetate in petroleum ether, gradient over 30 min).
  • the resulting mixture was stirred at 25°C for 2 hr.
  • the mixture was poured ice NH4Cl (5 ml) under N2. 10mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (15 mL*3) and the combined extracts were washed with brine (10 mL), dried with anhydrous Na 2 SO 4 and filtered, the filtrate was concentrated under reduced pressure to give a residue.
  • the crude product was purified by flash column (ISCO 10 g silica, 0 ⁇ 50% ethyl acetate in petroleum ether, gradient over 30 min).
  • the resulting mixture was stirred at 0°C for 2 h under N 2 atmosphere.
  • the mixture was quenched by H2O at 0°C and stirred for 10 min.
  • the resultant mixture was filtered and the filter cake was rinsed with THF (15 mL x 3).
  • the combined extracts were was extracted with Ethyl acetate (15 mL*2) and the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue.
  • the crude product was purified by flash column (ISCO 5 g silica, 0 ⁇ 30% ethyl acetate in petroleum ether, gradient over 30 min).
  • the mixture was stirred at 60°C for 12 h.20 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (10 mL*2) and the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated to give a residue.
  • the crude product was purified by flash column (ISCO 10 g silica, 0 ⁇ 50% ethyl acetate in petroleum ether, gradient over 30 min).
  • the mixture was stirred at 60°C for 3 hr.5 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (10 mL*2), and the combined extracts were washed with brine (10 mL), dried with anhydrous Na 2 SO 4 and filtered, the filtrate was concentrated under reduced pressure to give a residue.
  • the crude product was purified by flash column (ISCO 2 g silica, 0 ⁇ 50% ethyl acetate in petroleum ether, gradient over 30 min).
  • the crude product was purified by SFC (column: ChiralPak IH, 250*30mm, 10um;mobile phase: [CO2- EtOH];B%:50%, isocratic elution mode.4-[3-hydroxy-2-oxo-1-[[4-(3,3,4,4- tetrafluoropyrrolidin-1-yl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (1 mg, 1.87 ⁇ mol, 1.84% yield, 100% purity) was obtained.
  • Example 62 Synthesis of Compound NEM-117A - indolin-3-yl]benzenesulfonamide (2) [0439] A mixture of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N- tert-butyl-benzenesulfonamide (100 mg, 188.88 ⁇ mol, 1 eq), isoindoline (27.01 mg, 226.65 ⁇ mol, 25.72 ⁇ L, 1.2 eq), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy- palladium;dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (34.24 mg, 37.78 ⁇ mol, 0.2 eq), sodium; 2-methylpropan-2-olate (2 M, 188.88 ⁇ L, 2 e
  • the reaction mixture was degassed with N 2 for three times. The mixture was heated to 90°C and stirred for 12 h under N2 atmosphere. 10 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (20 mL*2) and the combined extracts was dried with anhydrous Na 2 SO 4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0-25 % ethyl acetate in petroleum ether, gradient over 20 min).
  • the mixture was heated to 80°C and stirred for 12 h under N 2 atmosphere.20 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (30 mL*2) and the combined extracts was dried with anhydrous Na 2 SO 4 and filtered, the filtrate was concentrated under reduced pressure to give a residue.
  • the residue was purified by flash column (ISCO 20 g silica, 0-20 % ethyl acetate in petroleum ether, gradient over 20 min).
  • the reaction was cooled to room temperature.
  • the mixture was diluted by water (2 mL), extracted with dichloromethane (2 mL * 2).
  • the combined organics were washed with brine (3 mL), dried over Na 2 SO 4 , filtered and the reaction mixture was concentrated under reduced pressure to give a residue.
  • the residue was purified by preparative HPLC (column: Waters Xbridge BEH C18100*25mm*10um;mobile phase: [H 2 O(10mM NH 4 HCO 3 )-ACN];gradient:25%- 60% B over 8.0 min).
  • N-tert-butyl-4-[3-hydroxy-1-(1,8- naphthyridin-3-ylmethyl)-2-oxo-indolin-3-yl]benzenesulfonamide (27 mg, crude) was obtained as a yellow solid.
  • Example 75 Synthesis of Compound NEM-135A [0471] A mixture of 6-bromoquinazoline (1 g, 4.78 mmol, 1 eq), tributylstannylmethanol (1.84 g, 5.74 mmol, 1.2eq), [2-(2-aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)- butyl-phosphane;methanesulfonate (348.38 mg, 478.37 ⁇ mol, 0.1 eq) in dioxane (20 mL) was degassed and purged with N 2 for 3 times and then the mixture was stirred at 110°C for 12 hr under N2 atmosphere.
  • the mixture was stirred at 60°C for 12hr.5 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (3 mL*2) and the combined extracts were washed with brine (5 mL), dried with anhydrous Na 2 SO 4 and filtered, the filtrate was concentrated under reduced pressure to give a residue.
  • the crude product was purified by flash column (ISCO 4 g silica, 0 ⁇ 60% ethyl acetate in petroleum ether, gradient over 30 min).
  • Example 76 Synthesis of Compound NEM-136A [0475] A mixture of 6-bromo-1H-quinolin-2-one (500 mg, 2.23 mmol, 1 eq), tributylstannylmethanol (859.84 mg, 2.68 mmol, 1.2 eq), [2-(2- aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl-phosphane;methanesulfonate (162.52 mg, 223.16 ⁇ mol, 0.1 eq) in dioxane (13 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 110°C for 12hr under N2 atmosphere.
  • the mixture was stirred at 60°C for 12 hr.5 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (5 mL*2), and the combined extracts were washed with brine (5 mL), dried with anhydrous Na 2 SO 4 and filtered, the filtrate was concentrated under reduced pressure to give a residue.
  • the crude product was purified by flash column (ISCO 4 g silica, 0 ⁇ 80% ethyl acetate in petroleum ether, gradient over 30 min).
  • Example 77 Synthesis of Compound NEM-138A [0479] To a solution of methyl 2-chloroquinoline-6-carboxylate (1 g, 4.51 mmol, 1 eq) in THF (20 mL) was added LiAlH4 (2.5 M, 3.61 mL, 2 eq) at 0°C under N 2 atmosphere. The resulting mixture was stirred at 0°C for 2 hr under N 2 atmosphere. The mixture was quenched by Na2SO4.10H2O at 0°C and stirred for 10 min. The resultant mixture was filtered and the filter cake was rinsed with dichloromethane (5 mL x 3). Then the combined filtrates were concentrated under reduced pressure to give as yellow solid.
  • LiAlH4 2.5 M, 3.61 mL, 2 eq
  • the mixture was stirred at 60 °C for 12hr.10 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (10 mL*2) and the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue.
  • the crude product was purified by flash column (ISCO 10 g silica, 0 ⁇ 60% ethyl acetate in petroleum ether, gradient over 10 min).
  • Stopped-flow IC50 values were established using an SX20 stopped-flow spectrometer from Applied Biophysics. In one syringe of the SX20, recombinant human Car1 was kept at a concentration of 9 ⁇ M in a sodium phosphate buffer and inhibitors were added to this solution at 0 nM, 10 nM, 20 nM, 80 nM and 100 nM. In a second syringe, a saturated CO2 solution was mixed with 0.2 mM phenol red.
  • Trichinella spiralis infection Mice were infected with 500 T. spiralis muscle stage larvae by oral gavage and were treated with vehicle (1:5, DMSO/PBS), 10-120 mg/kg MZ, or a test compound at 10-40 mg/kg, i.p. daily; mice were sacrificed between on day 10- post infection and mast cell responses in the small intestine were evaluated by esterase staining as described previously (Henry, E.K., et al., J Exp Med, 2016.213(9): p.1663-73).
  • MZ was used as a positive control at 30 ug/mL (126.97 uM) (its peak effective range based on a previous study (Henry, E.K., et al., J Exp Med, 2016.213(9): p.1663-73)).
  • Treatment with IL-3 resulted in increased mast cell numbers compared to media treated controls.
  • treatment with MZ resulted in significantly decreased mast cell numbers as previously reported (Henry, E.K., et al., J Exp Med, 2016. 213(9): p.1663-73).
  • Efficacies of compounds in inhibiting Car1 enzyme activity can be tested using the sopped-flow assay herein.
  • mice were infected with T. spiralis and treated with either vehicle, MZ or a test compound and intestinal mast cells were quantified via esterase staining and histological analysis (Henry, E.K., et al., J Exp Med, 2016.213(9): p.1663-73). As reported previously, mice infected with T.
  • POI of further Car enzyme inhibitors at 10 uM* POI on MC# POI on MC# Compound # 10 uM Compound # 10 uM NEM-77A 58.00 NEM-141A 35.00 NEM-78A 100.00 NEM-142A 97.00 up to 100%.
  • uM refers to micromolar or ⁇ M. Some of the compounds tested show a POI of 0 or a negative value; most of these compounds when tested in higher concentrations, show a positive POI. ** CAR-037 is 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide, shown here for comparison purposes.
  • mast cells are strategically positioned at barrier surfaces and are robust producers of inflammatory molecules in response to diverse stimuli (Voehringer, D., Nat Rev Immunol, 2013.13(5): p.362-75).
  • mast cells are critical players in several disease states including allergies, asthma, mastocytosis, mast cell activation syndrome and deadly anaphylaxis reactions (Henry, E.K., et al., J Exp Med, 2016. 213(9): p.1663-73; Voehringer, D., Nat Rev Immunol, 2013.13(5): p.362-75).

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Abstract

Provided herein are novel compounds, such as a compound of Formula I, as well as compositions comprising the novel compounds herein. The compounds are typically carbonic anhydrase inhibitors and are useful for the prophylactic or therapeutic treatment of a disease or condition mediated by a carbonic anhydrase enzyme.

Description

CARBONIC ANHYDRASE ENZYME INHIBITORS AND METHODS OF USE THEREOF CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority to U.S. Provisional Application Nos: 63/658,145, filed June 10, 2024, and 63/659,108, filed June 12, 2024, the entire contents of each of which are herein incorporated by reference. GOVERNMENT FUNDING [0002] This invention was made with government support under contract 1R43TR004219-01, awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND [0003] Mast cell-related diseases, such as allergies/allergic inflammation, mastocytosis, mast cell activation syndrome and anaphylaxis, are increasingly common. For example, allergic diseases have risen to epidemic proportions in developed areas of the world, and it is now estimated that 30-40% of the global population suffer from one or more allergic diseases, including atopic dermatitis, asthma and food allergies (Pawankar, et al., WAO White Book on Allergy 2011-2012: Executive Summary. World Allergy Organization (2012)). There are limited treatment options for patients suffering from chronic allergic inflammation and many of them have significant side effects (Bauer, et al., J Allergy Clin Immunol 135, 312-323 (2015)). For example, allergies and asthma are most commonly treated with steroids; however, it is well known that steroids have a limited effect in treating these disease states. Further, diseases such as mastocytosis and mast cell activation syndrome (MCAS) have very few effective treatments. Therefore, a compound that can effectively inhibit mast cell development and mast cell-mediated inflammation would fill an important clinical need. [0004] While the cellular pathways and growth factors that regulate mast cell responses have been challenging to detect, a unique mast cell progenitor cell defined by its expression of the enzyme Carbonic anhydrase (Car) 1, was recently identified (Henry, E.K., et al., J Exp Med, 2016.213(9): p.1663-73; Inclan-Rico, J.M., et al., PLoS Pathogens, 2020.16(5): p. e1008579; Voehringer, D., Nat Rev Immunol, 2013.13(5): p.362-75; Dahlin, J.S. and J. Hallgren, Mol Immunol, 2015.63(1): p.9-17). It was demonstrated that genetically or pharmacologically targeting Car1 via CRIPS/Cas9 technology or the use of Car enzyme inhibitors was sufficient to prevent murine mast cell responses in vitro. Further, targeting Car1 via Car enzyme inhibitors was also sufficient to prevent human mast cell development in culture assays (Henry, E.K., et al., J Exp Med, 2016.213(9): p.1663-73). Moreover, it was shown that targeting Car1 with Car enzyme inhibitors was sufficient to prevent murine mast cell responses and mast cell-mediated inflammation in vivo (Id.). Collectively, these data suggest that Car1 may be a therapeutic target for treating mast cell-related diseases. [0005] There are several FDA-approved Carbonic anhydrase inhibitors that are actively used in clinics. Among these inhibitors is methazolamide (MZ). MZ is capable of inhibiting mast cell development and mast cell mediated-inflammation at a high dose. There is a need for new carbonic anhydrase inhibitors, such as those with improved potency and/or selectivity (e.g., for use in the treatment of allergic inflammation and other mast cell- associated disorders). SUMMARY [0006] International Application No. PCT/US2023/082927, filed December 7, 2023, discloses certain novel compounds as carbonic anhydrase inhibitors, the content of PCT/US2023/082927 is herein incorporated by reference in its entirety. [0007] In various embodiments, the invention provides novel compounds that are carbonic anhydrase inhibitors, such as carbonic anhydrase 1 inhibitors, which are useful for treating diseases or conditions mediated by carbonic anhydrase, such as mastocytosis, mast cell-mediated inflammation, allergic diseases, bacterial infections, fungal infections and viral infections. [0008] In some embodiments, the present disclosure provides a compound according to Formula I, or a pharmaceutically acceptable salt thereof: , Formula I wherein the variables are defined herein. In some embodiments, the compound of Formula I can have a structure according to a subformula of Formula I, such as Formula I-A, I-B, I-C, I-D, I-E1, I-E2, I-A1, I-1, or I-1a, as defined herein. [0009] In some embodiments, the present disclosure provides a compound according to Formula II, or a pharmaceutically acceptable salt thereof: , wherein the variables are defined herein. [0010] In some embodiments, the present disclosure provides a compound according to Formula III, or a pharmaceutically acceptable salt thereof: , wherein the variables the compound of Formula III can have a structure according to a subformula of Formula III, such as Formula III-A or III-1, as defined herein. [0011] In some embodiments, the present disclosure provides a compound selected from Table A herein, or a pharmaceutically acceptable salt thereof. [0012] In some embodiments, the invention also provides a pharmaceutical composition comprising a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0013] Certain embodiments provide a method of inhibiting a carbonic anhydrase enzyme in vitro or in vivo comprising contacting the carbonic anhydrase enzyme with an effective amount of a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, or a pharmaceutically acceptable salt thereof. [0014] Certain embodiments provide a method of treating a disease or condition mediated by a carbonic anhydrase enzyme in a mammal (e.g., a human), comprising administering a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, to the mammal. [0015] Certain embodiments provide a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, for the prophylactic or therapeutic treatment of a disease or condition mediated by a carbonic anhydrase enzyme. [0016] Certain embodiments provide the use of a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating a disease or condition mediated by a carbonic anhydrase enzyme. [0017] In some embodiments, the invention also provides a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, for use in medical therapy. [0018] In some embodiments, the invention also provides a pharmaceutical composition comprising a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of of a disease or condition mediated by a carbonic anhydrase enzyme. [0019] In some embodiments, the invention also provides processes and intermediates disclosed herein that are useful for preparing a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a salt thereof. [0020] It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and are not restrictive of the invention herein. DETAILED DESCRIPTION [0021] The present disclosure generally relates to novel carbonic anhydrase inhibitors, such as carbonic anhydrase 1 inhibitors. [0022] International Application No. PCT/US2023/082927, filed December 7, 2023, discloses that certain novel compounds therein can inhibit carbonic anhydrase in vitro and/or in vivo and in some cases with similar or better efficacy than certain FDA-approved carbonic anhydrase inhibitor such as methazolamide. [0023] In various embodiments, the present disclosure provides novel compounds that can act as carbonic anhydrase inhibitors, which are useful for treating various diseases or disorders herein, such as mastocytosis, mast cell-mediated inflammation, various allergic diseases, osteoarthritis, ankylosing spondylitis, or neuropathic pain, etc. In embodiments, the novel compounds herein can also have favorable ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles, for example, a good aqueous solubility, metabolic stability, etc., and can be suitable for further pharmaceutical developments for treating the various diseases or disorders herein. Definitions [0024] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains. [0025] It is meant to be understood that proper valences are maintained for all moieties and combinations thereof. [0026] It is also meant to be understood that a specific embodiment of a variable moiety herein can be the same or different as another specific embodiment having the same identifier. [0027] The present disclosure encompasses all combinations of the aspects and/or embodiments of the disclosure herein. It is understood that any and all embodiments of the present disclosure may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the embodiments is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment. [0028] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987. The disclosure is not intended to be limited in any manner by the exemplary listing of substituents described herein. [0029] When a range of values is listed, it is intended to encompass each value and sub– range within the range. For example “C1–6” is intended to encompass, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6. [0030] The following definitions are used, unless otherwise described: halo or halogen is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to. [0031] The term "alkyl", by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e., C1-8 means one to eight carbons). Examples include (C1- C8)alkyl, (C2-C8)alkyl, C1-C6)alkyl, (C2-C6)alkyl and (C3-C6)alkyl. Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n- pentyl, n-hexyl, n-heptyl, n-octyl, and higher homologs and isomers. [0032] The term "alkoxy" refers to an alkyl groups attached to the remainder of the molecule via an oxygen atom (“oxy”). [0033] The term “cycloalkyl” refers to a saturated or partially unsaturated (non-aromatic) all carbon ring having 3 to 8 carbon atoms (i.e., (C3-C8)carbocycle). The term also includes multiple condensed, saturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings). Accordingly, carbocycle includes multicyclic carbocyles such as a bicyclic carbocycles (e.g., bicyclic carbocycles having about 3 to 15 carbon atoms , about 6 to 15 carbon atoms, or 6 to 12 carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g., tricyclic and tetracyclic carbocycles with up to about 20 carbon atoms). The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. For example, multicyclic carbocyles can be connected to each other via a single carbon atom to form a spiro connection (e.g., spiropentane, spiro[4,5]decane, etc), via two adjacent carbon atoms to form a fused connection (e.g., carbocycles such as decahydronaphthalene, norsabinane, norcarane) or via two non-adjacent carbon atoms to form a bridged connection (e.g., norbornane, bicyclo[2.2.2]octane, etc.). Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptane, pinane, and adamantane. [0034] The term “aryl” as used herein refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl includes a phenyl radical. Aryl also includes multiple condensed carbon ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., cycloalkyl). The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the point of attachment of a multiple condensed ring system, as defined above, can be at any position of the ring system including an aromatic or a carbocycle portion of the ring. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, indanyl, naphthyl, 1, 2, 3, 4- tetrahydronaphthyl, anthracenyl, and the like. [0035] The term “heteroaryl” as used herein, unless specified to have a different ring size, refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5–10 membered heteroaryl”). Ring sulfur and nitrogen atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, and thiadiazolyl. In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl). [0036] As used herein, the term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched-chain alkyl group, e.g., having from 2 to 14 carbons, such as 2 to 10 carbons in the chain, one or more of the carbons has been replaced by a heteroatom selected from S, O, P and N, and wherein the nitrogen, phosphine, and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. The heteroatom(s) S, O, P and N may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. When the heteroalkyl is said to be substituted, the substituent(s) can replace one or more hydrogen atoms attached to the carbon atom(s) and/or the heteroatom(s) of the heteroalkyl. In some embodiments, the heteroalkyl is a C1-4 heteroalkyl, which refers to the heteroalkyl defined herein having 1-4 carbon atoms. Examples of C1-4 heteroalkyl include, but are not limited to, C4 heteroalkyl such as -CH2-CH2-N(CH3)-CH3, C3 heteroalkyl such as -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2- CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, C2 heteroalkyl such as -CH2-CH2-OH, -CH2-CH2- NH2, -CH2-NH(CH3), -O-CH2-CH3 and C1 heteroalkyl such as, -CH2-OH, -CH2-NH2, -O- CH3. Preferably, the C1-4 heteroalkyl (or C1-4 heteroalkylene) herein contains 1 or 2 heteroatoms, such as one oxygen, one nitrogen, two oxygens, two nitrogens, or one oxygen and one nitrogen. Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-O-CH2-CH2- and –O-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. Where "heteroalkyl" is recited, together with recitations of specific heteroalkyl groups, such as alkoxy or -NR'R'' or the like, it will be understood that the terms heteroalkyl and alkoxy or -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as alkoxy or -NR'R'' or the like. [0037] “Heterocyclyl” or “heterocyclic” as used by itself or as part of another group, unless specified to have a different ring size, refers to a radical of a 3– to 10–membered non– aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3–10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system, such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. [0038] As used herein, unless specified or otherwise contrary, a "ring structure", "cyclic structure", or simply "ring", with a designated number of ring members, such as a "3-10 membered ring structure", a "3-12 membered ring structure", or a "5- or 6-membered ring", should be understood as encompassing any ring structure (e.g., carbocyclic, heterocyclic, aryl, heteroaryl, etc.) having the designated number of ring members, which can be (1) monocyclic or polycyclic (as chemically feasible), such as a monocyclic ring or a bicyclic ring (including fused, spiro, and bridged bicyclic ring, and those ring systems where two monocyclic rings are connected through a single or double bond); (2) aromatic, partially unsaturated, or fully saturated; and in the case of a polycyclic structure, each ring can be independently aromatic, partially unsaturated, or fully saturated; and (3) contain no heteroatom or 1-4 heteroatoms; in the case of a polycyclic structure, each ring can independently have no ring heteroatom or 1-4 ring heteroatoms (e.g., O, N, S, etc.). When a ring is said to contain a ring sulfur or nitrogen atom, the sulfur or nitrogen atom can be optionally oxidized. One or more ring carbon atoms in a ring structure can be present as C(=O). A fully saturated ring refers to a ring in which none of the ring carbon and nitrogen (if present) atoms forms a double bond or triple bond with any other atom. The ring structure can be optionally substituted with one or more substituents described herein. The substituents of a ring structure herein can also have a cyclic structure, and in some cases, two substituents of a ring structure may be said to be joined to form a cyclic structure. [0039] The term “alkoxycarbonyl” as used herein refers to a group (alkyl)-O-C(=O)-, wherein the term alkyl has the meaning defined herein. [0040] The term “alkanoyloxy” as used herein refers to a group (alkyl)-C(=O)-O-, wherein the term alkyl has the meaning defined herein. [0041] The term “alkanoyl” as used herein refers to a group (alkyl)-C(=O)-, wherein the term alkyl has the meaning defined herein. [0042] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si). [0043] As commonly understood in the art, alkylene, alkenylene, alkynylene, heteroalkylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene refer to the corresponding divalent radicals of alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, respectively. [0044] An “optionally substituted” group, such as an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl group, or an optionally substituted ring structure, refers to the respective group that is unsubstituted or substituted. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent can be the same or different at each position. Typically, when substituted, the optionally substituted groups herein can be substituted with 1-5 substituents. Substituents can be a carbon atom substituent, a nitrogen atom substituent, an oxygen atom substituent or a sulfur atom substituent, as applicable. [0045] In a broad aspect, the permissible substituents herein include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a cycloalkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, an aryl, or a heteroaryl, each of which can be substituted, if appropriate. [0046] Exemplary substituents include, but not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl, - alkynylene-heteroaryl, —OH, hydroxyalkyl, haloalkyl, —O-alkyl, —O-haloalkyl, -alkylene- O-alkyl, —O-aryl, —O-alkylene-aryl, acyl, —C(O)-aryl, halo, —NO2, —CN, —SF5, — C(O)OH, —C(O)O-alkyl, —C(O)O-aryl, —C(O)O—alkylene-aryl, —S(O)-alkyl, —S(O)2- alkyl, —S(O)-aryl, —S(O)2-aryl, —S(O)-heteroaryl, —S(O)2-heteroaryl, —S-alkyl, —S- aryl, —S-heteroaryl, —S-alkylene-aryl, —S-alkylene-heteroaryl, —S(O)2-alkylene-aryl, — S(O)2-alkylene-heteroaryl, cycloalkyl, heterocycloalkyl, —O—C(O)-alkyl, —O—C(O)-aryl, —O—C(O)-cycloalkyl, —C(═N—CN)—NH2, —C(═NH)—NH2, —C(═NH)— NH(alkyl), —N(Y1)(Y2), -alkylene-N(Y1)(Y2), —C(O)N(Y1)(Y2) and —S(O)2N(Y1)(Y2), wherein Y1 and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and -alkylene-aryl. [0047] Some examples of suitable substituents include, but not limited to, (C1-C8)alkyl groups, (C2-C8)alkenyl groups, (C2-C8)alkynyl groups, (C3-C10)cycloalkyl groups, halogen (F, Cl, Br or I), halogenated (C1-C8)alkyl groups (for example but not limited to —CF3), — O—(C1-C8)alkyl groups, —OH, —S—(C1-C8)alkyl groups, —SH, —NH(C1-C8)alkyl groups, —N((C1-C8)alkyl)2 groups, —NH2, —C(O)NH2, —C(O)NH(C1-C8)alkyl groups, — C(O)N((C1-C8)alkyl)2, —NHC(O)H, —NHC(O) (C1-C8)alkyl groups, —NHC(O) (C3- C8)cycloalkyl groups, —N((C1-C8)alkyl)C(O)H, —N((C1-C8)alkyl)C(O)(C1-C8)alkyl groups, —NHC(O)NH2, —NHC(O)NH(C1-C8)alkyl groups, —N((C1-C8)alkyl)C(O)NH2 groups, — NHC(O)N((C1-C8)alkyl)2 groups, —N((C1-C8)alkyl)C(O)N((C1-C8)alkyl)2 groups, —N((C1- C8)alkyl)C(O)NH((C1-C8)alkyl), —C(O)H, —C(O)(C1-C8)alkyl groups, —CN, —NO2, — S(O)(C1-C8)alkyl groups, —S(O)2(C1-C8)alkyl groups, —S(O)2N((C1-C8)alkyl)2 groups, — S(O)2NH(C1-C8)alkyl groups, —S(O)2NH(C3-C8)cycloalkyl groups, —S(O)2NH2 groups, — NHS(O)2(C1-C8)alkyl groups, —N((C1-C8)alkyl)S(O)2(C1-C8)alkyl groups, —(C1-C8)alkyl- O—(C1-C8)alkyl groups, —O—(C1-C8)alkyl-O—(C1-C8)alkyl groups, —C(O)OH, — C(O)O(C1-C8)alkyl groups, NHOH, NHO(C1-C8)alkyl groups, —O-halogenated (C1- C8)alkyl groups (for example but not limited to —OCF3), —S(O)2-halogenated (C1-C8)alkyl groups (for example but not limited to —S(O)2CF3), —S-halogenated (C1-C8)alkyl groups (for example but not limited to —SCF3), —(C1-C6) heterocycle (for example but not limited to pyrrolidine, tetrahydrofuran, pyran or morpholine), —(C1-C6) heteroaryl (for example but not limited to tetrazole, imidazole, furan, pyrazine or pyrazole), -phenyl, —NHC(O)O—(C1- C6)alkyl groups, —N((C1-C6)alkyl)C(O)O—(C1-C6)alkyl groups, —C(═NH)—(C1-C6)alkyl groups, —C(═NOH)—(C1-C6)alkyl groups, or —C(═N—O—(C1-C6)alkyl)-(C1-C6)alkyl groups. [0048] Exemplary carbon atom substituents include, but are not limited to, deuterium, halogen, –CN, –NO2, –N3, hydroxyl, alkoxy, cycloalkoxy, aryloxy, amino, monoalkyl amino, dialkyl amino, amide, sulfonamide, thiol, acyl, carboxylic acid, ester, sulfone, sulfoxide, alkyl, haloalkyl, alkenyl, alkynyl, C3–10 carbocyclyl, C6–10 aryl, 3–10 membered heterocyclyl, 5–10 membered heteroaryl, etc. For example, exemplary carbon atom substituents can include F, Cl, -CN, –SO2H, –SO3H, –OH, –OC1–6 alkyl, –NH2, –N(C1–6 alkyl)2, –NH(C1–6 alkyl), –SH, –SC1–6 alkyl, –C(=O)(C1–6 alkyl), –CO2H, –CO2(C1–6 alkyl), –OC(=O)(C1–6 alkyl), –OCO2(C1–6 alkyl), –C(=O)NH2, –C(=O)N(C1–6 alkyl)2, – OC(=O)NH(C1–6 alkyl), –NHC(=O)(C1–6 alkyl), –N(C1–6 alkyl)C(=O)( C1–6 alkyl), – NHCO2(C1–6 alkyl), –NHC(=O)N(C1–6 alkyl)2, –NHC(=O)NH(C1–6 alkyl), –NHC(=O)NH2, –NHSO2(C1–6 alkyl), –SO2N(C1–6 alkyl)2, –SO2NH(C1–6 alkyl), –SO2NH2,–SO2C1–6 alkyl, – SO2OC1–6 alkyl, –OSO2C1–6 alkyl, –SOC1–6 alkyl, C1–6 alkyl, C1–6 haloalkyl, C2–6 alkenyl, C2–6 alkynyl, C3–10 carbocyclyl, C6–10 aryl, 3–10 membered heterocyclyl, 5–10 membered heteroaryl; or two geminal substituents can be joined to form =O. [0049] In some embodiments, unless specified or otherwise contrary from context, an optionally substituted group herein can be unsubstituted or substituted with 1-5 substituents, as valency permits, wherein, when substituted: (i) each substituent is independently selected from halo, hydroxy, cyano, nitro, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1- C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, and NReRf, wherein any (C1- C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C3-C6)cycloalkyl, and (C1- C6)alkoxy, wherein each Re and Rf is independently selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or Re and Rf together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino and piperidino is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl; or (ii) two of the substituents are joined to form a 3-10 membered ring and the remaining substituent(s) are as defined in (i). [0050] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, acyl groups, esters, sulfone, sulfoxide, C1–10 alkyl, C1–10 haloalkyl, C2–10 alkenyl, C2–10 alkynyl, C3–10 carbocyclyl, 3–14 membered heterocyclyl, C6–14 aryl, and 5–14 membered heteroaryl, or two substituent groups attached to a nitrogen atom are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be further substituted as defined herein. In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated by reference herein. Exemplary nitrogen protecting groups include, but not limited to, those forming carbamates, such as Carbobenzyloxy (Cbz) group, p-Methoxybenzyl carbonyl (Moz or MeOZ) group, tert-Butyloxycarbonyl (BOC) group, Troc, 9-Fluorenylmethyloxycarbonyl (Fmoc) group, etc., those forming an amide, such as acetyl, benzoyl, etc., those forming a benzylic amine, such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, etc., those forming a sulfonamide, such as tosyl, Nosyl, etc., and others such as p-methoxyphenyl. [0051] Exemplary oxygen atom substituents include, but are not limited to, acyl groups, esters, sulfonates, C1–10 alkyl, C1–10 haloalkyl, C2–10 alkenyl, C2–10 alkynyl, C3–10 carbocyclyl, 3–14 membered heterocyclyl, C6–14 aryl, and 5–14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be further substituted as defined herein. In certain embodiments, the oxygen atom substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, those forming alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyls such as 4-methoxybenzyl, methoxymethyl (MOM), benzyloxymethyl (BOM), 2–methoxyethoxymethyl (MEM), etc., those forming silyl ethers, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t- butyldimethylsilyl (TBDMS), etc., those forming acetals or ketals, such as tetrahydropyranyl (THP), those forming esters such as formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, etc., those forming carbonates or sulfonates such as methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts), etc. [0052] Unless expressly stated to the contrary, combinations of substituents and/or variables are allowable only if such combinations are chemically allowed and result in a stable compound. A “stable” compound is a compound that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject). [0053] As used herein, the term "protecting group" refers to a substituent that is commonly employed to block or protect a particular functional group on a compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9- fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis 4th edition, Wiley-Interscience, New York, 2006. [0054] As used herein a wavy line “ ” that intersects a bond in a chemical structure indicates the point of attachment of the bond that the wavy bond intersects in the chemical structure to the remainder of a molecule. [0055] The terms “treat”, “treatment”, or “treating” to the extent it relates to a disease or condition includes inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition. The terms “treat”, “treatment”, or “treating” also refer to both therapeutic treatment and/or prophylactic treatment or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as, for example, the development or spread of a bacterial infection, a fungal infection, a viral infection, mastocytosis, mast cell- mediated inflammation or an allergic disease. For example, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or disorder, stabilized (i.e., not worsening) state of disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable. “Treat”, “treatment”, or “treating,” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease or disorder as well as those prone to have the disease or disorder or those in which the disease or disorder is to be prevented. In one embodiment “treat”, “treatment”, or “treating” does not include preventing or prevention. [0056] The term "therapeutically effective amount" or "effective amount" is an amount sufficient to effect beneficial or desired results such as clinical results. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state. [0057] The term “mammal” refers to any mammalian species such as a human, mouse, rat, dog, cat, hamster, guinea pig, rabbit, livestock, and the like. Accordingly, in certain embodiments, the mammal is a human, mouse, rat, dog, cat, hamster, guinea pig, rabbit or livestock. In certain embodiments, the mammal is a patient (e.g., a human patient). In certain embodiments, the mammal is a pet, such a dog, cat, hamster, guinea pig or rabbit. In certain embodiments, the mammal is a livestock mammal (e.g., a cow, sheep, horse, pig, chicken, etc.). [0058] The term “food” as used herein refers to a substance that can be consumed, e.g., to provide nutritional or therapeutic support to an organism. The term may include, but is not limited to, proteins, carbohydrates, fats, therapeutic agents, such as medicines, etc. [0059] As used herein, the singular form “a”, “an”, and “the”, includes plural references unless it is expressly stated or is unambiguously clear from the context that such is not intended. [0060] The term “and/or” as used in a phrase such as “A and/or B” herein is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone). [0061] Headings and subheadings are used for convenience and/or formal compliance only, do not limit the subject technology, and are not referred to in connection with the interpretation of the description of the subject technology. Features described under one heading or one subheading of the subject disclosure may be combined, in various embodiments, with features described under other headings or subheadings. Further it is not necessarily the case that all features under a single heading or a single subheading are used together in embodiments. [0062] The compounds disclosed herein can also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention. [0063] It is understood by one skilled in the art that this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium (2H or D). As a non-limiting example, a -CH3 group may be substituted with -CD3. [0064] The pharmaceutical compositions of the invention can comprise one or more excipients. When used in combination with the pharmaceutical compositions of the invention the term “excipients” refers generally to an additional ingredient that is combined with the compound defined herein, or the pharmaceutically acceptable salt thereof to provide a corresponding composition. For example, when used in combination with the pharmaceutical compositions of the invention the term “excipients” includes, but is not limited to: carriers, binders, disintegrating agents, lubricants, sweetening agents, flavoring agents, coatings, preservatives, and dyes. [0065] Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. The “enantiomeric purity” of a substance herein can typically be expressed by the enantiomeric excess (“ee”), which can be calculated by subtracting the molar percentage of one enantiomer in the substance from the molar percentage of the other enantiomer, with the total percentages of both enantiomers being 100%. Thus, a substance containing 90% of one enantiomer and 10% of the other enantiomer has an enantiomeric purity of 80% ee. Enantiomeric excess can be determined by analytical methods known in the art, such as through chiral HPLC or SFC methods, NMR, or optical rotations. [0066] It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase. [0067] When a bond in a compound formula herein is drawn in a non-stereochemical manner (e.g. flat), the atom to which the bond is attached includes all stereochemical possibilities. When a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge), it is to be understood that the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted. In one embodiment, the compound may be at least 51% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 60% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 80% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% the absolute stereoisomer depicted. [0068] Specific values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. It is to be understood that two or more values may be combined. It is also to be understood that the values listed herein below (or subsets thereof) can be excluded. [0069] Specifically, (C1-C6)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso- butyl, sec-butyl, pentyl, 3-pentyl, or hexyl; (C3-C6)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (C1-C6)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (C1- C6)alkanoyl can be acetyl, propanoyl or butanoyl; (C1-C6)alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl; (C1-C6)alkanoyloxy can be formyloxy, acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy; and aryl can be phenyl, indenyl, or naphthyl. Formula I [0070] Some embodiments of the present disclosure are directed to compounds of Formula I, or a pharmaceutically acceptable salt thereof: , wherein: R1 is hydrogen, OH, or O-R1A, wherein R1A is an optionally substituted alkanoyl; R2 is hydrogen or an optionally substituted alkanoyl; n is 0, 1, 2, 3, or 4, preferably, 0 or 1, R3 at each occurrence is independently halogen, C1-4 alkyl optionally substituted with halogen, C1-4 alkoxy optionally substituted with halogen, NH2, NH(C1-4 alkyl), or N(C1-4 alkyl)(C1-4 alkyl); R4 and R5 are each independently hydrogen or C1-4 alkyl optionally substituted with halogen; or R4 and R5 together represent oxo (=O); X is N, CH, or CR7; R6 is an optionally substituted group selected from phenyl, 5 or 6-membered heteroaryl, or a 5-10 membered heterocyclic ring; j is 0, 1, 2, or 3, preferably, 0 or 1; and R7 at each occurrence is independently halogen, C1-4 alkyl optionally substituted with halogen, or C1-4 alkoxy optionally substituted with halogen. [0071] In some embodiments, the genus of Formula I as defined above, or a subgenus as defined herein, excludes any of the specific compounds shown in Table B herein that would otherwise fall within the defined genus. [0072] Without wishing to be bound by theories, it is believed that at least in some cases, it is preferable to have a stereoisomer of certain enantiomeric purity, which can for example, have a better efficacy and/or have a better ADMET profile. For example, in some embodiments, the compound of Formula I can have a stereochemistry according to Formula I-E1: , wherein the variables are ents, with respect to the chiral center to which R1 is attached, the compound of Formula I-E1 can have an enantiomeric purity of at least 60% enantiomeric excess (“ee”), such as an enantiomeric purity of at least 80% ee, at least 90% ee, at least 95% ee, at least 98% ee, at least 99% ee, or 99.5% ee or higher. [0073] In some embodiments, the compound of Formula I can have a stereochemistry according to Formula I-E2: , wherein the variables with respect to the chiral center to which R1 is attached, the compound of Formula I-E2 can have an enantiomeric purity of at least 60% enantiomeric excess (“ee”), such as an enantiomeric purity of at least 80% ee, at least 90% ee, at least 95% ee, at least 98% ee, at least 99% ee, or 99.5% ee or higher. [0074] Without wishing to be bound by theories, it is also believed that the stereochemistry of Formula I-E1 is more favored in comparison with that of Formula I-E2, at least in some cases were found to have a better efficacy and/or better ADMET profile. However, it should be understood that the present disclosure is not limited to stereochemically enriched compounds. Instead, the present disclosure encompasses mixtures of stereoisomers of the compounds herein in any ratio, such as a racemic mixture. [0075] Typically, in Formula I, R1 is hydroxy. [0076] In some embodiments, R1 can also be O-R1A, wherein R1A is an optionally substituted alkanoyl. When R1 in a compound is O-R1A, the R1A can be cleaved in vivo to generate the corresponding compound with R1 being hydroxy, and thus, such compound can act as a prodrug. Suitable alkanoyl groups are not particularly limited, which can for example be -C(O)-(C1-6 alkyl), such as acetyl, etc. Preferably, the corresponding acid, which can be generated in vivo from cleavage of O-R1A, is pharmaceutically acceptable. In some embodiments, the alkanoyl group can be substituted. For example, in some embodiments, R1A can be an acyl derived from an amino acid, such as a natural amino acid (e.g., a proteinogenic amino acid), for example, R1A can . [0077] In some embodiments, in Formula I, hydrogen. [0078] Typically, in Formula I, R2 is hydrogen. [0079] In some embodiments, R2 can also be an optionally substituted alkanoyl. In such embodiments, R2 in a compound can be cleaved in vivo to generate the corresponding compound with R2 being hydrogen, and thus, such compound can act as a prodrug. Suitable alkanoyl groups are not particularly limited, which can for example be -C(O)-(C1-6 alkyl), such as acetyl, etc. Preferably, the corresponding acid, R2-OH, which can be generated in vivo, is pharmaceutically acceptable. [0080] Typically, in Formula I, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. [0081] When n is not 0, R3 at each occurrence is typically independently selected from halogen, C1-4 alkyl optionally substituted with halogen, C1-4 alkoxy optionally substituted with halogen, or N(C1-4 alkyl)(C1-4 alkyl). It should be noted that the two C1-4 alkyl groups in “N(C1-4 alkyl)(C1-4 alkyl)” can be the same or different. Other similar expressions herein should be understood similarly. In some embodiments, n is not 0, and R3 at each occurrence can be independently F, Cl, methyl optionally substituted with F, or methoxy optionally substituted with F. [0082] In some embodiments, in Formula I, n is 1, and R3 is F, Cl, methyl optionally substituted with F (e.g., CH3 or CF3), or methoxy optionally substituted with F (e.g., OCF3). [0083] Typically, R4 and R5 in Formula I are independently hydrogen or C1-4 alkyl (e.g., methyl). In some embodiments, R4 is hydrogen or methyl. In some embodiments, R5 is hydrogen or methyl. In some specific embodiments, both R4 and R5 are hydrogen. In some embodiments, one of R4 and R5 in Formula I is hydrogen and the other of R4 and R5 in Formula I is defined herein, e.g., a methyl group. [0084] In some embodiments, in Formula I, R4 and R5 together can represent oxo (=O). [0085] In some embodiments, the compound of Formula I can have a structure according to Formula I-A: wherein X, R6, R7, and j are [0086] In some embodiments, the compound of Formula I can have a structure according to Formula I-B: wherein X, R4, R6, R7, and j are defined herein. [0087] In some embodiments, the compound of Formula I can have a structure according to Formula I-C: wherein X, R6, R7, and j are defined herein. [0088] In some embodiments, the compound of Formula I can have a structure according to Formula I-D: wherein X, R3, R4, R6, R7, are be understood that in Formula I-D, one R3 is present, which can be at any available position of the phenyl portion of the oxindole ring. Exemplary suitable substitution patterns are shown in the specific examples disclosed herein. [0089] In some embodiments, the compound of Formula I-A, I-B, I-C, or I-D can have a stereochemistry according to Formula I-E1. In some embodiments, the compound of Formula I-A, I-B, I-C, or I-D can have a stereochemistry according to Formula I-E2. [0090] For example, in some embodiments, the compound of Formula I-A can be characterized as having a structure according to Formula I-A1: In some embodiments, with respect the compound of Formula I-A1 can have an enantiomeric purity of at least 60% enantiomeric excess (“ee”), such as an enantiomeric purity of at least 80% ee, at least 90% ee, at least 95% ee, at least 98% ee, at least 99% ee, or 99.5% ee or higher. [0091] In some embodiments, in Formula I (such as a subformulae I-E1, I-E2, I-A, I-B, I-C, I-D, or I-A1), R6 is an optionally substituted phenyl. When substituted, the phenyl is typically substituted with 1-3 substituents, which can for example, be independently selected from halogen (e.g., F), OH, C1-4 alkyl, C1-4 alkoxy, C1-4 heteroalkyl, or 3-6 membered ring, wherein the C1-4 alkyl, C1-4 alkoxy, C1-4 heteroalkyl or 3-6 membered ring is optionally substituted with one or more substituents each independently halogen, CN, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, C1-4 alkoxy optionally substituted with 1-3 fluorine, or C3-4 cycloalkyl optionally substituted with 1 or 2 substituents each independently F or methyl. For example, in some embodiments, R6 can have a , wherein: k2 is 0, 1, 2, or 3, and G3 at each occurrence is independently F, Cl, C1-4 alkyl optionally substituted with 1-3 fluorine, C1-4 alkoxy optionally substituted with 1-3 fluorine, or C3-4 cycloalkyl optionally substituted with 1 or 2 substituents each independently F or methyl. In some embodiments, k2 is 0. In some embodiments, k2 is 1 or 2, and each G3 is independently F, Cl, or methyl optionally substituted with 1-3 fluorine. For example, in some specific embodiments, R6 can be 4-trifluoromethylphenyl. [0092] In some embodiments, in Formula I (such as a subformulae I-E1, I-E2, I-A, I-B, I-C, I-D, or I-A1), R6 is an optionally substituted 5 or 6-membered heteroaryl, such as pyridyl. When substituted, the 5 or 6-membered heteroaryl is typically substituted with 1-3 substituents as valency permits, which can for example, be independently selected from halogen (e.g., F), OH, C1-4 alkyl, C1-4 alkoxy, C1-4 heteroalkyl, or 3-6 membered ring, wherein the C1-4 alkyl, C1-4 alkoxy, C1-4 heteroalkyl or 3-6 membered ring is optionally substituted with one or more substituents each independently halogen, CN, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, C1-4 alkoxy optionally substituted with 1-3 fluorine, or C3-4 cycloalkyl optionally substituted with 1 or 2 substituents each independently F or methyl. [0093] For example, in some embodiments, in Formula I (such as a subformulae I-E1, I- E2, I-A, I-B, I-C, I-D, or I-A1), R6 can have a structure of , wherein: k2 is 0, 1, 2, or 3, and G3 at each occurrence is independently F, Cl, C1-4 alkyl optionally substituted with 1-3 fluorine, C1-4 alkoxy optionally substituted with 1-3 fluorine, or C3-4 cycloalkyl optionally substituted with 1 or 2 substituents each independently F or methyl. In some embodiments, k2 is 0. In some embodiments, k2 is 1 or 2, and each G3 is independently F, Cl, or methyl optionally substituted with 1-3 fluorine. For example, in some specific embodiments, R6 can . In some specific embodiments, R6 can be . In some specific embodiments, R6 can be . [0094] In some embodiments, in Formula I (such as a subformulae I-E1, I-E2, I-A, I-B, I-C, I-D, or I-A1), R6 can be pyrrolyl, which is optionally substituted, for example, with substituents independently selected from halogen (e.g., F), C1-4 alkyl optionally substituted with 1-3 fluorine, or a 3-6 membered ring optionally substituted with one or more substituents each independently halogen, CN, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, C1-4 alkoxy optionally substituted with 1-3 fluorine, or C3-4 cycloalkyl optionally substituted with 1 or 2 substituents each independently F or methyl. For example, in some specific embodiments, R6 can be difluoropyrrolyl, e.g., . [0095] In some embodiments, in Formula I (such as a subformulae I-E1, I-E2, I-A, I-B, I-C, I-D, or I-A1), R6 is an optionally substituted 5-10 membered heterocyclic ring. Typically, the 5-10 membered heterocyclic ring has one or two ring heteroatoms, which can be independently N, O, or S. In some embodiments, the 5-10 membered heterocyclic ring can be a monocyclic 5 or 6 membered ring having one or two ring heteroatoms, such as one or two ring nitrogen atoms. In some embodiments, the 5-10 membered heterocyclic ring can be a bicyclic ring having one or two ring heteroatoms, such as one or two ring nitrogen atoms. When substituted, the 5-10 membered heterocyclic ring can be substituted with 1-5 independently selected substituents, such as 1-5 independently selected RA as defined herein. [0096] In some preferred embodiments, the compound of Formula I (such as a subformulae I-E1, I-E2, I-A, I-B, I-C, I-D, or I-A1) can be characterized as having a structure according to Formula I-1: , wherein: X, R1, R2, R3, n, R4, R5, R7, and j are defined herein, k is 0, 1, 2, 3, or 4; and RA at each occurrence is independently F, OH, NH2, COOH, CONH2, GA, C(O)-GA, O-GA, NH-GA, N(C1-4 alkyl)-GA, C(O)-O-GA, C(O)-NH-GA, or C(O)-N(C1-4 alkyl)-GA; wherein GA at each occurrence is independently C1-4 alkyl or a 3-10 membered ring (more preferably, 3-8 membered ring, such as phenyl ring), wherein the C1-4 alkyl or 3-10 membered ring is optionally substituted, for example, with 1-3 substituents each independently a halogen, CN, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, C1-4 alkoxy optionally substituted with 1-3 fluorine, or a 3-6 membered ring optionally substituted with 1-3 G1, wherein G1 at each occurrence is independently halogen, oxo, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, or C1-4 alkoxy optionally substituted with 1-3 fluorine. [0097] In some embodiments, k in Formula I-1 is 0. [0098] In some embodiments, k in Formula I-1 is 1. [0099] In some embodiments, k in Formula I-1 is 2. [0100] In some embodiments, RA at each occurrence is independently F, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, or C1-4 alkoxy optionally substituted with 1-3 fluorine. [0101] In some embodiments, one RA is an optionally substituted 3-8 membered ring, such as an optionally substituted phenyl, and any remaining RA at each occurrence is independently F, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, or C1-4 alkoxy optionally substituted with 1-3 fluorine. [0102] In some embodiments, the compound of Formula I (such as a subformulae I-E1, I-E2, I-A, I-B, I-C, I-D, or I-A1) or I-1 can be characterized as having a structure according to Formula I-1a: , wherein: X, R1, R2, R3, n, R4, R5, R7, and j are defined herein, k1 is 0, 1, 2, 3, or 4; and G2 at each occurrence is independently halogen, CN, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, C1-4 alkoxy optionally substituted with 1-3 fluorine, or C3-4 cycloalkyl optionally substituted with 1 or 2 substituents each independently F or methyl. In some embodiments, k1 is 1-3, and G2 at each occurrence is independently F, Cl, or C1-4 alkyl optionally substituted with 1-3 fluorine. For example, in some specific embodiments, . as a subformulae I-E1, I-E2, I-A, I-B, I-C, I-D, or I-A1), R6 can be a fused, spiro, or bridged 6-10 membered bicyclic heterocyclic ring having 1-3 ring heteroatoms each independently N, S, or O, preferably, the 6-10 membered bicyclic heterocyclic ring has only one ring heteroatom, wherein the bicyclic heterocyclic ring is optionally substituted, for example, with 1-3 substituents each independently a halogen, CN, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, C1-4 alkoxy optionally substituted with 1-3 fluorine, or a 3-5 membered ring optionally substituted with 1-3 G1, wherein G1 at each occurrence is independently halogen, oxo, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, or C1-4 alkoxy optionally substituted with 1-3 fluorine. [0104] For example, in some embodiments, R6 can be selected from the following: , . I (such as a subformulae I-E1, I-E2, I-A, I-B, I-C, I-D, I-A1, I-1, or I- 1a), X is typically CH or CR7, wherein R7 is defined herein, e.g., R7 can be F. For example, in some preferred embodiments, X is CH. [0106] In some embodiments, in Formula I (such as a subformulae I-E1, I-E2, I-A, I-B, I-C, I-D, I-A1, I-1, or I-1a), X can also be N. [0107] The integer j in Formula I (such as a subformulae I-E1, I-E2, I-A, I-B, I-C, I-D, I- A1, I-1, or I-1a) is typically 0 or 1. In some preferred embodiments, j is 0. In some embodiments, j is 1. In some embodiments, R7 at each occurrence is independently F, Cl, C1-4 alkyl optionally substituted with F, or C1-4 alkoxy optionally substituted with F. Formula II [0108] Some embodiments of the present disclosure are directed to compounds of Formula II, or a pharmaceutically acceptable salt thereof: , wherein: R1 is hydrogen, OH, or O-R1A, wherein R1A is an optionally substituted alkanoyl; R2 is hydrogen or an optionally substituted alkanoyl; n is 0, 1, 2, 3, or 4, preferably, 0 or 1, R3 at each occurrence is independently halogen, C1-4 alkyl optionally substituted with halogen, C1-4 alkoxy optionally substituted with halogen, NH2, NH(C1-4 alkyl), or N(C1-4 alkyl)(C1-4 alkyl); R10 and R11 are each independently hydrogen, halogen, OH, NH2, GA, O-GA, NH-GA, or N(C1-4 alkyl)-GA; wherein GA at each occurrence is independently C1-4 alkyl or a 3-10 membered ring, wherein the C1-4 alkyl or 3-10 membered ring is optionally substituted, for example, with 1-3 substituents each independently a halogen, CN, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, C1-4 alkoxy optionally substituted with 1-3 fluorine, or a 3-6 membered ring optionally substituted with 1-3 substituents each independently halogen, oxo, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, or C1-4 alkoxy optionally substituted with 1-3 fluorine; m is 0, 1, 2, or 3, preferably, 0 or 1; and R12 at each occurrence is independently halogen, C1-4 alkyl optionally substituted with halogen, or C1-4 alkoxy optionally substituted with halogen. [0109] In some embodiments, the genus of Formula II as defined above, or a subgenus as defined herein, excludes any of the specific compounds shown in Table B herein that would otherwise fall within the defined genus. [0110] Suitable further definitions of R1, R2, R3, and n for Formula II can include any of those described herein in connection with Formula I or its subformulae, in any combinations. [0111] In some embodiments, R10 is hydrogen. [0112] In some embodiments, R10 is halogen. [0113] In some embodiments, R10 is GA, wherein GA is defined herein. In some embodiments, R10 is GA, wherein GA is C1-4 alkyl which is optionally substituted as described herein. In some embodiments, R10 is GA, wherein GA is a 3-10 membered ring, such as a 5 or 6 membered heterocyclic ring having one or two ring heteroatoms, such as one or two ring nitrogen atoms or one ring nitrogen and one ring oxygen atom, or a 5 or 6 membered heteroaryl, e.g., pyridyl, which can be optionally substituted as described herein. For example, in some embodiments, R10 can be . In some embodiments, R10 can be [0114] In some embodiments, R10 is O-GA, wherein GA is defined herein. In some embodiments, R10 is O-GA, wherein GA is C1-4 alkyl which is optionally substituted as described herein. For example, in some embodiments, R10 can be O-CF3. [0115] In some embodiments, R11 is hydrogen. [0116] In some embodiments, R11 is halogen. [0117] In some embodiments, R11 is GA, wherein GA is defined herein. In some embodiments, R11 is GA, wherein GA is a 3-10 membered ring, such as a 5 or 6 membered heterocyclic ring having one or two ring heteroatoms, such as one or two ring nitrogen atoms or one ring nitrogen and one ring oxygen atom, or a 5 or 6 membered heteroaryl, e.g., pyridyl, which can be optionally substituted as described herein. In some embodiments, R11 is GA, wherein GA is defined herein. In some embodiments, R11 is GA, wherein GA is C1-4 alkyl which is optionally substituted as described herein. [0118] In some embodiments, R11 is O-GA, wherein GA is defined herein. In some embodiments, R11 is O-GA, wherein GA is C1-4 alkyl which is optionally substituted as described herein. For example, in some embodiments, R11 can be O-CF3. [0119] Typically, R10 and R11 are different. For example, in some embodiments, one of R10 and R11 is hydrogen or halogen, and the other of R10 and R11 is GA or O-GA as defined herein. [0120] Typically, m in Formula II is 0. In some embodiments, m is 1 and R12 is halogen, C1-4 alkyl optionally substituted with F, or C1-4 alkoxy optionally substituted with F. Formula III [0121] Some embodiments of the present disclosure are directed to compounds of Formula III, or a pharmaceutically acceptable salt thereof: , wherein: R1 is hydrogen, OH, or O-R1A, wherein R1A is an optionally substituted alkanoyl; R2 is hydrogen or an optionally substituted alkanoyl; n is 0, 1, 2, 3, or 4, preferably, 0 or 1, R3 at each occurrence is independently halogen, C1-4 alkyl optionally substituted with halogen, C1-4 alkoxy optionally substituted with halogen, NH2, NH(C1-4 alkyl), or N(C1-4 alkyl)(C1-4 alkyl); R4 and R5 are each independently hydrogen or C1-4 alkyl optionally substituted with halogen; or R4 and R5 together represent oxo (=O); Ring E is a 5-membered heteroaryl ring, a 6-membered heteroaryl ring having 1 or 2 ring nitrogen, a bicyclic heteroaryl ring, or a 5-14 membered heterocyclic ring; j2 is 0, 1, 2, 3, or 4, as valency permits, preferably, 0 or 1; and R20 at each occurrence is independently halogen, OH, NH2, COOH, CONH2, GB, C(O)-GB, O-GB, NH-GB, N(C1-4 alkyl)-GB, C(O)-O-GB, C(O)-NH-GB, or C(O)-N(C1-4 alkyl)-GB; wherein GB at each occurrence is independently C1-4 alkyl or a 3-10 membered ring, wherein the C1-4 alkyl or 3-10 membered ring is optionally substituted, for example, with 1-3 substituents each independently a halogen, CN, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, C1-4 alkoxy optionally substituted with 1-3 fluorine, or a 3-6 membered ring optionally substituted with 1-3 substituents each independently halogen, oxo, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, or C1-4 alkoxy optionally substituted with 1-3 fluorine. [0122] In some embodiments, the genus of Formula III as defined above, or a subgenus as defined herein, excludes any of the specific compounds shown in Table B herein that would otherwise fall within the defined genus. [0123] Suitable further definitions of R1, R2, R3, R4, R5, and n for Formula III can include any of those described herein in connection with Formula I or its subformulae, in any combinations. [0124] For example, in some embodiments, the compound of Formula III can be characterized as having a structure according to Formula III-A: , Formula III-A, wherein Ring E, j2, and R20 are defined herein. [0125] In some embodiments, the compound of Formula III can be characterized as having a structure according to Formula III-B: O S NH2 O j2 , wherein Ring E, j2, R3, and R20 are defined herein. [0126] In some embodiments, Ring E in Formula III can be a monocyclic 5 or 6 membered heteroaryl, for example, an oxazole, thiazole, pyridine, pyrazine, pyrimidine ring, etc. [0127] For example, Ring E, together with the optional substituent(s) (R20)j2, are selected , 1-3 ring heteroatoms. For example, the bicyclic heteroaryl can be a fused ring from two rings, with one ring being a pyridine, pyridone, pyrimidine, thiazole, imidazole, or oxazole, and another ring being a phenyl or pyridine ring, wherein the fusion can occur at any two available ring atoms. [0129] For example, in some embodiments, Ring E, together with the optional substituent(s) (R20)j2, are selected from the , N (R20)j2 . [0130] In some embodiments, Ring E in Formula III can be a 5-14 membered heterocyclic ring, such as piperidine, tetrahydropyran ring, etc. [0131] In some embodiments, Ring E, together with the optional substituent(s) (R20)j2, can , wherein j2 and R20 are defined herein. [0132] be 0. [0133] In embodiments, j2 can be 1. [0134] In embodiments, j2 can be 2. [0135] When present, R20 at each occurrence is typically independently halogen, GB, O- GB, NH-GB, or N(C1-4 alkyl)-GB, wherein GB is defined herein. [0136] For example, in some embodiments, one or more R20 is GB, wherein GB is defined herein. In some embodiments, one or more R20 is GB, wherein GB is C1-4 alkyl which is optionally substituted as described herein. In some embodiments, one or more R20 is GB, wherein GB is a 3-10 membered ring, such as (i) a phenyl ring, (ii) a 5 or 6 membered heterocyclic ring having one or two ring heteroatoms, such as one or two ring nitrogen atoms or one ring nitrogen and one ring oxygen atom, or (iii) a 5 or 6 membered heteroaryl, e.g., pyridyl, each of (i)-(iii) can be optionally substituted as described herein. For example, in some embodiments, one R20 can . In some embodiments, one R20 can be phenyl. [0137] In some specific embodiments, the compound of Formua III can be characterized as having a structure according to Formula III-1: , wherein: 1 2 3 4 R , R , R , R , R5, and n are R21 is hydrogen or R20 as defined herein. For example, in some embodiments, R21 is hydrogen. In some embodiments, R21 can have any of the definition defined for R20 herein. In some embodiments, R21 is an optionally substituted phenyl. In some embodiments, R21 is an optionally substituted 5 or 6 membered heteroaryl. When substituted, the phenyl, or 5 or 6 membered heteroaryl, can be typically substituted with 1-3 substituents each independently F, Cl, C1-4 alkyl optionally substituted with 1-3 fluorine, or C1-4 alkoxy optionally substituted with 1-3 fluorine. [0138] In some embodiments, the present disclosure also provides novel specific compounds as described in the Examples section herein, including any new synthetic intermediate or target compound, as well as a stereoisomer thereof, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof. [0139] In some embodiments, the present disclosure provides a compound selected from the following Table A: Table A. Exemplary Compounds of the Present Disclosure
O O S NH 2 O NH
O O S NH 2
O O S NH2
[0140] In some embodiments, the present disclosure provides an enantiomerically enriched compound selected from the following: O O S NH O O S NH 2 HO ee, at least 95% ee, at least 98% ee, at least 99% ee, or 99.5% ee or higher. [0141] For example, in some embodiments, the present disclosure provides a compound of: , wherein the compound has an enantiomeric purity of at least 80% ee, preferably, at least 90% ee, at least 95% ee, at least 98% ee, at least 99% ee, or 99.5% ee or higher. It was found that the S-enantiomer, NEM-23AS, has a better aqueous solubility, and less CYP inhibition, compared to the R-enantiomer, NEM-23AR. The S-enantiomer, NEM-23AS, was also found to be more active in inhibiting carbonic anhydrase enzyme compared to the R-enantiomer, NEM-23AR. Thus, at least with respect to NEM-23A, the S-enantiomer is the preferred enantiomer. [0142] In some embodiments, the present disclosure provides a compound of: , wherein the compound has an least 80% ee, preferably, at least 90% ee, at least 95% ee, at least 98% ee, at least 99% ee, or 99.5% ee or higher. [0143] In some embodiments, the present disclosure provides a compound of: , wherein the compound has an enant at least 80% ee, preferably, at least 90% ee, at least 95% ee, at least 98% ee, at least 99% ee, or 99.5% ee or higher. [0144] In some embodiments, the present disclosure provides a compound of: , wherein the compound has an enantiomeric purity of at least 80% ee, preferably, at least 90% ee, at least 95% ee, at least 98% ee, at least 99% ee, or 99.5% ee or higher. [0145] In some embodiments, the present disclosure provides a compound of: O O S NH 2 , wherein the compound has an enantiomeric purity of at least 80% ee, preferably, at least 90% ee, at least 95% ee, at least 98% ee, at least 99% ee, or 99.5% ee or higher. [0146] In some embodiments, the present disclosure provides a compound of: O O S N , wherein the compound has an enantiomeric purity of at least 80% ee, preferably, at least 90% ee, at least 95% ee, at least 98% ee, at least 99% ee, or 99.5% ee or higher. [0147] In some embodiments, the present disclosure provides a salt of a compound selected from Table A. [0148] In some embodiments, the present disclosure provides a pharmaceutically acceptable salt of a compound selected from Table A. [0149] In some embodiments, the present disclosure provides a stereoisomer of a compound selected from Table A, or a salt thereof. [0150] In some embodiments, the present disclosure provides a stereoisomer of a compound selected from Table A, or a pharmaceutically acceptable salt thereof. [0151] In some embodiments, the present disclosure provides a deuterated analog of a compound selected from Table A, or a salt thereof. [0152] In some embodiments, the present disclosure provides a deuterated analog of a compound selected from Table A, or a pharmaceutically acceptable salt thereof. [0153] The present disclosure also lists the following compounds:
Table B. List of Compounds [0154] In some embodiments, the genus of compounds described herein can exclude any of the specific compounds in Table B in racemic forms. Compounds of Table B are also described in PCT/US2023/082927. [0155] In cases where compounds are sufficiently basic or acidic, a salt of a compound of Formula I, II, or III herein can be useful as an intermediate for isolating or purifying a compound of Formula I, II, or III. Additionally, administration of a compound of Formula I, II, or III as a pharmaceutically acceptable acid or base salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, α-ketoglutarate, and α- glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts. [0156] Salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made. [0157] The compounds of the present disclosure can be readily synthesized by those skilled in the art in view of the present disclosure. Exemplified syntheses are also shown in the Examples section. Certain Methods of Use [0158] As described herein, compounds of Formula I, II, or III may be used as carbonic anhydrase inhibitors. Carbonic anhydrases (Car) are a family of metabolic enzymes that regulate pH and CO2 homeostasis (Supuran, C.T.2008. Nat Rev Drug Discov 7:168-181, which is hereby incorporated by reference herein). The Car enzymes found in mammals are divided into four broad subgroups, which, in turn consist of several isoforms: cytosolic Car (Car1, Car2, Car3, Car7, Car13), mitochondrial Car (Car5A, Car5B), secreted Car (Car6), and membrane-associated Car (Car4, Car9, Car12, Car14). Additionally, there are three additional "acatalytic" Car isoforms (Car8, Car10, Car11) whose functions remain unclear. [0159] Accordingly, certain embodiments of the invention provide a method of inhibiting a carbonic anhydrase enzyme (e.g., the enzyme’s activity or function) in vitro or in vivo, the method comprising contacting the carbonic anhydrase enzyme with an effective amount of a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof). In certain embodiments, such a method comprises contacting a cell comprising the carbonic anhydrase enzyme. In certain embodiments, the cell is in a mammal. In certain embodiments, the cell is contacted by administering the compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, a salt thereof (e.g., a pharmaceutically acceptable salt thereof) to the mammal. [0160] In certain embodiments, the activity or function of the carbonic anhydrase is inhibited by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% (e.g., as compared to a control, such as a cell or a mammal not contacted with the compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein). In some preferred embodiments, compounds of Formula I, II, or III, or salts thereof for the methods or uses herein are those selected from Table A which have a POI as tested in the in vitro mast cell development assay equal or higher than that of MZ, for example, those showing a POI at 10 uM (or below) of 80% or above, preferably, 90% or above, more preferably, 95% or above. [0161] Certain embodiments also provide a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a salt thereof, for use in inhibiting a carbonic anhydrase enzyme in vitro or in vivo. [0162] Certain embodiments provide the use of a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a salt thereof, for the manufacture of a medicament for inhibiting a carbonic anhydrase enzyme in vitro or in vivo. [0163] In certain embodiments, the carbonic anhydrase enzyme is carbonic anhydrase (Car) 1 (see, UniProKB No P00915). [0164] Certain embodiments also provide a method of inhibiting mast cell development and/or mast cell function (e.g., mast cell activation) in a mammal, comprising administering a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, to the mammal. [0165] Certain embodiments provide a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, for use in the inhibition of mast cell development and/or mast cell function (e.g., mast cell activation). [0166] Certain embodiments also provide the use of a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, to prepare a medicament for inhibiting mast cell development and/or mast cell function (e.g., mast cell activation). [0167] Certain embodiments also provide a method of treating a disease or condition mediated by a carbonic anhydrase enzyme in a mammal (e.g., a human), comprising administering a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, to the mammal. [0168] Certain embodiments provide a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, for the prophylactic or therapeutic treatment of a disease or condition mediated by a carbonic anhydrase enzyme. [0169] Certain embodiments also provide the use of a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, to prepare a medicament for treating a disease or condition mediated by a carbonic anhydrase enzyme. [0170] Examples of diseases or conditions mediated by a carbonic anhydrase enzyme (e.g., mediated by carbonic anhydrase enzyme activity/function) are known in the art, and include, e.g., mast cell-mediated diseases. For example, diseases associated with carbonic anhydrase enzymes and/or mast cells include, but are not limited to, e.g., allergic diseases, bacterial infections, fungal infections, viral infections, mastocytosis and mast cell-mediated inflammation. [0171] In certain embodiments, the disease or condition mediated by a carbonic anhydrase enzyme is an allergic disease. [0172] The term “allergic disease” refers to a condition caused by hypersensitivity of the immune system in response to an environmental exposure. Examples of the allergic diseases that can be treated include, but are not limited to, asthma (e.g. fungal asthma), atopic dermatitis, contact dermatitis, chronic itch (pruritus), urticaria, hay fever, allergic conjunctivitis, allergic rhinitis, anaphylaxis, eosinophilic esophagitis, food allergies, and allergen-induced mastocytosis. [0173] In certain other embodiments, the disease or condition mediated by a carbonic anhydrase enzyme is a bacterial, fungal or viral infection. [0174] Non-limiting examples of bacterial infections include, e.g., Klebsiella pneumoniae and Pseudomonas aeruginosa. In certain embodiments, the bacterial infection is a gram-negative bacterial infection. [0175] Non-limiting examples of fungal infections include infections caused by Aspergillus fumigates, or other Aspergiullus species, as well as Candida species, Cryptococcus species, Histoplasma capsulatum, Pneumocystis jirovecii, and Stachybotrys chartarum. [0176] Non-limiting examples of viral infections include HIV, SARS-CoV-2, and Dengue. [0177] In another aspect, the disease or condition mediated by a carbonic anhydrase enzyme is mastocytosis. [0178] As used herein, the term “mastocytosis” refers to a disease characterized by the presence of too many mast cells in various organs and tissues, including but not limited to, infection- or allergen-induced mastocytosis, cutaneous mastocytosis, indolent systemic mastocytosis, systemic mastocytosis with associated clonal hematologic non-mast cell lineage diseases (such as myelodysplastic syndrome, myeloproliferative syndrome, acute myeloid leukemia, non-Hodgkin’s lymphoma), aggressive systemic mastocytosis, mast cell leukemia, mast cell activation syndrome, and localized mast cell proliferations (such as mast cell sarcoma and extracutaneous mastocytoma). In certain embodiments, the mastocytosis is mast cell activation syndrome. [0179] In another aspect, the disease or condition mediated by a carbonic anhydrase enzyme is mast cell-mediated inflammation. [0180] As used herein, the term “mast cell-mediated inflammation” refers to any inflammatory response and/or pathology that is promoted or supported by mast cell development and/or activation. This includes mast cell responses promoted by exposure to allergens, infectious agents, or unknown stimuli. In certain embodiments, the mast cell- mediated inflammation is caused by mastocytosis, an infection (e.g., a parasite infection, such as a helminth parasite (e.g., a Trichinella spiralis infection)), or an allergy (e.g., a food allergy or food allergy-like disease). In certain embodiments, the mast cell-mediated inflammation is mast cell-mediated intestinal inflammation. In certain embodiments, the mast cell-mediated inflammation is mast cell-mediated airway inflammation (e.g., eosinophilic airway inflammation). [0181] In certain embodiments, the disease or condition mediated by a carbonic anhydrase enzyme is osteoarthritis. In certain embodiments, the disease or condition mediated by a carbonic anhydrase enzyme is ankylosing spondylitis. Carbonic anhydrase has been shown to be associated with osteoarthritis, and carbonic anhydrase inhibitors have been shown to be antiarthritic, for example, methazolamide was previously shown to have an effect in treating ankylosing spondylitis. See e.g., Sun et. al. Sci Rep 13:15370 (2023); Nolan et al. Pharmacol Res.24(4):377-83(1991); Chang et al. Arthritis Res Ther. 14(4):R176 (2012); Kenny, Calcif Tissue Int.40(4):212-8 (1987); and Chang et al. Int J Med Sci.8(5):413-9 (2011). In certain embodiments, the disease or condition mediated by a carbonic anhydrase enzyme is neuropathic pain. Neuropathic pain has also been shown to be associated with carbonic anhydrase inhibition. See e.g., Expert Rev Neurother.16(8):961-8 (2016). [0182] In some embodiments, the present disclosure provides a method of treating osteoarthritis, the method comprising administering a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or any of the compounds in Table A or Table B herein, or any of the compounds disclosed in PCT/US2023/082927, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. [0183] In some embodiments, the present disclosure provides a method of treating ankylosing spondylitis, the method comprising administering a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or any of the compounds in Table A or Table B herein, or any of the compounds disclosed in PCT/US2023/082927, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. [0184] In some embodiments, the present disclosure provides a method of treating neuropathic pain, the method comprising administering a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or any of the compounds in Table A or Table B herein, or any of the compounds disclosed in PCT/US2023/082927, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. [0185] In certain embodiments, administration of a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, reduces a mast cell response, such as mast cell-mediated inflammation (e.g., mast cell-mediated intestinal inflammation; or mast cell-mediated airway inflammation). In certain embodiments, the mast cell response (e.g., mast cell-mediated inflammation) is induced by an allergy, such as a food allergy. [0186] In certain embodiments, a mast cell response (e.g., mast cell activation and/or mast-cell mediated inflammation) causes airway constriction. In certain embodiments, administration of a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, is capable of treating such airway constriction. [0187] In certain embodiments, a method described herein may further comprise administering one or more additional therapeutic agent(s). For example, such as an agent may be useful for treating a disease or condition mediated by a carbonic anhydrase enzyme (e.g., for treating allergic diseases, bacterial infections, fungal infections, viral infections, mastocytosis and/or mast cell-mediated inflammation). [0188] In certain embodiments, the one or more additional therapeutic agent(s) is/are administered simultaneously or sequentially with a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the one or more additional therapeutic agent(s) is/are administered simultaneously with a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, a pharmaceutical composition/formulation comprising a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, and the one or more additional therapeutic agent(s) is administered. In certain embodiments, a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, and the one or more additional therapeutic agent(s) are administered sequentially. In certain embodiments, the compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, is administered first and the one or more additional therapeutic agent(s) is administered second. In certain embodiments the one or more additional therapeutic agent(s) is administered first and the compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, is administered second. [0189] In certain embodiments, the one or more additional therapeutic agent(s) is an anti-histamine, a steroid, immunotherapy (e.g., an allergy shot, oral tolerance therapy, etc.), a decongestant, a bronchodilator, a mast cell stabilizer, a prostaglandin antagonist, a blocking/neutralizing antibody (e.g. an anti-IgE therapy, an anti-IL-4R alpha therapy, or an anti-SIGLEC8 therapy), and/or a leukotriene modifier. In certain embodiments, a combination of such agents is administered. [0190] In certain embodiments, the one or more additional therapeutic agent(s) is an anti-histamine. A histamine antagonist, commonly called an antihistamine, is a pharmaceutical drug class that includes two types of drugs: histamine H1-receptor antagonists and histamine H2-receptor antagonists. Antagonists of the histamine H1-receptor are used to treat allergic reactions in the nose (e.g., itching, runny nose, and sneezing) and which are used off-label for insomnia. They are sometimes also used to treat motion sickness or vertigo caused by problems with the inner ear. Antagonists of the histamine H2-receptor are used to treat gastric acid conditions (e.g., peptic ulcers and acid reflux). They work by binding to histamine H1 receptors in mast cells, smooth muscle, and endothelium in the body and tuberomammillary nucleus the brain or histamine H2 receptors in the upper gastrointestinal tract, primarily in the stomach. [0191] Non-limiting examples of antihistamines that may be used in the present invention include: acrivastine, azelastine, bilastine, brompheniramine, buclizine, bromodiphenhydramine, carbinoxamine, cetirizine (Zyrtec; metabolite of hydroxyzine, its prodrug), chlorpromazine, cimetidine, cyclizine, chlorphenamine, chlorodiphenhydramine, clemastine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimetindene, diphenhydramine (Benadryl), ebastine, embramine, famotidine, fexofenadine (Allegra), hydroxyzine (Vistaril), lafutidine, levocetirizine, loratadine (Claritin), nizatidine, olopatadine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, ranitidine, roxatidine, rupatadine, tiotidine, tripelennamine, and triprolidine. [0192] In certain embodiments, the one or more additional therapeutic agent(s) is a blocking and/or neutralizing antibody (e.g., an antibody useful for treating inflammation). For example, such an antibody may target IgE, IL-4R alpha or SIGLEC8. [0193] Thus, in certain embodiments, the one or more additional therapeutic agent(s) is an anti-IgE therapy. Anti-IgE therapies that may be used in the present invention include anti-IgE therapeutic antibodies, such as a monoclonal antibody. A non-limiting example of a suitable monoclonal antibody is Omalizumab (Xolair). [0194] In certain embodiments, the one or more additional therapeutic agent(s) is an anti-IL-4R alpha therapy. Anti-IL-4R therapies that may be used in the present invention include anti-IL-4R alpha therapeutic antibodies, such as a monoclonal antibody. A non- limiting example of a suitable antibody is dupilumab. [0195] In certain embodiments, the one or more additional therapeutic agent(s) is an anti-SIGLEC8 alpha therapy. Anti- SIGLEC8 therapies that may be used in the present invention include anti-SIGLEC8 alpha therapeutic antibodies, such as a monoclonal antibody. A non-limiting example of a suitable antibody is lirentelimab. [0196] In certain embodiments, the one or more additional therapeutic agent(s) is a prostaglandin antagonist. A prostaglandin antagonist is a hormone antagonist acting upon one or more prostaglandins, a subclass of eicosanoid compounds, which function as signaling molecules in numerous types of animal tissues. Non-limiting examples of prostaglandin antagonists that may be used in the present invention include NSAIDs and seratrodast. [0197] In certain embodiments, the one or more additional therapeutic agent(s) a steroid. A steroid is an organic compound, typically containing four rings arranged in a specific configuration. Steroids have two principal biological functions: certain steroids (such as cholesterol) are important components of cell membranes which alter membrane fluidity, and many steroids are signaling molecules which activate steroid hormone receptors. Generally, the steroid core structure is composed of seventeen carbon atoms, bonded in four "fused" rings: three six-member cyclohexane rings (rings A, B and C in the first illustration) and one five-member cyclopentane ring (the D ring). Steroids vary by the functional groups attached to this four-ring core and by the oxidation state of the rings. Sterols are forms of steroids with a hydroxyl group at position three and a skeleton derived from cholestane. Steroids can also vary more markedly by changes to the ring structure (for example, ring scissions which produce secosteroids, such as vitamin D3). [0198] Non-limiting examples of steroids that may be used in the present invention include: beclomethasone, ciclesonide, fluticasone proprionate, fluticasone furoate, mometasone, budesonide, triamcinolone, dexamethasone, deltasone, and prednisone. [0199] In certain embodiments, the one or more additional therapeutic agent(s) is an immunotherapy. Immunotherapy is the treatment of a disease or condition by inducing, enhancing, or suppressing an immune response. Immunotherapies that are designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. [0200] Non-limiting examples of immunotherapies that may be used in the present invention include, allergy shots and oral tolerance therapies. [0201] In certain embodiments, the one or more additional therapeutic agent(s) is a decongestant. Decongestants are a type of agent that is used to relieve nasal congestion in the upper respiratory tract. Non-limiting examples of decongestants that may be used in the present invention include pseudoephedrine, phenylephrine, and oxymetazoline. [0202] In certain embodiments, the one or more additional therapeutic agent(s) is a bronchodilator. Bronchodilators are a type of agent that dilates the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lungs. Non- limiting examples of bronchodilators that may be used in the present invention include albuterol and levalbuterol. [0203] In certain embodiments, the one or more additional therapeutic agent(s) is a mast cell stabilizer. Mast cell stabilizers are generally cromone medications that are used to prevent or control certain allergic disorders. They block a calcium channel essential for mast cell degranulation, stabilizing the cell and thereby preventing the release of histamine and related mediators. Non-limiting examples of mast cell stabilizers that may be used in the present invention include cromolyn sodium, lodoxamide, and nedocromil. [0204] In certain embodiments, the one or more additional therapeutic agent(s) is a leukotriene modifier. Leukotriene modifiers are a type of agent that functions as a leukotriene-related enzyme inhibitor (arachidonate 5-lipoxygenase) or leukotriene receptor antagonist (cysteinyl leukotriene receptors), and consequently, opposes the function of these inflammatory mediators. Non-limiting examples of leukotriene modifiers that may be used in the present invention include monteleukast, zafirlukast, and zyflo. [0205] In certain embodiments, the one or more additional therapeutic agent(s) is a tyrosine kinase inhibitor (TKIs), such as KIT inhibitors. Tyrosine kinases are enzymes that activate signal transduction cascades by phosphorylating proteins involved in those signaling processes. TKIs inhibit tyrosine kinase phosphorylation. Non-limiting examples of TKIs that may be used in the present invention include imatinib, sunitinib, dasatinib, nilotinib, avapritinib, and bezuclatinib. Administration and Formulation [0206] The compounds of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or salts thereof, can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes. [0207] Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. For example, in some embodiments, the oral formulation can be a suspension of a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or salts thereof, in an aqueous methylcellulose solution, such as a 0.5% methylcellulose solution having a viscosity of 400-4000 cPs. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained. [0208] The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices. [0209] The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. [0210] The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. For example, in some embodiments, an injectable formulation can be a solution/suspension of a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a salt thereof, in an aqueous vehicle. In some embodiments, such injectable formulation can include one or more solubilizer to increase the solubility of the active compound in the aqueous vehicle. Suitable solubilizers are not particularly limited and can include any of those conventionally used in formulation science, for example, cyclodextrins, etc. In some specific embodiments, a formulation of compounds herein can be formulated together with beta-cyclodextrin, in particular, sulfobutylether beta-cyclodextrin (SBE-β-CD) in an aqueous vehicle. As a non- limiting example, it was found that NEM-24A can be formulated at 6 mg/mL with 20% SBE-β-CD in water, which can be suitable for injection. SBE-β-CD is commercially available, for example, under the tradename Captisol for SBE6.5-β-CD. [0211] Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions. [0212] For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid. [0213] Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers. [0214] Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user. [0215] Examples of useful dermatological compositions which can be used to deliver the compounds of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No.4,608,392), Geria (U.S. Pat. No.4,992,478), Smith et al. (U.S. Pat. No.4,559,157) and Wortzman (U.S. Pat. No.4,820,508). [0216] Useful dosages of the compounds of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No.4,938,949. [0217] The amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. [0218] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub- doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye. [0219] Compounds of the invention can also be administered in combination with other therapeutic agents. Examples of such agents include anti-histamines, steroids, immunotherapies (e.g., allergy shots, oral tolerance therapies, etc.), decongestants, bronchodilators, mast cell stabilizers, leukotriene modifiers, prostaglandin antagonists, and blocking/neutralizing antibodies (e.g., anti-IgE therapies, anti-IL-4R alpha therapies, and anti-SIGLEC8 therapies). [0220] Accordingly, one embodiment the invention also provides a composition comprising a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent (e.g., an additional agent described herein), and a pharmaceutically acceptable diluent or carrier. The invention also provides a kit comprising a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein or the pharmaceutically acceptable salt thereof and the other therapeutic agent or agents to an animal to treat a disease or condition that is mediated by carbonic anhydrase. [0221] The invention will now be illustrated by the following non-limiting Examples. EXAMPLES [0222] Mast cells are potent innate immune cells that activate in response to diverse stimuli, including cytokines and antigen-antibody complexes. Upon activation, mast cells release numerous effector molecules that are well described for their ability to promote detrimental inflammation in the context of allergies, asthma, mastocytosis and mast cell activation syndrome. Despite the clinical need, therapeutic strategies to target mast cell responses and reduce mast cell activation remain limited. [0223] Mast cell progenitors that express high levels of the enzyme Carbonic anhydrase (Car)1 were recently identified. Using these cells, it was demonstrated that targeting Car1 with the inhibitor methazolamide (MZ) was sufficient to prevent mast cell development and mast cell-mediated inflammation. [0224] PCT/US2023/082927 discloses more potent Car1 inhibitors, such as those shown in Table B of the present disclosure or (4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3- yl)benzenesulfonamide (CAR0037)), which can more efficiently inhibits mast cell responses as compared to MZ. [0225] Compounds of Formula I, II, or III herein can have similar or better efficacy in inhibiting carbonic anhydrase than MZ and can be used for the treatment of mast cell- mediated inflammation and other mast-cell mediated diseases or conditions. [0226] The abbreviations used in the Examples section should be understood as having their ordinary meanings in the art unless specifically indicated otherwise or obviously contrary from context. Example 1. Synthesis of Compound NEM-5A [0227] To a solution of 2-methylpropan-2-amine (1.43 g, 19.49 mmol, 2.05 mL, 5 eq) in DCM (10 mL) was added 5-bromopyridine-2-sulfonyl chloride (1 g, 3.90 mmol, 1 eq) slowly and the reaction mixture allowed to stir at 20°C for 3 h. The mixture was evaporated to afford a residue. The residue was purified by flash chromatography on silica gel (Petroleum ether/ EtOAc = 10:1~1:1) to give 5-bromo-N-tert-butyl-pyridine-2-sulfonamide (1 g, 3.41 mmol, 87.49% yield) as a yellow solid. MS (M + H)+ = 293.1/295.1 Synthesis of N-tert-butyl-5-[3-hydroxy-1-[(4-methoxyphenyl)methyl]-2-oxo-indolin-3- yl]pyridine-2-sulfonamide (3) [0228] To a solution of 5-bromo-N-tert-butyl-pyridine-2-sulfonamide (153.57 mg, 523.80 umol, 1 eq) in THF (1 mL) was added n-BuLi (2.5 M, 419.04 uL, 2 eq) dropwise at - 70oC. The yellow solution was stirred for 0.5 h, and to the above solution was added a solution of 1-[(4-methoxyphenyl)methyl]indoline-2,3-dione (140 mg, 523.80 umol, 1 eq) in anhydrous THF (1 mL) at -70oC. The reaction mixture was stirred at -70oC for 1 h and at 20°C for 3 hrs. The reaction was quenched with the addition of saturated ammonium chloride (5 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers was dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water( NH4HCO3)-ACN];B%: 35%-65%,8min). Compound N-tert-butyl-5-[3-hydroxy-1-[(4-methoxyphenyl)methyl]-2-oxo-indolin-3- yl]pyridine-2-sulfonamide (160 mg, 332.25 μmol, 63.4% yield) was obtained as a yellow solid. MS (M + H)+ = 482.2 Synthesis of 5-[3-hydroxy-1-[(4-methoxyphenyl)methyl]-2-oxo-indolin-3-yl]pyridine-2- sulfonamide (NEM-5A) [0229] A mixture of N-tert-butyl-5-[3-hydroxy-1-[(4-methoxyphenyl)methyl]-2-oxo- indolin-3-yl]pyridine-2-sulfonamide (160 mg, 332.25 umol, 1 eq) in DCM (1 mL) and TFA (3.08 g, 27.01 mmol, 2 mL, 81.30 eq). The mixture was stirred at 60°C for 2 h. The mixture was evaporated to afford the crude product. The residue was purified by prep-HPLC (column: Phenomenex C1880*30mm*3um;mobile phase: [water(TFA)-ACN];B%: 20%- 50%,8min) to give a crude product. The crude product was re-purified by prep-HPLC (column: NP-1;mobile phase: [Heptane-EtOH];B%: 15%-95%,10min]. The white solid was re-crystallized from water, dried by hyophilization to give Compound 5-[3-hydroxy-1-[(4- methoxyphenyl)methyl]-2-oxo-indolin-3-yl]pyridine-2-sulfonamide (10.5 mg, 24.20 umol, 44.77% yield, 98.06% purity) as a white solid. 1H NMR (400 MHz, Acetonitrile-d3) δ 8.66 (d, J = 1.0 Hz, 1H), 7.93 - 7.86 (m, 2H), 7.37 - 7.32 (m, 1H), 7.31 - 7.24 (m, 3H), 7.13 - 7.07 (m, 1H), 6.99 (d, J = 7.9 Hz, 1H), 6.90 (d, J = 8.6 Hz, 2H), 5.71 (s, 2H), 4.93 - 4.86 (m, 2H), 4.84 - 4.77 (m, 1H), 3.76 (s, 3H) MS (M + H)+ = 426.0 Example 2. Synthesis of Compound NEM-23AR and NEM-23AS yl]benzenesulfonamide (2) [0230] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (670 mg, 1.86 mmol, 1 eq) in DMF (5 mL) was added K2CO3 (770.74 mg, 5.58 mmol, 3 eq) and 4-[4-(chloromethyl)phenyl]pyridine (492.18 mg, 2.42 mmol, 1.3 eq). The mixture was stirred at 60°C for 3 h. The reaction mixture was cooled to room temperature and diluted by water (40 mL), extracted with ethyl acetate (40 mL * 2). The combined organics were washed with brine (40 mL), dried over Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica, 20-70 % ethyl acetate in petroleum ether, gradient over 20 min). Compound N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3- yl]benzenesulfonamide (750 mg, 1.42 mmol, 76.47% yield) was obtained as a yellow solid. MS (M + H)+ = 528.2 Synthesis of 4-[3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3- yl]benzenesulfonamide (NEM-23A) [0231] To a solution of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (750 mg, 1.42 mmol, 1 eq) in DCM (6 mL) was added TFA (4.32 g, 37.86 mmol, 2.81 mL, 26.64 eq). The mixture was stirred at 60°C for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18250*50mm*10 um;mobile phase: [water(TFA)-ACN];B%: 5%-30%,10min). Compound 4-[3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (600 mg, 1.25 mmol, 87.73% yield, 98% purity). Synthesis of 4-[(3R)-3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3- yl]benzenesulfonamide&4-[(3S)-3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide [0232] 4-[3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3- yl]benzenesulfonamide was purified by prep-SFC (column: ChiralPak IH, 250*30mm, 10um;mobile phase: [0.1%NH3H2O ETOH];B%: 50%-50%,14min).4-[(3R)-3-hydroxy-2- oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (163 mg, 345.69 μmol, 32.60% yield) was obtained. (Rt=1.628). 1H NMR (400 MHz, METHANOL-d4) δ 8.56 (d, J = 6.0 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.56 - 7.50 (m, 4H), 7.32 (dt, J = 1.2, 7.8 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.10 (dt, J = 1.2, 7.8 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 5.04 (d, J = 1.9 Hz, 2H) MS (M + H)+ = 472.0. [0233] 4-[(3S)-3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3- yl]benzenesulfonamide (271 mg, 574.73 μmol, 54.20% yield) was obtained. (Rt=1.889) The structure has been confirmed by X-ray crystallographic analysis. 1H NMR (400 MHz, METHANOL-d4) δ 8.60 (d, J = 6.4 Hz, 2H), 7.87 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 7.0 Hz, 4H), 7.54 (d, J = 8.4 Hz, 4H), 7.35 - 7.30 (m, 1H), 7.23 (d, J = 6.6 Hz, 1H), 7.14 - 7.08 (m, 1H), 7.02 (d, J = 8.0 Hz, 1H), 5.09 - 5.03 (m, 2H) MS (M + H)+ = 472.0 Example 3. Synthesis of HCl salt of Compound NEM-23AS 3- yl]benzenesulfonamide (NEM-23AS_HCl) [0234] A mixture of 4-[(3S)-3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3- yl]benzenesulfonamide (50 mg, 106.04 μmol, 1 eq) in HCl/EtOAc (4 M, 1 mL) was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The mixture was filtered and the solid was dried by lyophilization. Compound 4- [(3R)-3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (35 mg, 66.37 μmol, 62.59% yield, 96.33% purity, HCl salt) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ 8.83 (d, J = 6.8 Hz, 2H), 8.35 (d, J = 6.8 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.87 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.33 (br d, J = 1.1 Hz, 1H), 7.25 (d, J = 6.6 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 7.02 (d, J = 7.9 Hz, 1H), 5.10 (d, J = 4.1 Hz, 2H) MS (M + H)+ = 472.0. Example 4. Synthesis of Compound NEM-24AR and NEM-24AS benzenesulfonamide (2) [0235] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (1 g, 2.77 mmol, 1 eq) and 1-bromo-4-(bromomethyl)benzene (901.46 mg, 3.61 mmol, 1.3 eq) in DMF (20 mL) was added Cs2CO3 (2.71 g, 8.32 mmol, 3 eq), the reaction was stirred at 60°C for 12 h. The reaction mixture was cooled to room temperature.50 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (50 mL*2) and the combined extracts was dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica, 0-45 % ethyl acetate in petroleum ether, gradient over 20 min).4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N-tert-butyl- benzenesulfonamide (850 mg, 1.61 mmol, 57.86% yield, 100% purity) was obtained as a brown oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.01 (s, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.49 (t, J = 9.0 Hz, 4H), 7.32 - 7.28 (m, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.13 - 7.06 (t, 1H), 6.80 (d, J = 7.8 Hz, 1H), 4.99 - 4.91 (m, 1H), 4.89 - 4.80 (m, 1H), 1.24 (s, 9H). Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[(4-pyrrolidin-1- ylphenyl)methyl]indolin-3-yl]benzenesulfonamide (3) [0236] To a solution of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]- N-tert-butyl-benzenesulfonamide (850 mg, 1.61 mmol, 1 eq) and pyrrolidine (171.27 mg, 2.41 mmol, 201.02 μL, 1.5 eq) in 2-methylbutan-2-ol (10 mL) were added BrettPhos Pd G3 (291.07 mg, 321.09 μmol, 0.2 eq) and t-BuONa (2 M, 1.61 mL, 2 eq), the reaction mixture was bubbled with N2 for a while and heated to 90°C, stirred for 12 h under N2 atmosphere. The reaction mixture was cooled to room temperature.10 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (20 mL*2) and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0- 20 % ethyl acetate in petroleum ether, gradient over 20 min). Compound N-tert-butyl-4-[3- hydroxy-2-oxo-1-[(4-pyrrolidin-1-ylphenyl)methyl]indolin-3-yl]benzenesulfonamide (460 mg, 770.13 μmol, 47.97% yield, 87% purity) was obtained as a yellow oil. MS (M + H)+ = 520.3. Synthesis of 4-[3-hydroxy-2-oxo-1-[(4-pyrrolidin-1-ylphenyl)methyl]indolin-3- yl]benzenesulfonamide (4) [0237] A solution of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[(4-pyrrolidin-1- ylphenyl)methyl]indolin-3-yl]benzenesulfonamide (460 mg, 885.20 μmol, 1 eq) in DCE (5 mL) and TFA (5 mL) was stirred at 50°C for 2 h. The mixture was concentrated under reduced pressure to give the crude product.4-[3-hydroxy-2-oxo-1-[(4-pyrrolidin-1- ylphenyl)methyl]indolin-3-yl]benzenesulfonamide (200 mg, crude, TFA salt) was obtained. MS (M + H)+ = 464.1 Synthesis of (R)-4-(3-hydroxy-2-oxo-1-(4-(pyrrolidin-1-yl)benzyl)indolin-3- yl)benzenesulfonamide (NEM-24AR) and (S)-4-(3-hydroxy-2-oxo-1-(4-(pyrrolidin-1- yl)benzyl)indolin-3-yl)benzenesulfonamide (NEM-24AS) [0238] 4-[3-hydroxy-2-oxo-1-[(4-pyrrolidin-1-ylphenyl)methyl]indolin-3- yl]benzenesulfonamide (200 mg, crude, TFA salt) was purified by SFC: column: REGIS (s,s) WHELK-O1 (250mm*30mm,5um);mobile phase: [CO2-EtOH(0.1% NH3H2O)];B%:50%, isocratic elution mode. (R)-4-(3-hydroxy-2-oxo-1-(4-(pyrrolidin-1- yl)benzyl)indolin-3-yl)benzenesulfonamide (41 mg, 84.03 μmol, 19.48% yield, 95% purity) was obtained. SFC (Rt=1.625). 1H NMR (400 MHz, METHANOL-d4) δ 7.84 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.29 (dt, J = 1.2, 7.8 Hz, 1H), 7.21 - 7.14 (m, 3H), 7.09 - 6.98 (m, 2H), 6.52 (d, J = 8.8 Hz, 2H), 4.91 (m, 1H), 4.78 - 4.74 (m, 1H), 3.27 - 3.17 (m, 4H), 2.00 (m, 4H). MS (M + H)+ = 464.2. [0239] (S)-4-(3-hydroxy-2-oxo-1-(4-(pyrrolidin-1-yl)benzyl)indolin-3- yl)benzenesulfonamide (54.9 mg, 112.51 μmol, 26.08% yield, 95% purity) was obtained. SFC(Rt=1.743). 1H NMR (400 MHz, METHANOL-d4) δ 7.84 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.35 - 7.26 (m, 1H), 7.23 - 7.13 (m, 3H), 7.11 - 6.99 (m, 2H), 6.53 (d, J = 8.8 Hz, 2H), 4.91 - 4.87 (m, 1H), 4.79 - 4.74 (m, 1H), 3.28 - 3.18 (m, 4H), 2.09 - 1.89 (m, 4H). MS (M+H)+ =464.2. Example 5. Synthesis of Compound NEM-26AR and NEM-26AS [0240] To a solution of 6-quinolylmethanol (1 g, 6.28 mmol, 1 eq) in DCM (10 mL) was added SOCl2 (3.74 g, 31.41 mmol, 2.28 mL, 5 eq). The mixture was stirred at 25°C for 12 hr. The product fraction was evaporated under reduced pressure. Compound 6- (chloromethyl)quinoline (1.2 g, crude, HCl salt) was obtained as a Brown solid. MS (M + H)+ = 178.0 Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-(6-quinolylmethyl)indolin-3- yl]benzenesulfonamide (3) [0241] To a solution of 6-(chloromethyl)quinoline (570.23 mg, 2.66 mmol, 1.2 eq, HCl salt) in DMF (13 mL) was added K2CO3 (766.92 mg, 5.55 mmol, 2.5 eq) and N-tert-butyl-4- (3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (800 mg, 2.22 mmol, 1 eq). The mixture was stirred at 60°C for 12 hr.20 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (10 mL*2) and the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. Compound N-tert-butyl-4-[3-hydroxy-2-oxo-1-(6- quinolylmethyl)indolin-3-yl]benzenesulfonamide (1 g, crude) was obtained. MS (M + H)+ = 502.4 Synthesis of (R)-4-(3-hydroxy-2-oxo-1-(quinolin-6-ylmethyl)indolin-3- yl)benzenesulfonamide (NEM-26AR) and (S)-4-(3-hydroxy-2-oxo-1-(quinolin-6- ylmethyl)indolin-3-yl)benzenesulfonamide (NEM-26AS) [0242] A solution of N-tert-butyl-4-[3-hydroxy-2-oxo-1-(6-quinolylmethyl)indolin-3- yl]benzenesulfonamide (800 mg, 1.59 mmol, 1 eq) in DCE (8 mL) and TFA (8.55 mL) was stirred at 60oC for 2 h. The mixture was evaporated under reduced pressure. The mixture was adjusted pH = 7 by adding sat NaHCO3 aqueous solution slowly at 0 °C. Then extracted with ethyl acetate (10 mL * 2) and some yellow solid was obtained and filtered to give a residue. The crude product was triturated with acetonitrile (5mL) at 25oC for 5 min. The solid was collected by filtration to give 4-(3-hydroxy-2-oxo-1-(quinolin-6-ylmethyl)indolin-3- yl)benzenesulfonamide as a solid. Then it was purified by preparative SFC (column: DAICEL CHIRALCEL OJ(250mm*30mm,10um); mobile phase: [CO2- MeOH(0.1%NH3H2O)];B%:50%, isocratic elution mode). Compound (R)-4-(3-hydroxy-2- oxo-1-(quinolin-6-ylmethyl)indolin-3-yl)benzenesulfonamide (63.7 mg, 141.56 μmol, 8.88% yield, 99% purity) was obtained. SFC (Rt=1.568). 1H NMR (400 MHz, METHANOL-d4) δ 8.84 (dd, J = 1.2, 4.0 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.93 (s, 1H), 7.90 - 7.85 (m, 2H), 7.77 (dd, J = 2.0, 8.8 Hz, 1H), 7.58 - 7.52 (m, 3H), 7.30 (dt, J = 1.2, 7.6 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.13 - 7.08 (m, 1H), 7.04 (d, J = 7.9 Hz, 1H), 5.24 - 5.14 (m, 2H) MS (M + H)+ = 446.1. [0243] Compound (S)-4-(3-hydroxy-2-oxo-1-(quinolin-6-ylmethyl)indolin-3- yl)benzenesulfonamide (63.5 mg, 139.69 μmol, 8.76% yield, 98% purity) was obtained. SFC (Rt=1.740). 1H NMR (400 MHz, METHANOL-d4) δ = 8.84 (dd, J = 1.2, 4.0 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.93 (s, 1H), 7.90 - 7.86 (m, 2H), 7.77 (dd, J = 2.0, 8.8 Hz, 1H), 7.58 - 7.52 (m, 3H), 7.31 (dt, J = 1.2, 7.6 Hz, 1H), 7.24 (dd, J = 0.8, 7.6 Hz, 1H), 7.13 - 7.08 (m, 1H), 7.04 (d, J = 7.9 Hz, 1H), 5.24 - 5.14 (m, 2H) MS (M + H)+ = 446.1. Example 6. Synthesis of Compound NEM-33A and NEM-40A (2) [0244] AT - 75 °C, precooled N-isopropylpropan-2-amine (2.52 g, 24.90 mmol, 3.52 mL, 2 eq) in THF (20 mL), furan (20 mL) and 1-bromo-4-(trifluoromethoxy)benzene (3 g, 12.45 mmol, 1.85 mL, 1 eq) were consecutively added dropwise to n-BuLi (2.5 M, 9.96 mL, 2 eq) in 20 min. The mixture was allowed to warm up to 20°C. The mixture was quenched with 1 N HCl aq.10 mL. The reaction mixture was partitioned between ethyl acetate (100 mL) and H2O (50 mL). The organic phase was separated, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 40 g silica, 0-30 % ethyl acetate in petroleum ether, gradient over 20 min). Compound 4-(trifluoromethoxy)-11-oxatricyclo[6.2.1.02,7]undeca- 2(7),3,5,9-tetraene (1.1 g, 4.82 mmol, 38.73% yield) was obtained as a yellow oil. MS (M + H)+ = 229.3 Synthesis of 6-(trifluoromethoxy)naphthalen-1-ol and 7-(trifluoromethoxy)naphthalen- 1-ol (3) [0245] To a solution of 4-(trifluoromethoxy)-11-oxatricyclo[6.2.1.02,7]undeca- 2(7),3,5,9-tetraene (1 g, 4.38 mmol, 1 eq) in MeOH (12 mL) was added HCl (159.70 mg, 4.38 mmol, 156.57 uL, 1 eq). The mixture was stirred at 75°C for 12 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with NaHCO3 aq 50 mL and extracted with Ethyl acetate 100 mL (50 mL * 2). The combined organic layers were washed with brine 50 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. A mixture of 6- (trifluoromethoxy)naphthalen-1-ol and 7-(trifluoromethoxy)naphthalen-1-ol (600 mg, 2.63 mmol, 60.04% yield) was obtained as a yellow oil which was used into the next step without further purification. Synthesis of [6-(trifluoromethoxy)-1-naphthyl] trifluoromethanesulfonate & [7- (trifluoromethoxy)-1-naphthyl] trifluoromethanesulfonate (4) [0246] To a solution of 6-(trifluoromethoxy)naphthalen-1-ol and 7- (trifluoromethoxy)naphthalen-1-ol (550 mg, 2.41 mmol, 1 eq) in dichloromethane (10 mL) was added DIEA (1.25 g, 9.64 mmol, 1.68 mL, 4 eq) and Tf2O (1.36 g, 4.82 mmol, 795.32 uL, 2 eq) at 0°C .The mixture was stirred at 20°C for 2 hr.10 mL of water was added to the mixture, the mixture was extracted with dichloromethane (20 mL*2), the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 25 g silica, 0-1 % ethyl acetate in petroleum ether, gradient over 10 min). [6-(trifluoromethoxy)- 1-naphthyl] trifluoromethanesulfonate and [7-(trifluoromethoxy)-1-naphthyl] trifluoromethanesulfonate (500 mg, 1.39 mmol, 57.59% yield) was obtained as yellow oil. Synthesis of 4,4,5,5-tetramethyl-2-(6-(trifluoromethoxy)naphthalen-1-yl)-1,3,2- dioxaborolane and 4,4,5,5-tetramethyl-2-(7-(trifluoromethoxy)naphthalen-1-yl)-1,3,2- dioxaborolane (5 and 5A) [0247] A mixture of [6-(trifluoromethoxy)-1-naphthyl] trifluoromethanesulfonate and [7-(trifluoromethoxy)-1-naphthyl] trifluoromethanesulfonate (500 mg, 1.39 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.76 g, 6.94 mmol, 5 eq), triethylamine (561.81 mg, 5.55 mmol, 772.78 uL, 4 eq), Pd(dppf)Cl2.CH2Cl2 (226.70 mg, 277.60 umol, 0.2 eq) in dioxane (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2 atmosphere. The mixture was poured into ice sat. NaHCO3 aqueous (20 mL), extracted with dichloromethane (20 mL*2). The combined extracts were dried with anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. The residue was purified by flash column (ISCO 20 g silica, 0-5 % ethyl acetate in petroleum ether, gradient over 20 min). A mixture of 4,4,5,5-tetramethyl-2-[6-(trifluoromethoxy)-1-naphthyl]-1,3,2- dioxaborolane and 4,4,5,5-tetramethyl-2-(7-(trifluoromethoxy)naphthalen-1-yl)-1,3,2- dioxaborolane (300 mg, 887.24 umol, 63.92% yield) were obtained as a yellow oil. Synthesis of [6-(trifluoromethoxy)-1-naphthyl]boronic acid and (7- (trifluoromethoxy)naphthalen-1-yl)boronic acid (6 and 6A) [0248] To a mixture of 4,4,5,5-tetramethyl-2-[6-(trifluoromethoxy)-1-naphthyl]-1,3,2- dioxaborolane and 4,4,5,5-tetramethyl-2-(7-(trifluoromethoxy)naphthalen-1-yl)-1,3,2- dioxaborolane (550 mg, 975.96 umol, 60% purity, 1 eq) in THF (10 mL) and H2O (3 mL) was added NaIO4 (1.57 g, 7.32 mmol, 405.60 uL, 7.5 eq) and NH4OAc (112.84 mg, 1.46 mmol, 1.5 eq) in portions. The mixture was stirred at 20°C for 12 hr. The mixture was acidified by adding HCl (1 M, 10 mL) dropwise at 0°C to pH = 6. Then THF was removed under reduced pressure, and the solid was collected by filtration, washed with H2O (5 mL x 3) and dried under reduced pressure to give crude product. A mixture of [6- (trifluoromethoxy)-1-naphthyl]boronic acid and (7-(trifluoromethoxy)naphthalen-1- yl)boronic acid (450 mg, crude) was obtained as yellow solid. MS (M - H)-= 255.1 Synthesis of N-(tert-butyl)-4-(3-hydroxy-2-oxo-1-(6-(trifluoromethoxy)naphthalen-1- yl)indolin-3-yl)benzenesulfonamide and N-(tert-butyl)-4-(3-hydroxy-2-oxo-1-(7- (trifluoromethoxy)naphthalen-1-yl)indolin-3-yl)benzenesulfonamide (8 &8A) [0249] To a mixture of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (250 mg, 693.62 umol, 1 eq), [6-(trifluoromethoxy)-1- naphthyl]boronic acid and (7-(trifluoromethoxy)naphthalen-1-yl)boronic acid (355.11 mg, 1.39 mmol, 2 eq) in DCM (2 mL) was added Cu(OAc)2 (251.97 mg, 1.39 mmol, 2 eq), TEA (140.37 mg, 1.39 mmol, 193.09 uL, 2 eq) and pyridine (109.73 mg, 1.39 mmol, 111.97 uL, 2 eq). The mixture was stirred at 20°C for 2 hr.10 mL of water was added to the mixture, the mixture was extracted with dichloromethane (20 mL*2), the combined extracts were dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18250*50mm*10 um;mobile phase: [water(TFA)-ACN];B%: 40%-70%,10 min). N-(tert-butyl)-4-(3-hydroxy- 2-oxo-1-(6-(trifluoromethoxy)naphthalen-1-yl)indolin-3-yl)benzenesulfonamide and N-(tert- butyl)-4-(3-hydroxy-2-oxo-1-(7-(trifluoromethoxy)naphthalen-1-yl)indolin-3- yl)benzenesulfonamide (110 mg, 192.79 μmol, 27.79% yield) was obtained as yellow solid. MS (M + H)+ = 571.0 Synthesis of 4-(3-hydroxy-2-oxo-1-(6-(trifluoromethoxy)naphthalen-1-yl)indolin-3- yl)benzenesulfonamide and 4-(3-hydroxy-2-oxo-1-(7-(trifluoromethoxy)naphthalen-1- yl)indolin-3-yl)benzenesulfonamide (33A&40A) [0250] To a solution of N-(tert-butyl)-4-(3-hydroxy-2-oxo-1-(6- (trifluoromethoxy)naphthalen-1-yl)indolin-3-yl)benzenesulfonamide and N-(tert-butyl)-4-(3- hydroxy-2-oxo-1-(7-(trifluoromethoxy)naphthalen-1-yl)indolin-3-yl)benzenesulfonamide (100 mg, 175.26 μmol, 1 eq) in dichloromethane (2 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 76.81 eq). The mixture was stirred at 50°C for 3 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [water( NH4HCO3)-ACN];gradient:35%-55% B over 8 min) to give desired compound. A mixture of 4-(3-hydroxy-2-oxo-1-(6-(trifluoromethoxy)naphthalen-1-yl)indolin-3- yl)benzenesulfonamide and 4-(3-hydroxy-2-oxo-1-(7-(trifluoromethoxy)naphthalen-1- yl)indolin-3-yl)benzenesulfonamide (20 mg, 38.87 μmol, 22.18% yield, 100% purity) was obtained. 1H NMR (400 MHz, Methanol-d4) δ 8.21 - 8.13 (m, 3H), 8.00 - 7.92 (m, 5H), 7.81 - 7.63 (m, 9H), 7.36 (br d, J = 0.6 Hz, 9H), 6.48 (ddd, J = 2.9, 7.7, 14.9 Hz, 2H) MS (M + H)+ = 515.0 Example 7. Synthesis of Compound NEM-42A benzenesulfonamide (2) [0251] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (150 mg, 416.17 μmol, 1 eq) in DMF (2 mL) was added K2CO3 (143.79 mg, 1.04 mmol, 2.5 eq) and 1-bromo-4-(1-bromoethyl)benzene (153.79 mg, 582.64 μmol, 1.4 eq). The mixture was stirred at 60°C for 2 h. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl, extracted with EtOAc (10 mL*3). The residue was purified by flash silica gel chromatography (ISCO; 4 g SepaFlash Silica Flash Column, Eluent of 0~90% Ethyl acetate/Petroleum ether gradient @ 36 mL/min). Compound 4-[1-[1- (4-bromophenyl)ethyl]-3-hydroxy-2-oxo-indolin-3-yl]-N-tert-butyl-benzenesulfonamide (150 mg, 276.00 μmol, 66.32% yield) as a yellow solid. Synthesis of N-tert-butyl-4-[3-hydroxy-1-[1-(4-morpholinophenyl)ethyl]-2-oxo-indolin- 3-yl]benzenesulfonamide (3) [0252] A mixture of 4-[1-[1-(4-bromophenyl)ethyl]-3-hydroxy-2-oxo-indolin-3-yl]-N- tert-butyl-benzenesulfonamide (100 mg, 184.00 μmol, 1 eq), morpholine (32.06 mg, 368.00 μmol, 32.38 μL, 2 eq), BrettPhos Pd G3 (33.36 mg, 36.80 μmol, 0.2 eq), sodium;2- methylpropan-2-olate (53.05 mg, 552.01 μmol, 3 eq) in 2-methylbutan-2-ol (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 h under N2 atmosphere. The mixture quenched with H2O (5 mL), extracted with EtOAc (10 mL*3). The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash silica gel chromatography (ISCO; 4 g SepaFlash Silica Flash Column, Eluent of 10~50% Ethyl acetate/Petroleum ether gradient @ 36 mL/min). Compound N-tert-butyl-4-[3-hydroxy-1-[1-(4-morpholinophenyl)ethyl]-2-oxo- indolin-3-yl]benzenesulfonamide (78 mg, 141.90 μmol, 77.12% yield) as a yellow solid. MS (M + H)+ = 550.2 Synthesis of 4-[3-hydroxy-1-[1-(4-morpholinophenyl)ethyl]-2-oxo-indolin-3- yl]benzenesulfonamide (NEM-42A) [0253] To a solution of N-tert-butyl-4-[3-hydroxy-1-[1-(4-morpholinophenyl)ethyl]-2- oxo-indolin-3-yl]benzenesulfonamide (60 mg, 109.15 μmol, 1 eq) in DCE (2 mL) was added TFA (2.30 g, 20.19 mmol, 1.50 mL, 185.00 eq), the mixture was stirred at 60°C for 2 h. The mixture was evaporated to afford the crude product. The residue was purified by prep-HPLC (column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1%TFA)- ACN];gradient:20%-50% B over 8.0 min).4-[3-hydroxy-1-[1-(4-morpholinophenyl)ethyl]- 2-oxo-indolin-3-yl]benzenesulfonamide (13 mg, 25.55 μmol, 23.41% yield, 97% purity) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ 7.87 (dd, J = 8.5, 12.3 Hz, 2H), 7.55 - 7.46 (m, 2H), 7.41 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.21 - 7.15 (m, 2H), 7.12 - 7.00 (m, 3H), 6.77 (dd, J = 4.9, 7.9 Hz, 1H), 5.68 (quin, J = 7.3 Hz, 1H), 3.89 - 3.83 (m, 4H), 3.25 - 3.20 (m, 4H), 1.85 (dd, J = 4.6, 7.2 Hz, 3H) MS (M + H)+ = 494.2
Example 8. Synthesis of Compound NEM-43A [0254] To a solution of 4-bromo-3,5-difluoro-benzoic acid (2 g, 8.44 mmol, 1 eq) in THF (20 mL) was added dropwise BH3.THF (1 M, 25.32 mL, 3 eq) at 0°C over 15 min. After addition, the mixture was stirred at this temperature for 30 min then stirred at 20°C for 5 hr. The mixture was cooled to 0°C and quenched with MeOH (5 mL), then diluted with H2O 30 mL and extracted with ethyl acetate 90 mL (30mL * 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure to give a residue. Compound (4-bromo-3,5-difluorophenyl)methanol (1.5 g, crude) was obtained as a white solid. Synthesis of 2-bromo-5-(bromomethyl)-1,3-difluoro-benzene (3) [0255] To a solution of (4-bromo-3,5-difluoro-phenyl)methanol (1.35 g, 6.05 mmol, 1 eq) in DCM (15 mL) was added dropwise PBr3 (1.80 g, 6.66 mmol, 1.1 eq) at 0°C. After addition, the mixture was stirred at this temperature for 5 min, and then the resulting mixture was stirred at 20°C for 1hr. The reaction mixture was quenched by addition NaHCO3 aq (20 mL) at 0°C, and then extracted with dichloromethane 60 mL (20 mL * 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give crude product. Compound 2-bromo-5-(bromomethyl)-1,3-difluoro- benzene (800 mg, 2.80 mmol, 46.22% yield) was obtained as a yellow solid which was used into the next step without further purification. Synthesis of 4-[1-[(4-bromo-3,5-difluoro-phenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]- N-tert-butyl-benzenesulfonamide (4) [0256] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (100 mg, 277.45 μmol, 1eq) in DMF (3 mL) was added K2CO3 (115.03 mg, 832.35 μmol, 3 eq) and 2-bromo-5-(bromomethyl)-1,3-difluoro-benzene (103.12 mg, 360.68 μmol, 1.3 eq). The mixture was stirred at 60°C for 3 h. The reaction mixture was diluted with H2O (10 mL), extracted with ethyl acetate (10 mL*2). The organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give a residue. Compound 4-[1-[(4-bromo-3,5-difluoro-phenyl)methyl]-3-hydroxy-2-oxo- indolin-3-yl]-N-tert-butyl-benzenesulfonamide (100 mg, 176.86 μmol, 63.74% yield) was obtained as a yellow solid. MS (M + H)+ = 565.1 Synthesis of N-tert-butyl-4-[1-[(3,5-difluoro-4-morpholino-phenyl)methyl]-3-hydroxy- 2-oxo-indolin-3-yl]benzenesulfonamide [0257] A mixture of 4-[1-[(4-bromo-3,5-difluoro-phenyl)methyl]-3-hydroxy-2-oxo- indolin-3-yl]-N-tert-butyl-benzenesulfonamide (100 mg, 176.86 μmol, 1 eq), morpholine (30.82 mg, 353.72 μmol, 31.13 μL, 2 eq) and Cs2CO3 (115.25 mg, 353.72 μmol, 2 eq), t- BuBrettphos Pd G3 (22.67 mg, 26.53 μmol, 0.15 eq) in 2-methylbutan-2-ol (1 mL) was stirred at 90°C for 12 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove 2-methylbutan-2-ol. The residue was diluted with water (5 mL) and extracted with ethyl acetate (5 mL*3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 8 g silica, 0-50 % ethyl acetate in petroleum ether, gradient over 20 min). Compound N-tert-butyl-4-[1-[(3,5-difluoro-4-morpholino- phenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (50 mg, 87.47 μmol, 49.46% yield) was obtained as a yellow solid. MS (M + H)+ = 572.4. Synthesis of 4-[1-[(3,5-difluoro-4-morpholino-phenyl)methyl]-3-hydroxy-2-oxo-indolin- 3-yl]benzenesulfonamide (NEM-43A) [0258] To a solution of N-tert-butyl-4-[1-[(3,5-difluoro-4-morpholino-phenyl)methyl]-3- hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (50 mg, 87.47 μmol, 1 eq) in DCM (1 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 153.91 eq). The mixture was stirred at 60°C for 2 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [water( NH4HCO3)-ACN];gradient:35%-55% B over 8 min).4-[1-[(3,5-difluoro-4-morpholino-phenyl)methyl]-3-hydroxy-2-oxo-indolin-3- yl]benzenesulfonamide (6 mg, 11.06 μmol, 12.64% yield, 95% purity) was obtained.1H NMR (400 MHz, METHANOL-d4) δ 7.86 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.37 - 7.32 (m, 1H), 7.23 (d, J = 6.8 Hz, 1H), 7.15 - 7.10 (m, 1H), 7.01 - 6.93 (m, 3H), 4.98 - 4.91 (m, 2H), 3.78 - 3.73 (m, 4H), 3.16 - 3.12 (m, 4H) MS (M + H)+ = 516.0. Example 9. Synthesis of Compound NEM-44A dioxaborolan-2-yl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (2) [0259] A mixture of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N- tert-butyl-benzenesulfonamide (200 mg, 377.75 μmol, 1 eq), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(1,3,2-dioxaborolane) (287.78 mg, 1.13 mmol, 3 eq), cyclopentyl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron (61.70 mg, 75.55 μmol, 0.2 eq), KOAc (74.15 mg, 755.51 μmol, 2 eq) in dioxane (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 2 h under N2 atmosphere.10 mL of water was added to the mixture and the mixture was extracted with ethyl acetate (20 mL*2). The combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica, 0-20 % ethyl acetate in petroleum ether, gradient over 20 min). Compound N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (200 mg, 346.92 μmol, 91.84% yield) was obtained as a brown oil. MS (M + H)+ = 577.2 Synthesis of tert-butyl 4-[4-[[3-[4-(tert-butylsulfamoyl)phenyl]-3-hydroxy-2-oxo- indolin-1-yl]methyl]phenyl]-2-oxo-piperidine-1-carboxylate (3) [0260] A mixture of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (180 mg, 312.22 μmol, 1 eq), tert-butyl 6-oxo-2,3-dihydropyridine-1-carboxylate (80.05 mg, 405.89 μmol, 1.3 eq), chlororhodium;(1Z,5Z)-cycloocta-1,5-diene (3.85 mg, 7.81 μmol, 0.025 eq), K3PO4 (1.5 M, 312.22 μL, 1.5 eq) in dioxane (3 mL) and H2O (0.2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 2 hr under N2 atmosphere.10 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (20 mL*2). The combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica, 0-60 % ethyl acetate in petroleum ether, gradient over 20 min). Compound tert-butyl 4-[4-[[3-[4-(tert-butylsulfamoyl)phenyl]-3-hydroxy-2-oxo-indolin-1- yl]methyl]phenyl]-2-oxo-piperidine-1-carboxylate (50 mg, 77.19 μmol, 24.72% yield) was obtained as a yellow solid. MS (M + H)+ = 648.2 Synthesis of 4-[3-hydroxy-2-oxo-1-[[4-(2-oxo-4-piperidyl)phenyl]methyl]indolin-3- yl]benzenesulfonamide (NEM-44A) [0261] A mixture of tert-butyl 4-[4-[[3-[4-(tert-butylsulfamoyl)phenyl]-3-hydroxy-2- oxo-indolin-1-yl]methyl]phenyl]-2-oxo-piperidine-1-carboxylate (40 mg, 61.75 μmol, 1 eq) in DCE (2 mL) and TFA (0.8 mL). The mixture was stirred at 45°C for 2 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1%TFA)- ACN];gradient:15%-45% B over 8.0 min. Compound 4-[3-hydroxy-2-oxo-1-[[4-(2-oxo-4- piperidyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (5.23 mg, 10.64 μmol, 17.23% yield, 100% purity). 1H NMR (400 MHz, METHANOL-d4) δ 7.87 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.39 - 7.35 (m, 2H), 7.33 (s, 1H), 7.30 - 7.26 (m, 2H), 7.23 (d, J = 7.4 Hz, 1H), 7.11 (s, 1H), 7.01 (d, J = 8.0 Hz, 1H), 4.97 (d, J = 9.9 Hz, 2H), 3.42-3.38 (m, 2H), 3.18 - 3.10 (m, 1H), 2.62 - 2.54 (m, 1H), 2.49 - 2.40 (m, 1H), 2.09 - 2.01 (m, 1H), 2.01 - 1.89 (m, 1H) MS (M + H)+ = 492.0 Example 10. Synthesis of Compound NEM-46A [0262] To a solution of 4-[4-(chloromethyl)phenyl]pyridine (200 mg, 832.89 μmol, 1 eq, HCl) in DCM (2 mL) was added NaOH (2 M, 832.89 μL, 2 eq) in H2O (2 mL). The mixture was stirred at 20°C for 30 min and then the reaction mixture was extracted with chloroform (20 mL) twice. The chloroform layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue dissolved in DCM (2 mL) was added m-CPBA (359.32 mg, 1.67 mmol, 80% purity, 2 eq) and the reaction was stirred at 20°C for 2 hrs. The mixture was poured into Na2SO3 aqueous (5 mL), and then aqueous NaHCO3(5 mL) was added. The mixture was extracted with DCM (10 mL*3). The organic layer was washed with brine (5 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)- ACN];gradient:17%-47% B over 8.0 min) to give 4-[4-(chloromethyl)phenyl]-1-oxido- pyridin-1-ium (0.05 g, 227.62 μmol, 27.33% yield) as a yellow solid . 1H NMR (400 MHz, METHANOL-d4) δ 8.41 - 8.36 (d, J = 6.8 Hz, 2H), 7.89 (d, J = 6.8 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 4.71 (s, 2H). Synthesis of N-tert-butyl-4-[3-hydroxy-1-[[4-(1-oxidopyridin-1-ium-4- yl)phenyl]methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (3) [0263] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (36.96 mg, 102.56 μmol, 1 eq) in DMF (1 mL) was added K2CO3 (35.44 mg, 256.40 μmol, 2.5 eq) and 4-[4-(chloromethyl)phenyl]-1-oxido-pyridin-1-ium (24.78 mg, 112.81 μmol, 1.1 eq). The mixture was stirred at 60°C for 3 h. The mixture was cooled to 20°C, 5 mL water was added to the mixture. The mixture was filtered through a Celite pad, and the filtrate was concentrated to give crude product N-tert-butyl-4-[3- hydroxy-1-[[4-(1-oxidopyridin-1-ium-4-yl)phenyl]methyl]-2-oxo-indolin-3- yl]benzenesulfonamide (40 mg, crude) as a yellow solid. MS (M + H)+ = 544.2 Synthesis of 4-[3-hydroxy-1-[[4-(1-oxidopyridin-1-ium-4-yl)phenyl]methyl]-2-oxo- indolin-3-yl]benzenesulfonamide (NEM-46A) [0264] To a solution of N-tert-butyl-4-[3-hydroxy-1-[[4-(1-oxidopyridin-1-ium-4- yl)phenyl]methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (30 mg, 55.18 μmol, 1 eq) in DCM (1 mL) was added TFA (345.38 mg, 3.03 mmol, 225.00 μL, 54.89 eq). The mixture was stirred at 40°C for 2 h. The reaction was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:5%-45% B over 8.0 min).4-[3-hydroxy-1-[[4-(1-oxidopyridin-1-ium-4-yl)phenyl]methyl]-2-oxo-indolin-3- yl]benzenesulfonamide (9.8 mg, 20.10 μmol, 36.43% yield, 100% purity) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ 8.35 - 8.33 (d, J = 8.4 Hz, 2H), 7.90 - 7.82 (m, 4H), 7.76 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.6 Hz, 4H), 7.32 (dt, J = 1.3, 7.8 Hz, 1H), 7.23 (dd, J = 0.8, 7.4 Hz, 1H), 7.15 - 7.08 (m, 1H), 7.01 (d, J = 8.0 Hz, 1H), 5.04 (d, J = 2.4 Hz, 2H). Example 11. Synthesis of Compound NEM-47A [0265] To a solution of 4-bromo-N-tert-butyl-benzenesulfonamide (707.82 mg, 2.42 mmol, 2 eq) in THF (5 mL) was added dropwise n-BuLi (2.5 M, 1.94 mL, 4 eq) at -70°C and stirred for 20 min, then added dropwise 5-fluoroindoline-2,3-dione (200 mg, 1.21 mmol, 1 eq) in THF (2 mL) at -70 °C, the mixture was stirred at -70 °C for 2 hr. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl, extracted with EtOAc (10 mL*3). The organic layer was washed with brine, dried over MgSO4 and evaporated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 5- 30% ethyl acetate in petroleum ether). N-tert-butyl-4-(5-fluoro-3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (120 mg, 317.11 μmol, 26.18% yield) was obtained as a light yellow oil.1H NMR (400 MHz, ACETONITRILE-d3) δ 8.64 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz 2H), 7.11 - 7.02 (m, 1H), 7.01 - 6.92 (m, 2H), 5.67 (s, 1H), 4.91 (s, 1H), 1.13 (s, 9H). 2. Synthesis of N-tert-butyl-4-[5-fluoro-3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (3) [0266] To a solution of N-tert-butyl-4-(5-fluoro-3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (70 mg, 184.98 μmol, 1 eq) in DMF (2 mL) was added 4-[4- (chloromethyl)phenyl]pyridine (48.98 mg, 240.48 μmol, 1.3 eq), K2CO3 (76.70 mg, 554.94 μmol, 3 eq), the mixture was stirred at 60°C for 2 hr.10 mL of water was added to the mixture, the mixture was extracted with EtOAc (10 mL*3). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give a residue. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-60% ethyl acetate in petroleum ether). N-tert-butyl-4-[5-fluoro-3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3- yl]benzenesulfonamide (100 mg, 183.28 μmol, 99.08% yield) was obtained as a yellow solid. MS (M + H)+ = 546.2 3. Synthesis of 4-[5-fluoro-3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3- yl]benzenesulfonamide (4) [0267] To a solution of N-tert-butyl-4-[5-fluoro-3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (90 mg, 164.95 μmol, 1 eq) in DCE (2 mL) was added TFA (767.50 mg, 6.73 mmol, 0.5 mL, 40.81 eq), the mixture was stirred at 60°C for 2hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:30%-50% B over 8.0 min).4-[5-fluoro-3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3- yl]benzenesulfonamide (12.8 mg, 26.15 μmol, 15.85% yield, 100% purity) was obtained.1H NMR (400 MHz, METHANOL-d4) δ 8.60 - 8.54 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.73 - 7.69 (m, 2H), 7.57 - 7.50 (m, 4H), 7.11 - 7.04 (m, 1H), 7.04 - 6.98 (m, 2H), 5.04 (d, J = 1.9 Hz, 2H). MS (M + H)+ = 490.1 Example 12. Synthesis of Compound NEM-48A dioxaborolan-2-yl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (2) [0268] A mixture of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N- tert-butyl-benzenesulfonamide (100 mg, 188.88 μmol, 1 eq) and 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (143.89 mg, 566.63 μmol, 3 eq), KOAc (37.07 mg, 377.75 μmol, 2 eq), cyclopentyl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron (46.27 mg, 56.66 μmol, 0.3 eq) in dioxane (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 2 hr under N2 atmosphere.5 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (10 mL * 2) , and the combined extracts were washed with brine (10 mL), dried over anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether). Compound N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (90 mg, 156.11 μmol, 82.65% yield) was obtained as light yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ 7.85 - 7.83 (d, J = 7.6 Hz, 2H), 7.82 - 7.77 (m, 2H), 7.51 - 7.49 (d, J = 7.6 Hz, 2H), 7.32 (d, J = 7.6 Hz, 2H), 7.26 - 7.22 (m, 2H), 7.10 - 7.04 (m, 1H), 6.80 (d, J = 7.8 Hz, 1H), 5.09 (d, J = 15.6 Hz, 1H), 4.84 (d, J = 15.6 Hz, 1H), 4.57 (s, 1H), 1.29 - 1.27 (s, 9H), 1.25 (s, 12H) 2. Synthesis of N-tert-butyl-4-[1-[[4-(3,5-difluoro-4-pyridyl)phenyl]methyl]-3- hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (3) [0269] A mixture of 4-bromo-3,5-difluoro-pyridine (23.55 mg, 121.42 μmol, 1 eq), N- tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (70 mg, 121.42 μmol, 1 eq), K3PO4 (51.55 mg, 242.84 μmol, 2 eq), cyclopentyl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron (19.83 mg, 24.28 μmol, 0.2 eq) in DME (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2 atmosphere.5 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (5 mL * 3) and the combined extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether). Compound N-tert-butyl-4-[1-[[4-(3,5-difluoro-4-pyridyl)phenyl]methyl]-3-hydroxy-2-oxo- indolin-3-yl]benzenesulfonamide (45 mg, 79.84 μmol, 65.76% yield) was obtained as light yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ 8.41 (br s, 2H), 7.87 (d, J = 8.4 Hz, 2H), 7.57 - 7.41 (m, 6H), 7.40 - 7.29 (m, 2H), 7.16 - 7.09 (m, 1H), 6.89 (d, J = 7.8 Hz, 1H), 5.13 - 4.93 (m, 2H), 4.53 (s, 1H), 1.25 (s, 9H) 3. Synthesis of 4-[1-[[4-(3,5-difluoro-4-pyridyl)phenyl]methyl]-3-hydroxy-2-oxo- indolin-3-yl]benzenesulfonamide (NEM-48A) [0270] To a solution of N-tert-butyl-4-[1-[[4-(3,5-difluoro-4-pyridyl)phenyl]methyl]-3- hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (45 mg, 79.84 μmol, 1 eq) in DCE (1 mL) was added TFA (3.07 g, 26.92 mmol, 2 mL, 337.22 eq). The mixture was stirred at 50°C for 2 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 80*40mm*3um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:30%-60% B over 8.0 min). Compound 4-[1-[[4-(3,5-difluoro-4-pyridyl)phenyl]methyl]-3-hydroxy-2-oxo-indolin-3- yl]benzenesulfonamide (19.9 mg, 31.70 μmol, 39.70% yield, 99% purity, TFA salt) was obtained.1H NMR (400 MHz, METHANOL-d4) δ 8.48 (s, 2H), 7.87 (d, J = 7.8 Hz, 2H), 7.56 - 7.54 (m, 5H), 7.54 - 7.52 (m, 1H), 7.34 (dt, J = 1.1, 7.8 Hz, 1H), 7.26 - 7.22 (d, J = 7.8 Hz, 1H), 7.15 - 7.09 (dt, J = 1.1, 7.8 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 5.07 (s, 2H) MS (M + H)+ = 508.1. Example 13. Synthesis of Compound NEM-49A yl)benzenesulfonamide (2) [0271] To a solution of 4-bromo-N-tert-butyl-benzenesulfonamide (1.77 g, 6.06 mmol, 2 eq) in THF (10 mL) was added dropwise n-BuLi (2.5 M, 4.84 mL, 4 eq) at -70°C and stirred for 20 min, then added dropwise 5-fluoroindoline-2,3-dione (500 mg, 3.03 mmol, 1 eq) in THF (10 mL) at -70°C, the mixture was stirred at -70°C for 2 hr. The reaction was quenched by addition of ice sat NH4Cl (5 mL) at 0 °C, and extracted with ethyl acetate (15 mL * 3), the combined extracts were washed with brine (10 mL), dried over anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, 100-200 mesh, 5-30% ethyl acetate in petroleum ether). Compound N-tert-butyl-4-(5-fluoro-3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (350 mg, 924.91 μmol, 30.54% yield) was obtained as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.86 (d, J = 8.4 Hz, 2H), 7.63 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.10 - 6.90 (m, 3H), 4.63 (s, 1H), 3.59 (s, 1H), 1.24 (s, 9H) 2. Synthesis of 4-[1-[1-(4-bromophenyl)ethyl]-5-fluoro-3-hydroxy-2-oxo-indolin-3-yl]- N-tert-butyl-benzenesulfonamide (3) [0272] To a solution of N-tert-butyl-4-(5-fluoro-3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (250 mg, 660.65 μmol, 1 eq) in DMF (4 mL) was added K2CO3 (228.26 mg, 1.65 mmol, 2.5 eq) and 1-bromo-4-(1-bromoethyl)benzene (209.26 mg, 792.78 μmol, 1.2 eq). The mixture was stirred at 60°C for 12 hr.20 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (10 mL*2) , and the combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether). Compound 4-[1-[1-(4-bromophenyl)ethyl]-5-fluoro-3-hydroxy-2-oxo-indolin-3-yl]-N-tert- butyl-benzenesulfonamide (160 mg, 284.97 μmol, 43.14% yield) was obtained as light yellow oil. MS (M + H)+ = 561.0. 3. Synthesis of N-tert-butyl-4-[5-fluoro-3-hydroxy-2-oxo-1-[1-[4-[2-(trifluoromethyl)- 4-pyridyl]phenyl]ethyl]indolin-3-yl]benzenesulfonamide (4) [0273] A mixture of 4-[1-[1-(4-bromophenyl)ethyl]-5-fluoro-3-hydroxy-2-oxo-indolin- 3-yl]-N-tert-butyl-benzenesulfonamide (140 mg, 249.35 μmol, 1 eq), 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (74.90 mg, 274.28 μmol, 1.1 eq), K3PO4 (105.86 mg,498.70μmol,2eq), cyclopentyl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron (40.73 mg, 49.87 μmol, 0.2 eq) in DME (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2 atmosphere.5 mL of water was added to the mixture, the mixture was extracted with dichloromethane (10 mL*3), the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether). Compound N-tert-butyl-4-[5-fluoro-3-hydroxy-2-oxo-1-[1-[4-[2-(trifluoromethyl)-4- pyridyl]phenyl]ethyl]indolin-3-yl]benzenesulfonamide (50 mg, 79.66 μmol, 31.95% yield) was obtained as light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.81 - 8.77 (m, 1H), 7.91 - 7.84 (m, 3H), 7.74 - 7.65 (m, 3H), 7.55 - 7.46 (m, 4H), 7.00 - 6.95 (m, 1H), 6.93 - 6.84 (m, 1H), 6.62 - 6.57 (m, 1H), 4.80 (br d, J = 4.6 Hz, 1H), 1.98 - 1.89 (m, 3H), 1.26 (s, 9H) 4. Synthesis of 4-[5-fluoro-3-hydroxy-2-oxo-1-[1-[4-[2-(trifluoromethyl)-4- pyridyl]phenyl]ethyl]indolin-3-yl]benzenesulfonamide (NEM-49A) [0274] To a solution of N-tert-butyl-4-[5-fluoro-3-hydroxy-2-oxo-1-[1-[4-[2- (trifluoromethyl)-4-pyridyl]phenyl]ethyl]indolin-3-yl]benzenesulfonamide (50 mg, 79.66 μmol, 1 eq) in DCE (1 mL) was added TFA (3.07 g, 26.92 mmol, 2.00 mL, 337.98 eq). The mixture was stirred at 50°C for 2 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1% TFA)- ACN];gradient:40%-70% B over 8.0 min). Compound 4-[5-fluoro-3-hydroxy-2-oxo-1-[1-[4- [2-(trifluoromethyl)-4-pyridyl]phenyl]ethyl]indolin-3-yl]benzenesulfonamide (50 mg, 72.93 μmol, 91.55% yield, 100% purity, TFA salt) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ 8.78 - 8.71 (m, 1H), 8.09 (br d, J = 4.5 Hz, 1H), 7.95 - 7.82 (m, 5H), 7.66 (d, J = 8.3 Hz, 1H), 7.63-7.50 (m, 3H), 7.04 - 6.92 (m, 2H), 6.81 - 6.74 (m, 1H), 5.84 - 5.74 (m, 1H), 1.93 (dd, J = 4.6, 7.1 Hz, 3H) Example 14. Synthesis of Compound NEM-50A 1. Synthesis of 4-(4-pyridyl)benzoyl chloride (2) [0275] To a solution of 4-(4-pyridyl)benzoic acid (100 mg, 502.00 μmol, 1 eq) in DCM (1 mL) was added dropwise oxalyl dichloride (95.57 mg, 752.99 mol, 65.91 μL, 1.5 eq) at 0oC. Then DMF (55.04 mg, 752.99 μmol, 57.94 μL, 1.5 eq) was added. The mixture was stirred at 20oC for 1h. The product fraction was evaporated under reduced pressure. The crude product 4-(4-pyridyl)benzoyl chloride (80 mg, crude) was obtained as a white solid which was used into the next step without further purification. 2. Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[4-(4-pyridyl)benzoyl]indolin-3- yl]benzenesulfonamide (3) [0276] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (150 mg, 416.17 μmol, 1 eq) in DCM (3 mL) was added DIEA (161.36 mg, 1.25 mmol , 217.47 μL, 3 eq), then 4-(4-pyridyl)benzoyl chloride (181.16 mg, 832.35 μmol , 2 eq) was added dropwise at 0°C. The resulting mixture was stirred at 20°C for 5 hr.20 mL of water was added to the mixture, the mixture was extracted with dichloromethane (10 mL*2). The combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0-100 % ethyl acetate in petroleum ether, gradient over 20 min). Compound N-tert-butyl-4-[3-hydroxy-2-oxo-1-[4-(4- pyridyl)benzoyl]indolin-3-yl]benzenesulfonamide (70 mg, 129.24 μmol, 31.06% yield) was obtained as a light yellow oil. MS (M + H)+ = 542.2 3. Synthesis of 4-[3-hydroxy-2-oxo-1-[4-(4-pyridyl)benzoyl]indolin-3- yl]benzenesulfonamide (NEM-50A) [0277] To a solution of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[4-(4- pyridyl)benzoyl]indolin-3-yl]benzenesulfonamide (70 mg, 129.24 μmol, 1 eq) in DCE (1 mL) was added TFA (3.07 g, 26.92 mmol, 2 mL, 208.32 eq). The mixture was stirred at 50°C for 2 hr. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:15%-45%B over 8.0 min). Compound 4-[3-hydroxy-2-oxo- 1-[4-(4-pyridyl)benzoyl]indolin-3-yl]benzenesulfonamide (2.7 mg, 4.32 μmol, 3.35% yield, 96% purity, TFA salt) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ 8.81 (br d, J = 5.0 Hz, 2H), 8.29 (d, J = 8.4 Hz, 2H), 8.19 - 8.12 (m, 2H), 8.05 (d, J = 8.1 Hz, 2H), 7.96 (d, J = 8.6 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 7.41 (t, J = 7.7 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.13 - 7.05 (m, 2H) MS (M + H)+ = 486.1 Example 15. Synthesis of Compound NEM-51A [0278] To a solution of 4-morpholinobenzoic acid (200 mg, 965.13 μmol, 1 eq) in DCM (2 mL) was added oxalyl dichloride (147.00 mg, 1.16 mmol, 101.38 μL, 1.2 eq) and DMF (9.50 mg, 129.97 μmol, 10.00 μL, 1.35e-1 eq). The mixture was stirred at 20°C for 2 hr. The reaction mixture was concentrated under reduced pressure to give a solid. Compound 4- morpholinobenzoyl chloride (180 mg, crude) was obtained as a yellow solid which was used in next step without purification. 2. Synthesis of N-tert-butyl-4-[3-hydroxy-1-(4-morpholinobenzoyl)-2-oxo-indolin-3- yl]benzenesulfonamide (3) [0279] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (80 mg, 221.96 μmol, 1 eq) in DCM (2 mL) was added DIEA (114.75 mg, 887.84 μmol, 154.65 μL, 4 eq) and 4-morpholinobenzoyl chloride (100.18 mg, 443.92 μmol, 2 eq). The mixture was stirred at 20°C for 2 hr.10 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (20 mL*2). The combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)- ACN];gradient:32%-60% B over 8.0 min ). Compound N-tert-butyl-4-[3-hydroxy-1-(4- morpholinobenzoyl)-2-oxo-indolin-3-yl]benzenesulfonamide (30 mg, 54.58 μmol, 24.59% yield) was obtained as a yellow solid. MS (M + H)+ = 550.2 3. Synthesis of 4-[3-hydroxy-1-(4-morpholinobenzoyl)-2-oxo-indolin-3- yl]benzenesulfonamide (NEM-51A) [0280] To a solution of N-tert-butyl-4-[3-hydroxy-1-(4-morpholinobenzoyl)-2-oxo- indolin-3-yl]benzenesulfonamide (30 mg, 54.58 μmol, 1 eq) in DCE (1 mL) was added TFA (3.07 g, 26.92 mmol, 2 mL, 493.29 eq). The mixture was stirred at 50°C for 2 hr. The product fraction was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge C18150*50mm* 10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:20%-60% B over 8.0 min) the HPLC fractions were combined, lyophilized to give the desire compound as a white solid. Compound 4-[3- hydroxy-1-(4-morpholinobenzoyl)-2-oxo-indolin-3-yl]benzenesulfonamide (8 mg, 16.21 μmol, 29.70% yield, 100% purity) was obtained. 1H NMR (400 MHz, ACETONITRILE- d3) δ 8.65 (s, 1H), 7.96 (d, J = 8.6 Hz, 2H), 7.88 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 8.6 Hz, 2H), 7.39 - 7.34 (m, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.08 - 7.02 (m, 2H), 6.98 - 6.93 (d, J = 8.6 Hz, 2H), 5.65 (s, 2H), 3.82 - 3.74 (m, 4H), 3.35 - 3.26 (m, 4H) MS (M + H)+ = 494.1 Example 16. Synthesis of Compound NEM-61A yl)benzenesulfonamide (2) [0281] To a solution of 4-bromo-N-tert-butyl-benzenesulfonamide (321.84 mg, 1.10 mmol, 2 eq) in THF (2 mL) was added dropwise n-BuLi (2.5 M, 881.18 μL, 4 eq) at -70°C over 5 min. After addition, the mixture was stirred at this temperature for 25 min, and then 5-chloroindoline-2,3-dione (100 mg, 550.73 μmol, 1 eq) in THF (3 mL) was added dropwise at -70°C. The resulting mixture was stirred at -70°C for 2hr. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl, extracted with ethyl acetate (20 mL*2). The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash column (ISCO 10 g silica, 0-8 % methanol in dichloromethane, gradient over 20 min). N-tert-butyl-4-(5-chloro-3-hydroxy-2-oxo-indolin- 3-yl)benzenesulfonamide (100 mg, 253.25 μmol, 45.98% yield) as a yellow solid. 2. Synthesis of N-tert-butyl-4-[5-chloro-3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (3) [0282] To a solution of N-tert-butyl-4-(5-chloro-3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (50 mg, 126.62 μmol, 1 eq) in DMF (1 mL) was added K2CO3 (43.75 mg, 316.56 μmol, 2.5 eq) and 4-[4-(chloromethyl)phenyl]pyridine (33.45 mg, 164.22 μmol, 1.30 eq). The mixture was stirred at 60°C for 2 h.5 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (20 mL*2). The combined extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The crude product N-tert-butyl-4-[5- chloro-3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (0.05 g, 88.96 μmol, 70.25% yield) was obtained as a yellow solid which was used into the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.58 (br s, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.71 (br s, 2H), 7.61 (br d, J = 7.6 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.43 (br d, J = 7.6 Hz, 2H), 7.31 - 7.28 (m, 2H), 6.78 (d, J = 9.0 Hz, 1H), 5.05 - 4.92 (m, 2H), 4.54 (s, 1H), 1.28 - 1.26 (s, 9H). 3. Synthesis of 4-[5-chloro-3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3- yl]benzenesulfonamide [0283] To a solution of N-tert-butyl-4-[5-chloro-3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (50 mg, 88.96 μmol, 1 eq) in DCE (1 mL) was added TFA (767.50 mg, 6.73 mmol, 0.5 mL, 75.67 eq). The mixture was stirred at 60 °C for 2 h. The mixture was concentrated to afford the crude product. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1%TFA)- ACN];gradient:10%-40% B over 8.0 min).4-[5-chloro-3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (21.9 mg, 35.32 μmol, 39.71% yield, 100% purity, TFA salt) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ 8.78 (d, J = 6.8 Hz, 2H), 8.23 (d, J = 6.8 Hz, 2H), 7.91 (dd, J = 8.4, 17.6 Hz, 4H), 7.60 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.34 (dd, J = 2.1, 8.4 Hz, 1H), 7.23 (d, J = 2.0 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 5.08 (s, 2H) Example 17. Synthesis of Compound NEM-62A yl)benzenesulfonamide (2) [0284] To a solution of 4-bromo-N-tert-butyl-benzenesulfonamide (1.61 g, 5.51 mmol, 2 eq) in THF (10 mL) was added dropwise n-BuLi (2.5 M, 4.41 mL, 4 eq) at - 70°C. After addition, the mixture was stirred at this temperature for 1 h, and then 4-chloroindoline-2,3- dione (500 mg, 2.75 mmol, 1 eq) in THF (10 mL) was added dropwise at - 70°C. the mixture was stirred at - 70°C for 2 h. The reaction was quenched by addition of ice sat. NH4Cl (20 mL) at 0°C, and extracted with ethyl acetate (30 mL*2), and the combined extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 10 g silica, 0~30% ethyl acetate in petroleum ether, gradient over 30 min). Compound N-tert- butyl-4-(4-chloro-3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (400 mg, 810.39 μmol, 29.43% yield, 80% purity) was obtained as red oil. MS (M + H)+ = 395.1 2. Synthesis of N-tert-butyl-4-[4-chloro-3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (3) [0285] To a solution of N-tert-butyl-4-(4-chloro-3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (100 mg, 253.25 μmol, 1 eq) in DMF (1 mL) was added 4-[4- (chloromethyl)phenyl]pyridine (61.89 mg, 303.90 μmol, 1.2 eq) and K2CO3 (105.00 mg, 759.74 μmol, 3 eq), the reaction was stirred at 80°C for 12 h. The mixture was added H2O (5 mL), extracted with EtOAc (10 mL*2). The combined organic layers were washed with brine (5 mL) and dried over Na2SO4 and concentrated to dryness to give a residue. The crude product was purified by flash column (ISCO 10 g silica, 0~60% ethyl acetate in petroleum ether, gradient over 30 min). Compound N-tert-butyl-4-[4-chloro-3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (70 mg, 112.08 μmol, 44.26% yield, 90% purity) was obtained as a yellow oil. MS (M + H)+ = 562.3 3. Synthesis of 4-[4-chloro-3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3- yl]benzenesulfonamide (NEM-62A) [0286] A mixture of N-tert-butyl-4-[4-chloro-3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (70 mg, 124.54 μmol, 1 eq) in DCE (1 mL) and TFA (2 mL) was stirred at 50 °C for 2 h. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:10%-40% B over 8.0 min). Compound 4-[4-chloro-3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin- 3-yl]benzenesulfonamide (17.8 mg, 28.71 μmol, 23.05% yield, 100% purity, TFA salt) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ 8.79 (d, J = 6.4 Hz, 2H), 8.28 - 8.20 (m, 2H), 7.93 (d, J = 8.3 Hz, 2H), 7.88 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 7.36 - 7.30 (m, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.99 (d, J = 7.9 Hz, 1H), 5.07 (d, J = 9.1 Hz, 2H). MS (M + H)+ = 506.1 Example 18. Synthesis of Compound NEM-63A Synthesis of N-tert-butyl-4-(7-chloro-3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (2) [0287] To a solution of 4-bromo-N-tert-butyl-benzenesulfonamide (1.61 g, 5.51 mmol, 2 eq) in THF (16 mL) was added dropwise n-BuLi (2.5 M, 4.41 mL, 4 eq) at -70°C under N2 atmosphere. After addition, the mixture was stirred at this temperature for 1hr, and then 7- chloroindoline-2,3-dione (500 mg, 2.75 mmol, 1 eq) in THF (5 mL) was added dropwise at - 70°C. The resulting mixture was stirred at -70°C for 2 h under N2 atmosphere. The reaction was quenched by addition of ice sat. NH4Cl (20mL) at 0 °C, and extracted with ethyl acetate (30 mL*2), and the combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica, 0-50 % ethyl acetate in petroleum ether, gradient over 20 min). Compound N-tert-butyl-4-(7-chloro-3-hydroxy-2- oxo-indolin-3-yl)benzenesulfonamide (330 mg, 835.71 μmol, 30.35% yield) was obtained as a yellow solid. MS (M + H)+ = 395.0 Synthesis of N-tert-butyl-4-[7-chloro-3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (3) [0288] To a solution of N-tert-butyl-4-(7-chloro-3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (100.00 mg, 253.25 μmol, 1 eq) in DMF (1 mL) was added 4-[4- (chloromethyl)phenyl]pyridine (61.89 mg, 303.90 μmol, 1.2 eq) and K2CO3 (105.00 mg, 759.74 μmol, 3 eq), the reaction was stirred at 80°C for 24 h.10 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (10 mL*3), and the combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0-100 % ethyl acetate in petroleum ether, gradient over 20 min). Compound N-tert-butyl-4-[7-chloro-3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (80 mg, 142.33 μmol) was obtained as a yellow solid. MS (M + H)+ = 562.1 Synthesis of 4-[7-chloro-3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3- yl]benzenesulfonamide (NEM-63A) [0289] A mixture of N-tert-butyl-4-[7-chloro-3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (70 mg, 124.54 μmol, 1 eq) in DCE (1 mL) and TFA (2 mL) was stirred at 50°C for 2 h. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:5%-35% B over 8.0 min). Compound 4-[7-chloro-3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin- 3-yl]benzenesulfonamide (24.20 mg, 38.64 μmol, 31.03% yield, 99% purity, TFA salt) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ 8.81 - 8.76 (m, 2H), 8.25 (br d, J = 6.4 Hz, 2H), 7.93 (d, J = 8.1 Hz, 2H), 7.89 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.33 (dd, J = 1.1, 8.1 Hz, 1H), 7.22 (dd, J = 1.1, 7.4 Hz, 1H), 7.15 - 7.10 (m, 1H), 5.47 (d, J = 3.5 Hz, 2H). MS (M + H)+ = 506.0 Example 19. Synthesis of Compound NEM-64A (2) [0290] To a solution of 4-bromo-N-tert-butyl-benzenesulfonamide (1.61 g, 5.51 mmol, 2 eq) in THF (10 mL) was added dropwise n-BuLi (2.5 M, 4.41 mL, 4 eq) at -70°C under N2 atmosphere. After addition, the mixture was stirred at this temperature for 1hr, and then 6- chloroindoline-2,3-dione (500 mg, 2.75 mmol, 1 eq) in THF (10 mL) was added dropwise at -70°C. The resulting mixture was stirred at -70°C for 2 h under N2 atmosphere. The reaction was quenched by addition of ice sat. NH4Cl (20 mL) at 0°C, extracted with ethyl acetate (10 mL*2). The combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 12 g silica, 0-50 % ethyl acetate in petroleum ether, gradient over 20 min). Compound N-tert-butyl-4-(6-chloro-3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (1 g, 2.41 mmol, 87.37% yield, 95% purity) was obtained as yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.76 (s, 1H), 7.82 (d, J = 8.4, 2H), 7.46 (d, J = 8.4, 2H), 7.33 - 7.24 (m, 1H), 7.08 (d, J = 7.2, 1H), 7.13 - 6.91 (m, 1H), 5.34 (s, 1H), 1.18 (s, 9H). Synthesis of N-tert-butyl-4-[6-chloro-3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (3) [0291] To a solution of N-tert-butyl-4-(6-chloro-3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (100.00 mg, 253.25 μmol, 1 eq) in DMF (1 mL) was added 4-[4- (chloromethyl)phenyl]pyridine (61.89 mg, 303.90 μmol, 1.2 eq) and K2CO3 (105.00 mg, 759.74 μmol, 3 eq), the reaction was stirred at 80°C for 12 h. The mixture was added H2O (5 mL), extracted with EtOAc (5 mL*2). The combined organic layers were washed with brine (5 mL) and dried over Na2SO4. The combined organic layer was concentrated to dryness to give residue. The crude product was purified by flash column (ISCO 10 g silica, 0~60% ethyl acetate in petroleum ether, gradient over 30 min). Compound N-tert-butyl-4-[6-chloro- 3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (80 mg, 142.33 μmol, 56.20% yield) was obtained as a yellow oil. MS (M + H)+ = 562.1 Synthesis of 4-[6-chloro-3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3- yl]benzenesulfonamide (NEM-64A) [0292] A mixture of N-tert-butyl-4-[6-chloro-3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (80 mg, 142.33 μmol, 1 eq) in DCE (1 mL) and TFA (1.14 mL) was stirred at 50°C for 2 hr. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:15%-40% B over 8.0 min). Compound 4-[6-chloro-3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin- 3-yl]benzenesulfonamide (18.20 mg, 29.06 μmol, 20.42% yield, 99% purity, TFA salt) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ 8.79 (br d, J = 6.4 Hz, 2H), 8.24 (br d, J = 6.4 Hz, 2H), 7.98 - 7.93 (m, 2H), 7.92 - 7.85 (m, 2H), 7.61 (br d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.24 - 7.19 (m, 1H), 7.15 - 7.10 (m, 1H), 7.09 - 7.04 (m, 1H), 5.08 (s, 2H). MS (M + H)+ = 506.0 Example 20. Synthesis of Compound NEM-65A Synthesis of 1-(chloromethyl)-4-[4-(trifluoromethyl)phenyl]benzene (2) [0293] To a solution of [4-[4-(trifluoromethyl)phenyl]phenyl]methanol (100 mg, 396.46 μmol, 1 eq) in DCE (1 mL) was added SOCl2 (235.84 mg, 1.98 mmol, 143.98 μL, 5 eq). The mixture was stirred at 20°C for 2hr. The mixture was concentrated under reduced pressure give a residue. Compound 1-(chloromethyl)-4-[4-(trifluoromethyl)phenyl]benzene (100 mg, crude) was obtained as a white solid which was used directly without purification. Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-[4- (trifluoromethyl)phenyl]phenyl]methyl]indolin-3-yl]benzenesulfonamide (3) [0294] A mixture of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (80 mg, 221.96 μmol, 1 eq), 1-(chloromethyl)-4-[4-(trifluoromethyl)phenyl]benzene (84.11 mg, 310.74 μmol, 1.4 eq), K2CO3 (61.35 mg, 443.92 μmol, 2 eq) in DMF (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60°C for 3 h under N2 atmosphere.10 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (20 mL*2). The combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica, 0-50 % ethyl acetate in petroleum ether, gradient over 20 min). CompoundN-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-[4- (trifluoromethyl)phenyl]phenyl]methyl]indolin-3-yl]benzenesulfonamide (100 mg, 166.49 μmol, 75.01% yield, 99% purity) was obtained as a yellow solid. MS (M + H)+ = 595.3 Synthesis of 4-[3-hydroxy-2-oxo-1-[[4-[4- (trifluoromethyl)phenyl]phenyl]methyl]indolin-3-yl]benzenesulfonamide (NEM-65A) [0295] To a solution of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-[4- (trifluoromethyl)phenyl]phenyl]methyl]indolin-3-yl]benzenesulfonamide (80 mg, 134.53 μmol, 1 eq) in DCM (2 mL) was added TFA (306.80 mg, 2.69 mmol, 199.87 μL, 20 eq). The mixture was stirred at 50 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:45%-75% B over 8.0 min). Compound 4-[3-hydroxy-2-oxo-1-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]indolin-3- yl]benzenesulfonamide (59.8 mg, 109.89 μmol, 81.68% yield, 98.96% purity) was obtained. MS (M + H)+ = 539.0. 1H NMR (400 MHz, METHANOL-d4) δ 7.87 (d, J = 8.5 Hz, 2H), 7.83 - 7.78 (m, 2H), 7.76 - 7.71 (m, 2H), 7.67 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.35 - 7.30 (m, 1H), 7.23 (d, J = 6.6 Hz, 1H), 7.12-7.09 (m, 1H), 7.02 (d, J = 8.0 Hz, 1H), 5.04 (s, 2H). Example 21. Synthesis of Compound NEM-66A O O S O O N S O H N Cl Br H HO O Synthesis of N-tert-butyl-4-(5-chloro-3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (2 A) [0296] To a solution of 4-bromo-N-tert-butyl-benzenesulfonamide (6.44 g, 22.03 mmol, 2 eq) in THF (50 mL) was added dropwise n-BuLi (2.5 M, 17.62 mL, 4 eq) at -70°C under N2 atmosphere. After addition, the mixture was stirred at this temperature for 1 hr, and then 5-chloroindoline-2,3-dione (2 g, 11.01 mmol, 1 eq) in THF (20 mL) was added dropwise at - 70°C under N2 atmosphere. The resulting mixture was stirred at -70°C for 2 hr under N2 atmosphere. The reaction was quenched by addition of ice sat. NH4Cl (20mL) at 0°C, and extracted with ethyl acetate 100 mL*2), and the combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 20 g silica, 0~50% ethyl acetate in petroleum ether, gradient over 30 min). Compound N- tert-butyl-4-(5-chloro-3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (2.6 g, 6.58 mmol, 59.78% yield) was obtained as red oil . MS (M + H)+ = 395.0 Synthesis of (4-morpholinophenyl)methyl 4-methylbenzenesulfonate (3) [0297] To a solution of (4-morpholinophenyl)methanol (1 g, 5.17 mmol, 1 eq), DMAP (63.22 mg, 517.49 µmol, 0.1 eq) and TEA (1.05 g, 10.35 mmol, 1.44 mL, 2 eq) in DCM (10 mL) was added dropwise 4-methylbenzenesulfonyl chloride (986.57 mg, 5.17 mmol, 1 eq) at 0oC. After addition, the mixture was stirred at 25°C for 4 hr. The product fraction was evaporated under reduced pressure. Compound (4-morpholinophenyl)methyl 4- methylbenzenesulfonate (1.5 g, crude) was obtained as a light yellow solid which was used in next step without purification. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.77 (d, J = 8.0 Hz, 2H), 7.36 - 7.30 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 8.0 Hz, 2H), 4.48 (s, 2H), 3.88 - 3.82 (m, 4H), 3.22 - 3.17 (m, 4H), 2.31 (s, 3H). Synthesis of N-tert-butyl-4-[5-chloro-3-hydroxy-1-[(4-morpholinophenyl)methyl]-2-oxo-in dolin-3-yl]benzenesulfonamide (4) [0298] To a solution of N-tert-butyl-4-(5-chloro-3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (300 mg, 759.74 μmol, 1 eq) in DMF (6 mL) was added K2CO3 (262.50 mg, 1.90 mmol, 2.5 eq) and (4-morpholinophenyl)methyl 4-methylbenzenesulfonate (527.91 mg, 1.52 mmol, 2 eq). The mixture was stirred at 80°C for 12 h.20 mL of water was added to the mixture. The mixture was extracted with dichloromethane (10 mL*2) and the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 10 g silica, 0~60% ethyl acetate in petroleum ether, gradient over 30 min). Compound N-tert-butyl-4-[5-chloro-3-hydroxy-1-[(4- morpholinophenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (160 mg, 280.65 μmol, 36.94% yield) was obtained as red oil. MS (M + H)+ = 570.1 Synthesis of 4-[5-chloro-3-hydroxy-1-[(4-morpholinophenyl)methyl]-2-oxo-indolin-3-yl]ben zenesulfonamide (NEM-66A) [0299] To a solution of N-tert-butyl-4-[5-chloro-3-hydroxy-1-[(4- morpholinophenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (70 mg, 122.79 μmol, 1 eq) in DCE (1 mL) was added TFA (21.49 g, 188.47 mmol, 14.00 mL, 1534.95 eq). The mixture was stirred at 50°C for 2 hr. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 80*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:20%-50% B over 8.0 min). Compound 4-[5-chloro-3-hydroxy-1-[(4-morpholinophenyl)methyl]-2-oxo-indolin-3- yl]benzenesulfonamide (8.2 mg, 13.06 μmol, 10.63% yield, 100% purity, TFA salt) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ = 7.90 - 7.85 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.31 (dd, J = 2.0, 8.4 Hz, 3H), 7.18 (d, J = 2.0 Hz, 1H), 7.09 - 7.03 (m, 2H), 7.00 (d, J = 8.5 Hz, 1H), 4.96 - 4.89 (m, 2H), 3.85-3.84 (m, 4H), 3.22-3.21 (m, 4H). MS (M + H)+ = 514.0. Example 22. Synthesis of Compound NEM-67A [0300] A solution of tert-butyl nitrite (28.15 g, 273.01 mmol, 32.47 mL, 5 eq) in THF (100 mL) was added to a solution of 6-bromo-1-iodo-naphthalen-2-amine (19 g, 54.60 mmol, 1 eq) in THF (20 mL) at 0°C under N2 atmosphere, the reaction was stirred at 25°C for 0.5 h, then the mixture was heated at 50°C for 3 h. The reaction mixture was cooled to room temperature. The mixture was quenched by H2O (200 mL) at 0°C, extracted with ethyl acetate (200 mL*3). The combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 220 g silica, 0 % ethyl acetate in petroleum ether, gradient over 40 min). Compound 6-bromo-1-iodo-naphthalene (9.6 g, 28.83 mmol, 52.80% yield) was obtained as a brown gum.1HNMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 1.9 Hz, 1H), 8.18 (d, J = 7.3 Hz, 1H), 7.96 (dd, J = 8.7, 16.1 Hz, 2H), 7.78 (dd, J = 1.8, 8.9 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H) Synthesis of (6-bromo-1-naphthyl)boronic acid (3) [0301] To a solution of 6-bromo-1-iodo-naphthalene (3 g, 9.01 mmol, 1 eq) in THF (60 mL) was added dropwise i-PrMgCl (2 M, 13.52 mL, 3 eq) at 0°C, the mixture was stirred at 0°C for 1 h and then triisopropyl borate (5.08 g, 27.03 mmol, 6.21 mL, 3 eq) in THF (60 mL) was added dropwise at 0°C. The mixture was stirred at 0°C for 2 h under N2 atmosphere.2M HCl aq. (20 mL) was added at 0°C. The mixture was then allowed to reach room temperature and stirred for 20 min.20 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (60 mL*2), and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. Compound (6-bromo-1-naphthyl) boronic acid (1.6 g, 4.46 mmol, 49.55% yield, 70% purity) was obtained as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 8.41 (s, 2H), 8.36 (d, J = 9.1 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.79 (d, J = 6.9 Hz, 1H), 7.62 (dd, J = 2.1, 9.0 Hz, 1H), 7.55 - 7.50 (m, 1H) Synthesis of 4-[1-(6-bromo-1-naphthyl)-5-chloro-3-hydroxy-2-oxo-indolin-3-yl]-N-tert- butyl-benzenesulfonamide (5) [0302] To a solution of N-tert-butyl-4-(5-chloro-3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (300 mg, 759.74 μmol, 1 eq) in DCM (10 mL) was added (6-bromo- 1-naphthyl)boronic acid (544.59 mg, 1.52 mmol, 2 eq), Cu(OAc)2 (275.99 mg, 1.52 mmol, 2 eq), Py (120.19 mg, 1.52 mmol, 122.64 μL, 2 eq) and TEA (153.75 mg, 1.52 mmol, 211.49 μL, 2 eq), the reaction was stirred at 25°C under O2 atmosphere for 48 h at 15 Psi.3 mL of water was added to the mixture, the mixture was extracted with dichloromethane (5 mL*2), and the combined extracts were dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 12 g silica, 0-35% ethyl acetate in petroleum ether, gradient over 20 min). Compound 4-[1-(6-bromo-1-naphthyl)-5-chloro-3-hydroxy-2-oxo-indolin-3-yl]-N-tert-butyl- benzenesulfonamide (150 mg, 200.03 μmol, 26.33% yield, 80% purity) was obtained as a brown solid. MS (M + H)+ = 599.0 Synthesis of N-tert-butyl-4-[5-chloro-3-hydroxy-1-(6-morpholino-1-naphthyl)-2-oxo- indolin-3-yl]benzenesulfonamide (6) [0303] To a solution of 4-[1-(6-bromo-1-naphthyl)-5-chloro-3-hydroxy-2-oxo-indolin-3- yl]-N-tert-butyl-benzenesulfonamide (120 mg, 140.02 μmol, 1 eq) in 2-methylbutan-2-ol (1 mL) were added morpholine (12.20 mg, 140.02 μmol, 12.32 μL, 1 eq), RuPhos Pd G4 (5.95 mg, 7.00 μmol, 0.05 eq) and NaOtBu (2 M, 70.01 μL, 1 eq). Then the reaction mixture was bubbled with N2 for a while and heated to 90°C, stirred for 12 h under N2 atmosphere.3 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (5 mL*2) and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0-45% ethyl acetate in petroleum ether, gradient over 20 min). Compound N-tert-butyl-4-[5-chloro-3-hydroxy-1-(6-morpholino-1-naphthyl)-2-oxo-indolin- 3-yl]benzenesulfonamide (60 mg, 59.39 μmol, 42.42% yield, 60% purity) was obtained as a yellow solid. MS (M + H)+ = 606.1 Synthesis of 4-[5-chloro-3-hydroxy-1-(6-morpholino-1-naphthyl)-2-oxo-indolin-3- yl]benzenesulfonamide (NEM-67A) [0304] To a solution of N-tert-butyl-4-[5-chloro-3-hydroxy-1-(6-morpholino-1- naphthyl)-2-oxo-indolin-3-yl]benzenesulfonamide (30 mg, 49.49 μmol, 1 eq) in DCE (1 mL) was added TFA (2.30 g, 20.19 mmol, 1.50 mL, 407.99 eq), the reaction was stirred at 50°C for 1 h. The mixture was concentrated under reduced pressure to give the crude product. The residue was purified by prep-HPLC: column : Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:35%-65% B over 8.0 min. 4-[5-chloro-3-hydroxy-1-(6-morpholino-1-naphthyl)-2-oxo-indolin-3- yl]benzenesulfonamide (3.7 mg, 5.57 μmol, 11.26% yield, 100% purity, TFA) was obtained. 1HNMR (400 MHz, ACETONITRILE-d3) δ 7.98 - 7.89 (m, 3H), 7.78 - 7.68 (m, 2H), 7.62 - 7.55 (m, 1H), 7.44 - 7.22 (m, 6H), 6.48 (dd, J = 8.4, 12.5 Hz, 1H), 5.71 (br s, 2H), 5.28 - 5.02 (m, 1H), 3.86 - 3.80 (m, 4H), 3.30 - 3.23 (m, 4H). MS (M + H)+ = 550.1 Example 23. Synthesis of Compound NEM-68A acetate (2) [0305] To a solution of tert-butyl N-[4-(trifluoromethyl)phenyl]carbamate (1 g, 3.83 mmol, 1 eq) in THF (10 mL) was added dropwise s-BuLi (1.3 M, 8.83 mL, 3 eq) at -70°C over 15 min. After addition, the mixture was stirred at -40 °C for 1 h, and then diethyl oxalate (2.80 g, 19.14 mmol, 2.61 mL, 5 eq) in THF (3 mL) was added dropwise at -70 °C. The resulting mixture was stirred at -70 °C for 1 hr. The reaction was poured into ice NH4Cl aq.10 ml at 0 °C. The mixture was extracted with ethyl acetate (30 mL*2), the combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica, 0-20 % ethyl acetate in petroleum ether, gradient over 20 min). Compound ethyl 2-[2-(tert-butoxycarbonylamino)-5-(trifluoromethyl)phenyl]-2-oxo-acetate (1.2 g, 3.32 mmol, 86.76% yield) was obtained as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ 10.57 (br s, 1H), 8.71 (d, J = 9.0 Hz, 1H), 7.97 (d, J = 0.9 Hz, 1H), 7.81 (dd, J = 1.9, 9.1 Hz, 1H), 4.50 (q, 2H), 1.56 - 1.53 (m, 9H), 1.45 (t, J = 7.2 Hz, 3H) Synthesis of 5-(trifluoromethyl)indoline-2,3-dione (3) [0306] To a solution of ethyl 2-[2-(tert-butoxycarbonylamino)-5- (trifluoromethyl)phenyl]-2-oxo-acetate (1.1 g, 3.04 mmol, 1 eq) in THF (10 mL) was added HCl (3 M, 11.00 mL, 10.84 eq). The mixture was stirred at 75 °C for 6 h. Upon evaporation of the organic solvent, the product precipitated out of solution. It was collected by filtration, washed with water and dried under vacuum to give bright yellow crystals. Compound 5- (trifluoromethyl)indoline-2,3-dione (550 mg, 2.56 mmol, 83.98% yield) was obtained as a yellow solid. Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-5-(trifluoromethyl)indolin-3- yl]benzenesulfonamide (4) [0307] To a solution of 4-bromo-N-tert-butyl-benzenesulfonamide (1.36 g, 4.65 mmol, 2 eq) in THF (15 mL) was added dropwise n-BuLi (2.5 M, 3.72 mL, 4 eq) at -70°C over 30 min. After addition, the mixture was stirred at this temperature for 30 min, and then 5- (trifluoromethyl)indoline-2,3-dione (500 mg, 2.32 mmol, 1 eq) in THF (5 mL) was added dropwise at -70 °C. The resulting mixture was stirred at -70°C for 2hr. The reaction was poured into ice NH4Cl aq.20 mL at 0 °C, extracted with ethyl acetate (20 mL*2). The combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica, 0-20 % ethyl acetate in petroleum ether, gradient over 20 min). Compound N-tert-butyl-4-[3-hydroxy-2-oxo-5-(trifluoromethyl)indolin-3- yl]benzenesulfonamide (230 mg, crude) was obtained as a yellow solid. MS (M + H)+ = 429.2 Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]-5- (trifluoromethyl)indolin-3-yl]benzenesulfonamide (5) [0308] To a solution of N-tert-butyl-4-[3-hydroxy-2-oxo-5-(trifluoromethyl)indolin-3- yl]benzenesulfonamide (210 mg, 490.17 μmol, 1 eq) in DMF (3 mL) was added K2CO3 (169.36 mg, 1.23 mmol, 2.5 eq) and 4-[4-(chloromethyl)phenyl]pyridine (129.47 mg, 539.18 μmol, 1.1 eq, HCl). The mixture was stirred at 60°C for 2 h.10 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (20 mL*2), the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica, 0-20 % ethyl acetate in petroleum ether, gradient over 20 min). Compound N-tert- butyl-4-[3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]-5-(trifluoromethyl)indolin-3- yl]benzenesulfonamide (150 mg, 251.83 μmol, 51.38% yield) was obtained as a yellow solid. MS (M + H)+ = 596.2 Synthesis of 4-[3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]-5- (trifluoromethyl)indolin-3-yl]benzenesulfonamide (NEM-68A) [0309] To a solution of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]-5-(trifluoromethyl)indolin-3-yl]benzenesulfonamide (120 mg, 201.47 μmol, 1 eq) in DCM (4 mL) was added TFA (1.84 g, 16.15 mmol, 1.20 mL, 80.18 eq). The mixture was stirred at 50°C for 0.5 h. The reaction mixture was cooled and concentrated under reduced pressure to give a solid. The residue was purified by prep-HPLC (column: Phenomenex Luna C1880*30mm*3um;mobile phase: [H2O(0.1%TFA)- ACN];gradient:15%-45% B over 8.0 min). Compound 4-[3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]-5-(trifluoromethyl)indolin-3-yl]benzenesulfonamide (30 mg, 55.14 μmol, 27.37% yield, 99.16% purity) was obtained.1H NMR (400 MHz, METHANOL-d4) δ 8.78 (br d, J = 5.3 Hz, 2H), 8.27 - 8.20 (m, 2H), 7.92 (dd, J = 8.1, 17.2 Hz, 4H), 7.67 (dd, J = 1.0, 8.3 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 8.6 Hz, 2H), 7.49 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 5.14 (s, 2H) MS (M + H)+ = 540.0
Example 24. Synthesis of Compound NEM-69A benzenesulfonamide (2) [0310] To a solution of 4-bromo-N-tert-butyl-benzenesulfonamide (1.29 g, 4.42 mmol, 2 eq) in THF (5 mL) was added dropwise n-BuLi (2.5 M, 3.54 mL, 4 eq) at -70 °C over 10 min. After addition, the mixture was stirred at this temperature for 20 min, and then 5- bromoindoline-2,3-dione (500 mg, 2.21 mmol, 1 eq) in THF (5 mL) was added dropwise at - 70 °C. The resulting mixture was stirred at -70 °C for 3 hr. The reaction was poured into ice NH4Cl aq.50 ml at 0 °C. The mixture was extracted with ethyl acetate (45 mL*2), the combined extracts were washed with brine (50 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica, 0-60 % ethyl acetate in petroleum ether, gradient over 20 min). Compound 4-(5-bromo-3-hydroxy-2-oxo-indolin-3-yl)-N-tert-butyl-benzenesulfonamide (300 mg, 682.87 μmol, 30.87% yield) was obtained as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ 8.00 (s, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.51 - (m, 3H), 7.33 (d, J = 1.6 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 4.82 (s, 1H), 3.86 (s, 1H), 1.23 (s, 9H) Synthesis of 4-[5-bromo-3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3-yl]- N-tert-butyl-benzenesulfonamide (3) [0311] To a solution of 4-(5-bromo-3-hydroxy-2-oxo-indolin-3-yl)-N-tert-butyl- benzenesulfonamide (280 mg, 637.34 μmol, 1 eq) in DMF (4 mL) was added K2CO3 (264.25 mg, 1.91 mmol, 3 eq) and 4-[4-(chloromethyl)phenyl]pyridine (168.35 mg, 701.08 μmol, 1.1 eq, HCl). The mixture was stirred at 60°C for 2 h.20 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (30 mL*2), the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica, 0-60 % ethyl acetate in petroleum ether, gradient over 20 min). Compound 4-[5-bromo-3-hydroxy-2-oxo- 1-[[4-(4-pyridyl)phenyl]methyl]indolin-3-yl]-N-tert-butyl-benzenesulfonamide (300 mg, 494.62 μmol, 77.61% yield) was obtained as a yellow solid.1H NMR (400 MHz, METHANOL-d4) δ 8.57 (d, J = 6.0 Hz, 2H), 7.87 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 6.1 Hz, 2H), 7.56 - 7.49 (m, 5H), 7.36 (d, J = 1.8 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 5.04 (s, 2H), 1.17 (s, 9H) Synthesis of tert-butyl (3-(4-(N-(tert-butyl)sulfamoyl)phenyl)-3-hydroxy-2-oxo-1-(4- (pyridin-4-yl)benzyl)indolin-5-yl)carbamate (4) [0312] To a solution of 4-[5-bromo-3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]-N-tert-butyl-benzenesulfonamide (100 mg, 164.87 μmol, 1 eq) in dioxane (2 mL) was added XPhos (23.58 mg, 49.46 μmol, 0.3 eq), Pd(OAc)2 (5.55 mg, 24.73 μmol, 0.15 eq), Cs2CO3 (161.16 mg, 494.62 μmol, 3 eq) and tert-butyl carbamate (57.94 mg, 494.62 μmol, 3 eq). The mixture was stirred at 100 °C for 6 h under N2.10 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (20 mL*2), the combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0-100 % ethyl acetate in petroleum ether, gradient over 20 min). Compound tert-butyl (3-(4-(N-(tert-butyl)sulfamoyl)phenyl)-3-hydroxy-2-oxo-1-(4- (pyridin-4-yl)benzyl)indolin-5-yl)carbamate (75 mg, 116.68 μmol, 70.77% yield) was obtained as a yellow solid. MS (M + H)+ = 643.2 Synthesis of 4-[5-amino-3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3-yl]- N-tert-butyl-benzenesulfonamide (5) [0313] A mixture of tert-butyl N-[3-[4-(tert-butylsulfamoyl)phenyl]-3-hydroxy-2-oxo-1- [[4-(4-pyridyl)phenyl]methyl]indolin-5-yl]carbamate (55 mg, 85.57 μmol, 1 eq) in HCl/EtOAc (4 M, 2.75 mL, 128.55 eq) was stirred at 20 °C for 1h. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 4-[5-amino-3-hydroxy-2- oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3-yl]-N-tert-butyl-benzenesulfonamide (45 mg, crude, HCl) was obtained as a white solid. Synthesis of N-tert-butyl-4-[5-(dimethylamino)-3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (6) [0314] To a solution of 4-[5-amino-3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]-N-tert-butyl-benzenesulfonamide (40 mg, 69.07 μmol, 1 eq, HCl) in THF (1 mL) was added HCHO (56.05 mg, 690.72 μmol, 51.42 μL, 37% purity, 10 eq) and NaBH3CN (21.70 mg, 345.36 μmol, 5 eq), HOAc (0.1 mL). The mixture was stirred at 20 °C for 2 h.3 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (5 mL*2), the combined extracts were washed with brine (2 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0-100 % ethyl acetate in petroleum ether, gradient over 20 min). Compound N-tert-butyl-4-[5-(dimethylamino)-3-hydroxy-2- oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (20 mg, 21.38 μmol, 30.95% yield, 61% purity) was obtained as a white solid. MS (M + H)+ = 571.3 Synthesis of 4-[5-(dimethylamino)-3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (NEM-69A) [0315] To a solution of 4-[5-amino-3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]-N-tert-butyl-benzenesulfonamide (20 mg, 34.54 μmol, 1 eq, HCl) in DCE (1 mL) was added TFA (920.98 mg, 8.08 mmol, 599.98 μL, 233.88 eq). The mixture was stirred at 60 oC for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:15%-45% B over 8.0 min). Compound 4-[5-(dimethylamino)-3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (5.8 mg, 8.84 μmol, 25.58% yield, 95.76% purity, TFA salt) was obtained.1H NMR (400 MHz, ACETONITRILE-d3) δ 8.62 - 8.55 (m, 2H), 7.85 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.60 - 7.57 (m, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 6.82 (d, J = 8.5 Hz, 1H), 6.71 (d, J = 2.5 Hz, 1H), 6.69 - 6.65 (m, 1H), 5.65 (s, 2H), 4.93 (d, J = 6.3 Hz, 2H), 4.81 (s, 1H), 2.80 (s, 6H) MS (M + H)+ = 515.2
Example 25. Synthesis of Compound NEM-70A Synthesis of 4-[4-(chloromethyl)phenyl]pyridine (2) [0316] To a solution of [4-(4-pyridyl)phenyl]methanol (1 g, 5.40 mmol, 1 eq) in DCM (10 mL) was added dropwise SOCl2 (3.21 g, 26.99 mmol, 1.96 mL, 5 eq) at 0°C. The resulting mixture was stirred at 25°C for 2 hr. The product fraction was evaporated under reduced pressure. Compound 4-[4-(chloromethyl)phenyl]pyridine (1 g, crude) was obtained as a white solid which was used in next step without purification. Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3- yl]benzenesulfonamide (3) [0317] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (400 mg, 1.11 mmol, 1 eq) in DMF (5 mL) was added K2CO3 (383.45 mg, 2.77 mmol, 2.5 eq) and 4-[4-(chloromethyl)phenyl]pyridine (271.23 mg, 1.33 mmol, 1.2 eq). The mixture was stirred at 60°C for 12 hr.20 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (10 mL*2), and the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 5 g silica, 0~50% ethyl acetate in petroleum ether, gradient over 30 min). Compound N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin- 3-yl]benzenesulfonamide (370 mg, 701.25 μmol, 63.19% yield) was obtained as a light yellow solid. MS (M + H)+ = 528.1 Synthesis of 4-[2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (NEM-70A) [0318] To a solution of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (50 mg, 94.76 μmol, 1 eq) in DCM (1 mL) was added TEA (38.36 mg, 379.05 μmol, 52.76 μL, 4 eq) and SOCl2 (22.55 mg, 189.53 μmol, 13.77 μL, 2 eq) at 0°C. The mixture was stirred at 20°C for 2 hr.5 mL of water was added to the mixture, the mixture was extracted with dichloromethane (5 mL*2) and the combined extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. Compound 4- [3-chloro-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (40 mg, crude) was obtained as a light yellow solid which was used in next step without purification. To a solution of 4-[3-chloro-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3- yl]benzenesulfonamide (40 mg, 81.64 μmol, 1 eq) in THF (1.2 mL) was added Zn (26.69 mg, 408.19 μmol, 5 eq) and CH3COOH (209.80 mg, 3.49 mmol, 0.2 mL, 42.79 eq). The mixture was stirred at 20°C for 3 hr.3mL of water was added to the reaction, the reaction mixture was extracted with Ethyl acetate (3 mL*3). The combined organic layers were washed with brine (3 mL), dried over Na2SO4 and concentrated to dryness to give a residue. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:15%-45% B over 8.0 min) to give crude product which was further purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:30%- 60% B over 8.0 min). Compound 4-[2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3- yl]benzenesulfonamide (4.9 mg, 10.76 μmol, 13.18% yield, 100% purity) was obtained. 1H NMR (400 MHz, ACETONITRILE-d3) δ 8.61 (d, J = 6.0, 2H), 7.90 - 7.84 (d, J = 8.4, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.61 - 7.56 (d, J = 6.0, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.31 - 7.25 (m, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.10 - 7.03 (m, 1H), 6.94 (d, J = 8.0 Hz, 1H), 5.66 (s, 2H), 5.06 - 4.95 (m, 2H), 4.92 (s, 1H) MS (M + H)+ = 456.1
Example 26. Synthesis of Compound NEM-71A pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (2) [0319] To a solution of N-tert-butyl-4-(5-chloro-3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (200 mg, 506.49 μmol, 1 eq) in DMF (3 mL) was added K2CO3 (210.00 mg, 1.52 mmol, 3 eq) and 4-[4-(chloromethyl)phenyl]pyridine (123.79 mg, 607.79 μmol, 1.2 eq). The mixture was stirred at 60°C for 2 h. The reaction mixture was poured into water, the precipitate was filtered and dried in vacuo. Compound N-tert-butyl-4-[5-chloro-3- hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (200 mg, crude) was obtained as a yellow solid. MS (M + H)+ = 562.1 Synthesis of N-tert-butyl-4-[3,5-dichloro-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin- 3-yl]benzenesulfonamide (3) [0320] To a solution of N-tert-butyl-4-[5-chloro-3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (80 mg, 142.33 μmol, 1 eq) in CHCl3 (1 mL) was added SOCl2 (84.66 mg, 711.65 μmol, 51.69 μL, 5 eq). The mixture was stirred at 60°C for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure give a residue. Compound N-tert-butyl-4-[3,5-dichloro- 2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (80 mg, crude, HCl) was obtained as a white solid. MS (M + H)+ = 580.1 Synthesis of N-tert-butyl-4-[5-chloro-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3- yl]benzenesulfonamide (3) [0321] To a solution of N-tert-butyl-4-[3,5-dichloro-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (80 mg, 137.81 μmol, 1 eq) in THF (2 mL) and CH3COOH (279.72 mg, 4.66 mmol, 266.66 μL, 33.80 eq) was added Zn (90.11 mg, 1.38 mmol, 10 eq). The mixture was stirred at 20 °C for 2 h.3mL of water was added to the reaction at 0°C, the reaction mixture was extracted with Ethyl acetate (8 mL*3). The combined organic layers were washed with brine (3 mL) and dried over Na2SO4. The combined organic layer was concentrated to dryness to give a residue. Compound N-tert- butyl-4-[5-chloro-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (50 mg, crude, HOAc salt) was obtained as a white solid. MS (M + H)+ = 546.1 Synthesis of 4-[5-chloro-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3- yl]benzenesulfonamide (NEM-71A) [0322] A mixture of N-tert-butyl-4-[5-chloro-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (50 mg, 91.56 μmol, 1 eq) in dichloromethane (1 mL) and TFA (0.5 mL). was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1%TFA)- ACN];gradient:20%-50% B over 9.0 min). Compound 4-[5-chloro-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (7.8 mg, 12.17 μmol, 13.29% yield, 94.23% purity, TFA salt) was obtained. 1H NMR (400 MHz, ACETONITRILE-d3) δ 8.72 (br d, J = 6.1 Hz, 2H), 7.99 (d, J = 6.3 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 7.30 (dd, J = 1.7, 8.4 Hz, 1H), 7.22 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.68 (s, 2H), 5.02 (s, 2H), 4.97 (s, 1H) MS (M + H)+ =490.0 Example 27. Synthesis of Compound NEM-72A 3-yl]benzenesulfonamide (2) [0323] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (200 mg, 554.90 μmol, 1 eq) in DMF (5 mL) was added K2CO3 (191.72 mg, 1.39 mmol, 2.5 eq) and (4-morpholinophenyl)methyl 4-methylbenzenesulfonate (578.36 mg, 1.66 mmol, 3 eq). The mixture was stirred at 80°C for 24 hr.20 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (10 mL*2) and the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 4 g silica, 0~50% ethyl acetate in petroleum ether, gradient over 30 min) Compound N-tert-butyl-4-[3-hydroxy-1-[(4- morpholinophenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (250 mg, 466.72 μmol, 84.11% yield) was obtained as light yellow oil. MS (M + H)+ = 536.2 Synthesis of N-tert-butyl-4-[1-[(4-morpholinophenyl)methyl]-2-oxo-indolin-3- yl]benzenesulfonamide (3) [0324] To a solution of N-tert-butyl-4-[3-hydroxy-1-[(4-morpholinophenyl)methyl]-2- oxo-indolin-3-yl]benzenesulfonamide (20 mg, 37.34 μmol, 1 eq) in CH3CN (1 mL) was added SOCl2 (8.88 mg, 74.68 μmol, 5.42 μL, 2 eq) at 0°C. The mixture was stirred at 80°C for 2 hr. The product fraction was evaporated under reduced pressure. Compound N-tert- butyl-4-[3-chloro-1-[(4-morpholinophenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (15 mg, crude) was obtained as a white solid which was used in next step without purification. A mixture of N-tert-butyl-4-[3-chloro-1-[(4-morpholinophenyl)methyl]-2-oxo- indolin-3-yl]benzenesulfonamide (15 mg, 27.07 μmol, 1 eq), Zn (8.85 mg, 135.35 μmol, 5 eq) and CH3COOH (314.70 mg, 5.24 mmol, 300.00 μL, 193.58 eq) in THF (1.2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20°C for 3 hr under N2 atmosphere.3 mL of water was added to the reaction, the reaction mixture was extracted with Ethyl acetate (3 mL*3). The combined organic layers were washed with brine (3 mL) and dried over Na2SO4 and concentrated to dryness to give a residue. Compound N- tert-butyl-4-[1-[(4-morpholinophenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (10 mg, crude) was obtained as a light yellow solid which was used in next step without purification. MS (M + H)+ = 520.2 Synthesis of 4-[1-[(4-morpholinophenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (NEM-72A) [0325] A mixture of N-tert-butyl-4-[1-[(4-morpholinophenyl)methyl]-2-oxo-indolin-3- yl]benzenesulfonamide (10 mg, 19.24 μmol, 1 eq) in DCE (1 mL) and TFA ( 0.5 mL) was stirred at 50°C for 2 hr. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18100*40mm*3 um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:20%-50% B over 18.0 min). Compound 4-[1-[(4-morpholinophenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (5 mg, 8.66 μmol, 44.99% yield, 100% purity, TFA salt) was obtained.1H NMR (400 MHz, ACETONITRILE-d3) δ 7.85 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.29 - 7.22 (m, 3H), 7.14 (d, J = 7.4 Hz, 1H), 7.06 - 7.01 (m, 1H), 6.93 (d, J = 7.5 Hz, 3H), 5.65 (s, 2H), 4.89-4.82 (m, 3H), 3.79 - 3.74 (m, 4H), 3.13 - 3.08 (m, 4H) MS (M + H)+ = 464.1 Example 28. Synthesis of Compound NEM-73A yl]benzenesulfonamide (5) [0326] To a solution of N-tert-butyl-4-[5-chloro-3-hydroxy-1-[(4- morpholinophenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (50 mg, 87.70 μmol, 1 eq) in CH3CN (1 mL) was added SOCl2 (20.87 mg, 175.41 μmol, 12.74 μL, 2 eq) at 0°C. The mixture was stirred at 60°C for 2 hr. The reaction was cooled to room temperature. The product fraction was evaporated under reduced pressure. Compound N-tert-butyl-4-[3,5- dichloro-1-[(4-morpholinophenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (40 mg, crude) was obtained as a red oil which was used in next step without purification. A mixture of N-tert-butyl-4-[3,5-dichloro-1-[(4-morpholinophenyl)methyl]-2-oxo-indolin-3- yl]benzenesulfonamide (40 mg, 67.96 μmol, 1 eq), Zn (22.22 mg, 339.82 μmol, 5 eq) and CH3COOH (209.80 mg, 3.49 mmol, 200.00 μL, 51.40 eq) in THF (1.2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20°C for 8 hr under N2 atmosphere. Then another batch of Zn (22.22 mg, 339.82 μmol, 5 eq) was added to the mixture and then the mixture was stirred at 20°C for 8 hr under N2 atmosphere.3 mL of water was added to the reaction at 0°C, the reaction mixture was extracted with Ethyl acetate (3 mL*3). The combined organic layers were washed with brine (3 mL), dried over Na2SO4 and concentrated to dryness to give residue. Compound N-tert-butyl-4-[5-chloro-1-[(4- morpholinophenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (30 mg, crude) was obtained as a red oil which was used in next step without purification. MS (M + H)+ = 554.2 Synthesis of 4-[5-chloro-1-[(4-morpholinophenyl)methyl]-2-oxo-indolin-3- yl]benzenesulfonamide (NEM-73A) [0327] To a solution of N-tert-butyl-4-[5-chloro-1-[(4-morpholinophenyl)methyl]-2-oxo- indolin-3-yl]benzenesulfonamide (30 mg, 54.14 μmol, 1 eq) in DCE (2 mL) was added TFA (1.15 g, 10.10 mmol, 750.00 μL, 186.48 eq). The mixture was stirred at 50°C for 2 hr. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C1880*30mm*3um;mobile phase: [H2O(0.1%TFA)- ACN];gradient:30%-60% B over 8.0 min). Compound 4-[5-chloro-1-[(4- morpholinophenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (4 mg, 6.08 μmol, 11.23% yield, 93% purity, TFA salt) was obtained.1H NMR (400 MHz, ACETONITRILE- d3) δ = 7.86 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.28 (dd, J = 2.0, 8.4 Hz, 1H), 7.22 (d, J = 8.6 Hz, 2H), 7.17 (s, 1H), 6.95 - 6.87 (m, 3H), 5.66 (s, 2H), 4.89 (s, 1H), 4.82 - 4.76 (m, 2H), 3.79 - 3.73 (m, 4H), 3.13 - 3.07 (m, 4H). MS (M + H)+ = 498.0 Example 29. Synthesis of Compound NEM-74A benzenesulfonamide (5) [0328] A mixture of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (359.16 mg, 996.48 μmol, 1 eq), (6-bromo-1-naphthyl)boronic acid (300 mg, 1.20 mmol, 1.2 eq), Py (157.64 mg, 1.99 mmol, 160.86 μL, 2 eq), TEA (201.67 mg, 1.99 mmol, 277.40 μL, 2 eq) and Cu(OAc)2 (361.98 mg, 1.99 mmol, 2 eq) in DCM (7 mL) was degassed and purged with O2 for 3 times, and then the mixture was stirred at 25°C for 12 hr under O2 atmosphere. 5 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (5 mL*2), and the combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 2 g silica, 0~60% ethyl acetate in petroleum ether, gradient over 30 min). Compound 4-[1-(6-bromo-1-naphthyl)-3-hydroxy-2- oxo-indolin-3-yl]-N-tert-butyl-benzenesulfonamide (290 mg, 512.84 μmol, 51.47% yield) was obtained as Brown solid. MS (M + H)+ = 565.1 Synthes is of N-tert-butyl-4-[3-hydroxy-1-(6-morpholino-1-naphthyl)-2-oxo-indolin-3- yl]benzenesulfonamide (7) [0329] Three batches. A mixture of 4-[1-(6-bromo-1-naphthyl)-3-hydroxy-2-oxo- indolin-3-yl]-N-tert-butyl-benzenesulfonamide (50 mg, 88.42 μmol, 1 eq), morpholine (23.11 mg, 265.26 μmol, 23.34 μL, 3 eq), t-BuOK (24.80 mg, 221.05 μmol, 2.5 eq), palladium;tritert-butylphosphane (9.04 mg, 17.68 μmol, 0.2 eq) in Toluene (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2 atmosphere. The three batches were combined.20 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (15 mL*3), and the combined extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 4 g silica, 0~60% ethyl acetate in petroleum ether, gradient over 30 min) Compound N-tert-butyl-4-[3-hydroxy-1-(6-morpholino-1-naphthyl)-2-oxo-indolin-3- yl]benzenesulfonamide (90 mg, 157.43 μmol, 59.35% yield) was obtained as a light yellow solid. MS (M + H)+ = 572.2 Synthesis of N-tert-butyl-4-[1-(6-morpholino-1-naphthyl)-2-oxo-indolin-3- yl]benzenesulfonamide [0330] Two batches. To a solution of N-tert-butyl-4-[3-hydroxy-1-(6-morpholino-1- naphthyl)-2-oxo-indolin-3-yl]benzenesulfonamide (10 mg, 17.49 μmol, 1 eq) in CHCl3 (1 mL) was added SOCl2 (4.16 mg, 34.98 μmol, 2.54 μL, 2 eq). The mixture was stirred at 60°C for 0.5 h. After reaction, the mixture was cooled to room temperature. The product fraction was evaporated under reduced pressure. Compound N-tert-butyl-4-[3-chloro-1-(6- morpholino-1-naphthyl)-2-oxo-indolin-3-yl]benzenesulfonamide (20 mg, crude) was obtained as a brown solid which was used in next step without purification. A mixture of N- tert-butyl-4-[3-chloro-1-(6-morpholino-1-naphthyl)-2-oxo-indolin-3-yl]benzenesulfonamide (20 mg, 33.89 μmol, 1 eq), Zn (11.08 mg, 169.45 μmol, 5 eq) ,CH3COOH (1.05 g, 17.47 mmol, 1.00 mL, 515.43 eq) in THF (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25°C for 2hr under N2 atmosphere.3mL of water was added to the reaction at 0°C, the reaction mixture was extracted with Ethyl acetate (3 mL*3). The combined organic layers were washed with brine (3 mL) and dried over Na2SO4. The combined organic layer was concentrated to dryness to give residue. Compound N-tert- butyl-4-[1-(6-morpholino-1-naphthyl)-2-oxo-indolin-3-yl]benzenesulfonamide (18 mg, crude) was obtained as a brown solid which was used in next step without purification. MS (M + H)+ = 556.2 Synthesis of 4-[1-(6-morpholino-1-naphthyl)-2-oxo-indolin-3-yl]benzenesulfonamide (NEM-74A) [0331] A mixture of N-tert-butyl-4-[1-(6-morpholino-1-naphthyl)-2-oxo-indolin-3- yl]benzenesulfonamide (18 mg, 32.39 μmol, 1 eq) in DCE (1 mL) and TFA (900.00 μL). The mixture was stirred at 60°C for 2 hr. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:35%-65% B over 8.0 min). Compound 4-[1-(6-morpholino-1-naphthyl)-2-oxo-indolin-3-yl]benzenesulfonamide (2.4 mg, 3.83 μmol, 11.83% yield, 98% purity, TFA salt) was obtained.1H NMR (400 MHz, METHANOL-d4) δ = 7.99 - 7.91 (m, 3H), 7.66 - 7.49 (m, 4H), 7.47 - 7.20 (m, 6H), 7.19 - 7.11 (m, 1H), 6.46 - 6.42 (m, 1H), 3.91 - 3.85 (m, 4H), 3.30 - 3.25 (m, 4H) MS (M + H)+ = 500.2 Example 30. Synthesis of Compound NEM-77A yl]benzenesulfonamide (2) [0332] To a solution of 4-bromo-N-tert-butyl-benzenesulfonamide (814.93 mg, 2.79 mmol, 2 eq) in THF (5 mL) was added dropwise n-BuLi (2.5 M, 2.23 mL, 4 eq) at -70°C under N2 atmosphere. After addition, the mixture was stirred at this temperature for 1 h, and then 4-(trifluoromethyl)indoline-2,3-dione (300 mg, 1.39 mmol, 1 eq) in THF (3 mL) was added dropwise at -70°C. The resulting mixture was stirred at -70°C for 2 h under N2 atmosphere. The reaction was quenched by addition of ice sat. NH4Cl (5 mL) at 0°C under N2 atmosphere, and extracted with ethyl acetate (15 mL*2). The combined extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. [0333] The residue was purified by flash column (ISCO 4 g silica, 0-100 % ethyl acetate in petroleum ether, gradient over 20 min). Compound N-tert-butyl-4-[3-hydroxy-2-oxo-4- (trifluoromethyl)indolin-3-yl]benzenesulfonamide (80 mg, 186.73 μmol, 13.39% yield) was obtained as a white solid. MS (M + H)+ = 429.0 Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]-4- (trifluoromethyl)indolin-3-yl]benzenesulfonamide (3) [0334] To a solution of N-tert-butyl-4-[3-hydroxy-2-oxo-4-(trifluoromethyl)indolin-3- yl]benzenesulfonamide (70 mg, 163.39 μmol, 1 eq) in DMF (1 mL) was added K2CO3 (56.45 mg, 408.47 μmol, 2.5 eq) and 4-[4-(chloromethyl)phenyl]pyridine (39.93 mg, 196.07 μmol, 1.2 eq). The mixture was stirred at 60°C for 12 h.5 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (10 mL*3). The combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. Compound N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]-4-(trifluoromethyl)indolin-3-yl]benzenesulfonamide (80 mg, crude) was obtained as a light yellow solid which was used in next step without purification. MS (M + H)+ = 596.2 Synthesis of 4-[3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]-4- (trifluoromethyl)indolin-3-yl]benzenesulfonamide (NEM-77A) [0335] To a solution of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]-4-(trifluoromethyl)indolin-3-yl]benzenesulfonamide (70 mg, 117.52 μmol, 1 eq) in DCE (1 mL) was added TFA (2.69 g, 23.56 mmol, 1.75 mL, 200.46 eq). The mixture was stirred at 60°C for 1 h. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 80*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:10%-40% B over 8.0 min). Compound 4-[3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]-4-(trifluoromethyl)indolin- 3-yl]benzenesulfonamide (28 mg, 40.70 μmol, 34.63% yield, 95% purity, TFA salt) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ 8.78 (d, J = 6.8 Hz, 2H), 8.24 - 8.21 (d, J = 6 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.61 - 7.54 (m, 3H), 7.46 - 7.39 (m, 3H), 7.32 (d, J = 7.9 Hz, 1H), 5.19 - 5.01 (m, 2H) MS (M + H)+ = 540.1 Example 31. Synthesis of Compound NEM-78A [0336] To a solution of 4-bromo-N-tert-butyl-benzenesulfonamide (1.09 g, 3.72 mmol, 2 eq) in THF (10 mL) was added dropwise n-BuLi (2.5 M, 2.97 mL, 4 eq) at -70°C under N2 atmosphere. After addition, the mixture was stirred at this temperature for 1h, and then 6- (trifluoromethyl)indoline-2,3-dione (400 mg, 1.86 mmol, 1 eq) in THF (4 mL) was added dropwise at -70°C. The resulting mixture was stirred at -70°C for 2 hr under N2 atmosphere. The reaction was quenched by addition of ice sat. NH4Cl (15mL) at 0°C under N2 atmosphere, and extracted with ethyl acetate (15 mL*2). The combined extracts were washed with brine (10mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0- 80 % ethyl acetate in petroleum ether, gradient over 20 min). Compound N-tert-butyl-4-[3- hydroxy-2-oxo-6-(trifluoromethyl)indolin-3-yl]benzenesulfonamide (240 mg, 560.19 μmol, 30.13% yield) was obtained as a light yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ 8.59 (br s, 1H), 7.8 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.36 - 7.32 (m, 1H), 7.31 - 7.28 (m, 1H), 7.21 (s, 1H), 5.02 (br s, 1H), 1.20 (s, 9H) Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]-6- (trifluoromethyl)indolin-3-yl]benzenesulfonamide (3) [0337] To a solution of N-tert-butyl-4-[3-hydroxy-2-oxo-6-(trifluoromethyl)indolin-3- yl]benzenesulfonamide (100 mg, 233.41 μmol, 1 eq) in DMF (2 mL) was added K2CO3 (80.65 mg, 583.53 μmol, 2.5 eq) and 4-[4-(chloromethyl)phenyl]pyridine (57.05 mg, 280.10 μmol, 1.2 eq). The mixture was stirred at 80°C for 2 hr.10 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (10 mL*2). The combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. Compound N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]-6-(trifluoromethyl)indolin-3-yl]benzenesulfonamide (140 mg, crude) was obtained as a light yellow oil which was used in next step without purification. MS (M + H)+ = 596.2 Synthesis of 4-[3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]-6- (trifluoromethyl)indolin-3-yl]benzenesulfonamide (NEM-78A) [0338] To a solution of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]-6-(trifluoromethyl)indolin-3-yl]benzenesulfonamide (110 mg, 184.68 μmol, 1 eq) in DCE (1 mL) was added TFA (4.22 g, 37.02 mmol, 2.75 mL, 200.46 eq). The mixture was stirred at 50°C for 2 h. The mixture was concentrated to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 80*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN]; gradient:15%-45% B over 8.0 min). Compound 4-[3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]-6-(trifluoromethyl)indolin- 3-yl]benzenesulfonamide (66.7 mg, 101.04 μmol, 54.71% yield, 99% purity, TFA salt) was obtained.1H NMR (400 MHz, METHANOL-d4) δ 8.79 (d, J = 6.8 Hz, 2H), 8.25 (d, J = 6.8 Hz,2H), 7.96 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.47 - 7.40 (m, 2H), 7.28 (s, 1H), 5.15 (s, 2H) MS (M + H)+ = 540.1 Example 32. Synthesis of Compound NEM-79A yl]benzenesulfonamide (2) [0339] To a solution of 4-bromo-N-tert-butyl-benzenesulfonamide (1.36 g, 4.65 mmol, 2 eq) in THF (15 mL) was added dropwise n-BuLi (2.5 M, 3.72 mL, 4 eq) at -70 °C over 15 min. After addition, the mixture was stirred at this temperature for 30 min, and then 7- (trifluoromethyl)indoline-2,3-dione (500 mg, 2.32 mmol, 1 eq) in THF (5 mL) was added dropwise at -70 °C. The resulting mixture was stirred at -70 °C for 2 h. The reaction was poured into ice NH4Cl aq. at 0 °C and the mixture was extracted with ethyl acetate (20 mL*2). The combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 12 g silica, 0-20 % ethyl acetate in petroleum ether, gradient over 20 min). Compound N-tert-butyl-4-[3-hydroxy-2-oxo-7-(trifluoromethyl)indolin-3- yl]benzenesulfonamide (150 mg, 175.06 μmol, 7.53% yield, 50% purity) was obtained as a yellow solid. MS (M + Na)+ = 451.1 Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]-7- (trifluoromethyl)indolin-3-yl]benzenesulfonamide (3) [0340] A mixture of N-tert-butyl-4-[3-hydroxy-2-oxo-7-(trifluoromethyl)indolin-3- yl]benzenesulfonamide (130 mg, 303.44 μmol, 1 eq), 4-[4-(chloromethyl)phenyl]pyridine (74.16 mg, 364.12 μmol, 1.2 eq), K2CO3 (104.84 mg, 758.59 μmol, 2.5 eq) in DMF (2 mL) was degassed and purged with N2 for 3 times. Then the mixture was stirred at 60 °C for 1h under N2 atmosphere.10 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (20 mL*2), and the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 12 g silica, 0-60 % ethyl acetate in petroleum ether, gradient over 20 min). Compound N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]-7-(trifluoromethyl)indolin-3-yl]benzenesulfonamide (80 mg, 134.31 μmol, 44.26% yield) was obtained as a yellow solid. MS (M + H)+ = 596.2 Synthesis of 4-[3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]-7- (trifluoromethyl)indolin-3-yl]benzenesulfonamide (NEM-79A) [0341] A mixture of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]- 7-(trifluoromethyl)indolin-3-yl]benzenesulfonamide (100 mg, 167.89 μmol, 1 eq) in DCE (2 mL) and TFA (1.54 g, 13.46 mmol, 1.00 mL, 80.18 eq) was stirred at 50 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:35%-65% B over 8.0 min). Compound 4-[3- hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]-7-(trifluoromethyl)indolin-3- yl]benzenesulfonamide (4.4 mg, 7.50 μmol, 4.47% yield, 92% purity) was obtained.1H NMR (400 MHz, METHANOL-d4) δ 8.59 - 8.52 (d, J = 4.8, 2H), 7.90 (d, J = 8.6 Hz, 2H), 7.76 - 7.72 (m, 1H), 7.72 - 7.69 (m, 2H), 7.68 (d, J = 1.3 Hz, 2H), 7.58-7.53 (m, 3H), 7.36 - 7.28 (m, 3H), 5.35 - 5.20 (m, 2H) MS (M + H)+ = 540.1
Example 33. Synthesis of Compound NEM-80A O O O O S S O O S Cl N O N H H N HO N N yl]benzenesulfonamide (2) [0342] To a solution of 4-bromo-N-tert-butyl-benzenesulfonamide (1.26 g, 4.33 mmol, 2 eq) in THF (10 mL) was added dropwise n-BuLi (2.5 M, 3.46 mL, 4 eq) at -70°C under N2 atmosphere. After addition, the mixture was stirred at this temperature for 1 h, and then 5- (trifluoromethoxy)indoline-2,3-dione (500 mg, 2.16 mmol, 1 eq) in THF (5 mL) was added dropwise at -70 °C. The resulting mixture was stirred at -70°C for 2 hr under N2 atmosphere. The reaction was quenched by addition of ice sat. NH4Cl (15mL) at 0°C under N2 atmosphere, and extracted with ethyl acetate (15 mL*2). The combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0- 60 % ethyl acetate in petroleum ether, gradient over 20 min). Compound N-tert-butyl-4-[3- hydroxy-2-oxo-5-(trifluoromethoxy)indolin-3-yl]benzenesulfonamide (400 mg, 900.04 μmol, 41.60% yield) was obtained as a light yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ 8.51 (s, 1H), 7.81 (d, J = 8.8 Hz, (d, J = 8.4 Hz, 2H), 7.16 (dd, J = 1.4, 8.5 Hz, 1H), 7.06 (s, 1H), 6.94 (d, J = 8.5 Hz, 1H), 5.09 (s, 1H), 4.47 (s, 1H), 1.20 (s, 9H) Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]-5- (trifluoromethoxy)indolin-3-yl]benzenesulfonamide (3) [0343] To a solution of N-tert-butyl-4-[3-hydroxy-2-oxo-5-(trifluoromethoxy)indolin-3- yl]benzenesulfonamide (100 mg, 225.01 μmol, 1 eq) in DMF (2 mL) was added K2CO3 (77.74 mg, 562.53 μmol, 2.5 eq) and 4-[4-(chloromethyl)phenyl]pyridine (54.99 mg, 270.01 μmol, 1.2 eq). The mixture was stirred at 60°C for 12hr.5 mL of water was added to the mixture, the mixture was extracted with dichloromethane (5 mL*2), and the combined extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. Compound N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4- (4-pyridyl)phenyl]methyl]-5-(trifluoromethoxy)indolin-3-yl]benzenesulfonamide (120 mg, crude) was obtained as a light yellow solid which was used in next step without purification. MS (M + H)+ = 612.2 Synthesis of 4-[3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]-5- (trifluoromethoxy)indolin-3-yl]benzenesulfonamid (NEM-80A) [0344] A mixture of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]- 5-(trifluoromethoxy)indolin-3-yl]benzenesulfonamide (100 mg, 163.50 μmol, 1 eq) in DCE (1 mL) and TFA (1 mL). The mixture was stirred at 50°C for 2 h. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1%TFA)- ACN];gradient:20%-50% B over 8.0 min). Compound 4-[3-hydroxy-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]-5-(trifluoromethoxy)indolin-3-yl]benzenesulfonamide (60 mg, 85.13 μmol, 52.07% yield, 95% purity, TFA salt) was obtained.1H NMR (400 MHz, METHANOL-d4) δ 8.79 (dd, J = 1.3, 5.3 Hz, 2H), 8.27 - 8.21 (m, 2H), 7.94 (br d, J = 8.1 Hz, 2H), 7.90 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H), 7.56 - 7.52 (m, 2H), 7.27 (dd, J = 1.4, 8.6 Hz, 1H), 7.18 (d, J = 1.4 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 5.11 (s, 2H) MS (M + H)+ = 556.1
Example 34. Synthesis of Compound NEM-81A [0345] To a solution of (5-bromothiazol-2-yl)methanol (1 g, 5.15 mmol, 1 eq) in DCM (10 mL) was added SOCl2 (1.23 g, 10.31 mmol, 748.58 μL, 2 eq) at 0°C, the reaction was stirred at 25°C for 2 h. The reaction was concentrated under reduce pressure.5-bromo-2- (chloromethyl) thiazole (1 g, crude) was obtained as a red solid which was used directly without purification. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 5.08 (s, 2H) Synthesis of 4-[1-[ 2-yl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N-tert- butyl-benzenesulfonamide (3) [0346] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (500 mg, 1.39 mmol, 1 eq) in DMF (20 mL) were added 5-bromo-2- (chloromethyl)thiazole (501.13 mg, 2.36 mmol, 1.7 eq), Cs2CO3 (1.36 g, 4.16 mmol, 3 eq) and KI (345.43 mg, 2.08 mmol, 1.5 eq), the reaction was stirred at 60°C for 12 h. The reaction mixture was cooled to room temperature.20 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (40 mL*2). The combined extracts were dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 12 g silica, 0-20 % ethyl acetate in petroleum ether, gradient over 20 min).4-[1-[(5-bromothiazol-2-yl)methyl]-3-hydroxy-2-oxo-indolin- 3-yl]-N-tert-butyl-benzenesulfonamide (600 mg, 1.09 mmol, 78.37% yield, 97.2% purity) was obtained as a yellow solid. Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[5-(4-pyridyl)thiazol-2- yl]methyl]indolin-3-yl]benzenesulfonamide (4) [0347] To a solution of 4-[1-[(5-bromothiazol-2-yl)methyl]-3-hydroxy-2-oxo-indolin-3- yl]-N-tert-butyl-benzenesulfonamide (600 mg, 1.12 mmol, 1 eq) and 4-pyridylboronic acid (687.38 mg, 5.59 mmol, 5 eq) in dioxane (10 mL) and H2O (1 mL) was added Na2CO3 (355.63 mg, 3.36 mmol, 3 eq) and Pd(dppf)Cl2 (81.84 mg, 111.84 μmol, 0.1 eq). Then the reaction mixture was bubbled with N2 for a while and heated to 90°C and stirred for 12 h under N2 atmosphere. The reaction mixture was cooled to room temperature.10 mL of water was added to the mixture and the mixture was extracted with ethyl acetate (20 mL*2). The combined extracts were dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0- 35 % ethyl acetate in petroleum ether, gradient over 20 min). N-tert-butyl-4-[3-hydroxy-2- oxo-1-[[5-(4-pyridyl)thiazol-2-yl]methyl]indolin-3-yl]benzenesulfonamide (240 mg, 425.19 μmol, 38.02% yield, 94.72% purity) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 5.5 Hz, 2H), 8.45 (s, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 5.5 Hz, 2H), 7.57 - 7.47 (m, 3H), 7.40 - 7.30 (m, 1H), 7.24 - 7.14 (m, 2H), 7.13 - 7.01 (m, 2H), 5.43 - 5.24 (m, 2H), 1.06 (s, 9H) Synthesis of 4-[3-hydroxy-2-oxo-1-[[5-(4-pyridyl)thiazol-2-yl]methyl]indolin-3- yl]benzenesulfonamide (NEM-81A) [0348] A mixture of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[5-(4-pyridyl)thiazol-2- yl]methyl]indolin-3-yl]benzenesulfonamide (240 mg, 448.89 μmol, 1 eq) in DCE (3 mL) and TFA (1.5 mL) was stirred at 50°C for 2 h. The mixture was concentrated under reduced pressure to give the crude product. The residue was purified by prep-HPLC: column: Phenomenex luna C18250*50mm*10 um;mobile phase: [H2O(0.1% TFA)- ACN];gradient:5%-50% B over 10.0 min.4-[3-hydroxy-2-oxo-1-[[5-(4-pyridyl)thiazol-2- yl]methyl]indolin-3-yl]benzenesulfonamide (139.6 mg, 234.68 μmol, 52.28% yield, 99.614% purity, TFA salt) was obtained.1H NMR (400 MHz, ACETONITRILE-d3) δ 8.66 (d, J = 6.8 Hz, 2H), 8.38 (s, 1H), 7.92 - 7.83 (m, 4H), 7.60 (d, J = 8.4 Hz, 2H), 7.38 (dt, J = 1.3, 7.8 Hz, 1H), 7.28 - 7.19 (m, 1H), 7.17 - 7.08 (m, 2H), 5.68 (br s, 2H), 5.36 (d, J = 16.8 Hz, 1H), 5.21 (d, J = 16.8 Hz, 1H). MS (M + H)+ = 479.0 Example 35. Synthesis of Compound NEM-82A [0349] To a solution of oxazol-2-ylmethanol (3 g, 30.28 mmol, 1 eq) in THF (30 mL) was added imidazole (4.12 g, 60.55 mmol, 2 eq) and TBSCl (5.93 g, 39.36 mmol, 4.84 mL, 1.3 eq). The mixture was stirred at 25°C for 5 hr.20 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (30 mL*2), and the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 10 g silica, 0~30% ethyl acetate in petroleum ether, gradient over 30 min) to give product. Compound tert-butyl-dimethyl-(oxazol-2-ylmethoxy)silane (6 g, 28.12 mmol, 92.89% yield) was obtained as light yellow oil.1H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 0.8 Hz, 1H), 7.18 (s, 1H), 4.72 (s, 2H), (s, 9H), 0.08 - 0.04 (m, 6H) Synthesis of (5-bromooxazol-2-yl)methoxy-tert-butyl-dimethyl-silane (3) [0350] To a solution of tert-butyl-dimethyl-(oxazol-2-ylmethoxy)silane (2 g, 9.37 mmol, 1 eq) in THF (20 mL) was added dropwise n-BuLi (2.5 M, 4.50 mL, 1.2 eq) at -78 °C under N2 atmosphere. After addition, the mixture was stirred at -78°C for 0.5 hr, and then Br2 (2.25 g, 14.06 mmol, 724.42 μL, 1.5 eq) in THF (1 mL) was added dropwise to the mixture at - 78°C. The mixture was stirred at -78°C for 2 hr under N2 atmosphere. The reaction was quenched by addition of ice sat. NH4Cl (10 mL) and Na2SO3 (6 mL) at 0oC under N2 atmosphere and extracted with ethyl acetate (20 mL*2). The combined extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 10 g silica, 0~20% ethyl acetate in petroleum ether, gradient over 30 min). Compound (5-bromooxazol-2-yl)methoxy-tert-butyl-dimethyl-silane (1.5 g, 5.13 mmol, 54.75% yield) was obtained as light yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.26 (s, 1H), 4.70 (s, 2H), 0.86 (s, 9H), 0.07 (s, 6H) Synthesis of (5-bromooxazol-2-yl)methanol (4) [0351] To a solution of (5-bromooxazol-2-yl)methoxy-tert-butyl-dimethyl-silane (1.4 g, 4.79 mmol, 1 eq) in HCl/EtOAc (15 mL, 4M). The mixture was stirred at 25°C for 1 hr. The mixture was evaporated under reduced pressure. Compound (5-bromooxazol-2-yl)methanol (800 mg, crude, HCl salt) was obtained as a brown oil.1HNMR (400 MHz, DMSO-d6) δ 7.25 (s, 1H), 4.47 (s, 2H) Synthesis of 5-bromo-2-(chloromethyl)oxazole (5) [0352] To a solution of (5-bromooxazol-2-yl)methanol (300 mg, 1.40 mmol, 1 eq, HCl) in DCM (1 mL) was added SOCl2 (332.87 mg, 2.80 mmol, 203.22 μL, 2 eq). The mixture was stirred at 25°C for 12 hr. The product fraction was evaporated under reduced pressure. Compound 5-bromo-2-(chloromethyl)oxazole (260 mg, crude, HCl salt) was obtained as a brown solid. MS (M + H)+ = 196.1 Synthesis of 4-[1-[(5-bromooxazol-2-yl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N-tert- butyl-benzenesulfonamide (6) [0353] Seven batches. To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (20 mg, 55.49 μmol, 1 eq) in DMF (1 mL) was added Cs2CO3 (54.24 mg, 166.47 μmol, 3 eq), 5-bromo-2-(chloromethyl)oxazole (21.97 mg, 94.33 μmol, 1.7 eq, HCl) and KI (13.82 mg, 83.23 μmol, 1.5 eq). The mixture was stirred at 60°C for 12 hr.20 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (10 mL*2), and the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 2 g silica, 0~500% ethyl acetate in petroleum ether, gradient over 30 min) Compound 4-[1-[(5-bromooxazol-2-yl)methyl]-3- hydroxy-2-oxo-indolin-3-yl]-N-tert-butyl-benzenesulfonamide (120 mg, 230.59 μmol, 59.37% yield) was obtained as a light yellow solid. Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[5-(4-pyridyl)oxazol-2- yl]methyl]indolin-3-yl]benzenesulfonamide (7) [0354] A mixture of 4-[1-[(5-bromooxazol-2-yl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]- N-tert-butyl-benzenesulfonamide (70 mg, 134.51 μmol, 1 eq), 4-pyridylboronic acid (82.67 mg, 672.57 μmol, 5 eq), Pd(dppf)Cl2 (9.84 mg, 13.45 μmol, 0.1 eq), Na2CO3 (42.77 mg, 403.54 μmol, 3 eq) in dioxane (1 mL) and H2O (0.1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 3 hr under N2 atmosphere.20 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (10 mL*2), and the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 10 g silica, 0~70% ethyl acetate in petroleum ether, gradient over 30 min) Compound N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[5-(4- pyridyl)oxazol-2-yl]methyl]indolin-3-yl]benzenesulfonamide (60 mg, 115.70 μmol, 86.01% yield) was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.50 (br s, 2H), 7.86 (br d, J = 5.3 Hz, 2H), 7.60 (br d, J = 6.0 Hz, 3H), 7.48 (br s, 1H), 7.38 (br s, 3H), 7.30 (br d, J = 7.0 Hz, 1H), 7.20 - 7.01 (m, 3H), 5.26 - 5.07 (m, 2H), 4.50 (br s, 1H), 1.24 (s, 9H) Synthesis of 4-[3-hydroxy-2-oxo-1-[[5-(4-pyridyl)oxazol-2-yl]methyl]indolin-3- yl]benzenesulfonamide (NEM-82A) [0355] A mixture of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[5-(4-pyridyl)oxazol-2- yl]methyl]indolin-3-yl]benzenesulfonamide (50 mg, 96.42 μmol, 1 eq) in DCE (1 mL) and TFA (1mL) was stirred at 60°C for 2 hr. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:1%-30% B over 8.0 min). Compound 4-[3-hydroxy-2-oxo-1-[[5-(4-pyridyl)oxazol-2-yl]methyl]indolin-3- yl]benzenesulfonamide (18.9 mg, 31.47 μmol, 32.64% yield, 96% purity, TFA) was obtained. 1 HNMR (400 MHz, METHANOL-d4) δ 8.74 (br d, J = 5.6 Hz, 2H), 8.07 (s, 1H), 8.00 - 7.93 (m, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.61 - 7.56 (m, 2H), 7.43 - 7.37 (m, 1H), 7.26 (d, J = 7.0 Hz, 1H), 7.19 - 7.13 (m, 2H), 5.39 - 5.32 (m, 1H), 5.25 - 5.19 (m, 1H). MS (M + H)+ = 463.1.
Example 36. Synthesis of Compound NEM-84A [0356] A mixture of (2-chloropyrimidin-5-yl)methanol (1 g, 6.92 mmol, 1 eq), 4- pyridylboronic acid (1.28 g, 10.38 mmol, 1.5 eq), Pd(dppf)Cl2 (506.16 mg, 691.76 μmol, 0.1 eq), Na2CO3 (1.47 g, 13.84 mmol, 2 eq) in dioxane (10 mL) and H2O (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 5 hr under N2 atmosphere.20 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (20 mL*2). The combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. Compound [2- (4-pyridyl)pyrimidin-5-yl]methanol (220 mg, 1.18 mmol, 16.99% yield) was obtained as a white solid. Synthesis of 5-(chloromethyl)-2-(4-pyridyl)pyrimidine (3) [0357] To a solution of [2-(4-pyridyl)pyrimidin-5-yl]methanol (200 mg, 1.07 mmol, 1 eq) in CHCl3 (2 mL) was added SOCl2 (635.53 mg, 5.34 mmol, 387.99 μL, 5 eq). The mixture was stirred at 20°C for 2 h. The mixture was concentrated under reduced pressure to give a residue. Compound 5-(chloromethyl)-2-(4-pyridyl)pyrimidine (200 mg, crude) was obtained as a white solid which was used directly without further purification. MS (M + H)+ = 206.2 Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[2-(4-pyridyl)pyrimidin-5- yl]methyl]indolin-3-yl]benzenesulfonamide (4) [0358] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (100 mg, 277.45 μmol, 1 eq) in DMF (2 mL) was added K2CO3 (95.86 mg, 693.62 μmol, 2.5 eq) and 5-(chloromethyl)-2-(4-pyridyl)pyrimidine (68.47 mg, 332.94 μmol, 1.2 eq). The mixture was stirred at 60°C for 2 h.10 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (20 mL*2), and the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. Compound N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[2- (4-pyridyl)pyrimidin-5-yl]methyl]indolin-3-yl]benzenesulfonamide (100 mg, 188.82 μmol, 68.06% yield) was obtained as a yellow solid. MS (M + H)+ = 530.1 Synthesis of 4-[3-hydroxy-2-oxo-1-[[2-(4-pyridyl)pyrimidin-5-yl]methyl]indolin-3- yl]benzenesulfonamide (NEM-84A) [0359] A mixture of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[2-(4-pyridyl)pyrimidin-5- yl]methyl]indolin-3-yl]benzenesulfonamide (100 mg, 188.82 μmol, 1 eq) in DCE (2 mL) and TFA (1.54 g, 13.46 mmol, 1 mL, 71.30 eq) was stirred at 50 °C for 2 h. The mixture was concentrated to give crude product. The residue was purified by preparative HPLC (column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:5%- 30% B over 8.0 min). Compound 4-[3-hydroxy-2-oxo-1-[[2-(4-pyridyl)pyrimidin-5- yl]methyl]indolin-3-yl]benzenesulfonamide (72.6 mg, 122.33 μmol, 64.79% yield, 99% purity, TFA salt) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ 9.04 (s, 2H), 8.90 - 8.85 (d, J = 6.8, 2H), 8.81 - 8.76 (d, J = 6.8, 2H), 7.87 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 7.40 (dt, J = 1.3, 7.8 Hz, 1H), 7.29 - 7.24 (m, 1H), 7.21 - 7.14 (m, 2H), 5.22 - 5.08 (m, 2H) MS (M + H)+ = 474.1 Example 37. Synthesis of Compound NEM-85A
Synthesis of [1-(4-pyridyl)-4-piperidyl]methanol (2) [0360] To a solution of 1-(4-pyridyl)piperidine-4-carboxylic acid (500 mg, 2.42 mmol, 1 eq) in THF (10 mL) was added BH3.THF (1 M, 14.55 mL, 6 eq) at 0°C, the reaction mixture was bubbled with N2 for a while and heated to 70°C, stirred 12 h under N2 atmosphere. The mixture was quenched by MeOH (10 mL) at 0°C. The mixture was concentrated under reduced pressure to give the crude product. [1-(4-pyridyl)-4- piperidyl]methanol (450 mg, crude) was obtained as a white solid. MS (M + H)+ = 193.0 Synthesis of 4-[4-(chloromethyl)-1-piperidyl]pyridine (3) [0361] To a solution of [1-(4-pyridyl)-4-piperidyl]methanol (200 mg, 1.04 mmol, 1 eq) in DCM (3 mL) was added SOCl2 (1.49 g, 12.48 mmol, 906.68 μL, 12 eq), the reaction was stirred at 40°C for 12 h. The reaction was concentrated under reduce pressure.4-[4- (chloromethyl)-1-piperidyl]pyridine (200 mg, crude) was obtained as a yellow solid. Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[1-(4-pyridyl)-4- piperidyl]methyl]indolin-3-yl]benzenesulfonamide (4) [0362] To a solution of 4-[4-(chloromethyl)-1-piperidyl]pyridine (105.23 mg, 499.41 μmol, 3 eq) and N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (60 mg, 166.47 μmol, 1 eq) in DMSO (2 mL) were added t-BuOK (56.04 mg, 499.41 μmol, 3 eq) and KI (55.27 mg, 332.94 μmol, 2 eq), the reaction was stirred at 80°C for 12 h.3 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (5 mL*2), and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 10 g silica, 0-23 % methanol in dichloromethane, gradient over 20 min). N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[1-(4-pyridyl)-4-piperidyl]methyl]indolin-3- yl]benzenesulfonamide (80 mg, 74.81 μmol, 44.94% yield, 50% purity) was obtained as a yellow oil. MS (M + H)+ = 535.4 Synthesis of 4-[3-hydroxy-2-oxo-1-[[1-(4-pyridyl)-4-piperidyl]methyl]indolin-3- yl]benzenesulfonamide (NEM-85A) [0363] A mixture of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[1-(4-pyridyl)-4- piperidyl]methyl]indolin-3-yl]benzenesulfonamide (80 mg, 149.63 μmol, 1 eq) in DCE (1 mL) and TFA (1 mL) was stirred at 50°C for 1 h. The reaction mixture was cooled to room temperature. The mixture was concentrated under reduced pressure to give a residue and the residue was purified directly. The residue was purified by prep-HPLC:column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:5%-35% B over 8.0 min. Compound 4-[3-hydroxy-2-oxo-1-[[1-(4-pyridyl)-4-piperidyl]methyl]indolin-3- yl]benzenesulfonamide (7.9 mg, 12.86 μmol, 17.20% yield, TFA salt) was obtained.1H NMR (400 MHz, ACETONITRILE-d3) δ 8.04 (br d, J = 7.2 Hz, 2H), 7.87 - 7.72 (d, J = 8.8 Hz, 2H), 7.52 - 7.45 (d, J = 8.8 Hz, 2H), 7.40 (dt, J = 1.3, 7.8 Hz, 1H), 7.19 (d, J = 6.9 Hz, 1H), 7.13 - 7.06 (m, 2H), 6.93 (d, J = 7.8 Hz, 2H), 5.73 (br s, 2H), 4.17 - 4.08 (m, 2H), 3.72 - 3.64 (m, 1H), 3.63 - 3.55 (m, 1H), 3.18 - 3.07 (m, 2H), 1.92 - 1.78 (m, 3H), 1.44 - 1.24 (m, 2H). MS (M + H)+ = 479.2 Example 38. Synthesis of Compound NEM-87A naphthyl]indolin-3-yl]benzenesulfonamide (6) [0364] To a solution of 4-[1-(6-bromo-1-naphthyl)-5-chloro-3-hydroxy-2-oxo-indolin-3- yl]-N-tert-butyl-benzenesulfonamide (67 mg, 85.99 μmol, 1 eq) and 4-pyridylboronic acid (52.85 mg, 429.97 μmol, 5 eq) in DME (1 mL) were added K3PO4 (36.51 mg, 171.99 μmol, 2 eq) and cyclopentyl(diphenyl)phosphane; dichloromethane; dichloropalladium; iron (14.05 mg, 17.20 μmol, 0.2 eq), the reaction mixture was degassed with with N2 for three times. The mixture was heated to 90°C and stirred for 12 h under N2 atmosphere.10 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (5 mL*3) and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0-40 % ethyl acetate in petroleum ether, gradient over 20 min). N- tert-butyl-4-[5-chloro-3-hydroxy-2-oxo-1-[6-(4-pyridyl)-1-naphthyl]indolin-3- yl]benzenesulfonamide (20 mg, 31.10 μmol, 36.16% yield, 93% purity) was obtained as a brown oil. MS (M + H)+ = 598.1 Synthesis of 4-[5-chloro-3-hydroxy-2-oxo-1-[6-(4-pyridyl)-1-naphthyl]indolin-3- yl]benzenesulfonamide (NEM-87A) [0365] A mixture of N-tert-butyl-4-[5-chloro-3-hydroxy-2-oxo-1-[6-(4-pyridyl)-1- naphthyl]indolin-3-yl]benzenesulfonamide (20 mg, 33.44 μmol, 1 eq) in DCE (1 mL) and TFA (400.00 μL) was stirred at 50°C for 2 h. The mixture was concentrated under reduced pressure to give the crude product. The residue was purified by prep-HPLC column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1% TFA)- ACN];gradient:10%-50% B over 8.0 min.4-[5-chloro-3-hydroxy-2-oxo-1-[6-(4-pyridyl)-1- naphthyl]indolin-3-yl]benzenesulfonamide (3.5 mg, 5.22 μmol, 15.62% yield, 97.9% purity, TFA salt) was obtained. 1HNMR (400 MHz, METHANOL-d4) δ = 8.90 - 8.79 (m, 2H), 8.72 - 8.66 (m, 1H), 8.39 - 8.27 (m, 3H), 8.06 - 7.97 (m, 3H), 7.92 - 7.66 (m, 5H), 7.39 (dd, J = 2.1, 17.4 Hz, 2H), 6.60 - 6.46 (m, 1H). MS (M + H)+ = 542.0 Example 39. Synthesis of Compound NEM-88A yl)benzenesulfonamide (2) [0366] To a solution of 4-bromo-N-tert-butyl-benzenesulfonamide (1.81 g, 6.21 mmol, 2 eq) in THF (10 mL) was added dropwise n-BuLi (2.5 M, 4.96 mL, 4 eq) at -70°C under N2 atmosphere. After addition, the mixture was stirred at this temperature for 1 h, and then 5- methylindoline-2,3-dione (500 mg, 3.10 mmol, 1 eq) in THF (5 mL) was added dropwise at - 70°C. The resulting mixture was stirred at -70°C for 2 h under N2 atmosphere. The reaction was quenched by addition of ice sat. NH4Cl (10 mL) at 0°C under N2 atmosphere, and extracted with ethyl acetate (20 mL*3). The combined extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 12 g silica, 30-100 % ethyl acetate in petroleum ether, gradient over 20 min). Compound N-tert-butyl-4-(3-hydroxy-5-methyl-2- oxo-indolin-3-yl)benzenesulfonamide (500 mg, 1.34 mmol, 43.04% yield) was obtained as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.07 (br s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.10 (br d, J = 8.0 Hz, 1H), 7.01 (s, 1H), 6.84 (d, J = 8.0 Hz, 1H), 4.88 (s, 1H), 3.88 (br s, 1H), 2.28 (s, 3H), 1.22 (s, 9H) Synthesis of N-tert-butyl-4-[3-hydroxy-5-methyl-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (3) [0367] To a solution of N-tert-butyl-4-(3-hydroxy-5-methyl-2-oxo-indolin-3- yl)benzenesulfonamide (100 mg, 267.06 μmol, 1 eq) in DMF (2 mL) was added K2CO3 (92.27 mg, 667.64 μmol, 2.5 eq) and 4-[4-(chloromethyl)phenyl]pyridine (70.71 mg, 347.17 μmol, 1.3 eq). The mixture was stirred at 60°C for 12 h.5 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (15 mL*2), and the combined extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. Compound N-tert-butyl-4-[3-hydroxy-5-methyl-2-oxo-1- [[4-(4-pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (130 mg, crude) was obtained as a light yellow solid which was used in next step without purification. MS (M + H)+ = 542.2 Synthesis of 4-[3-hydroxy-5-methyl-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3- yl]benzenesulfonamide (NEM-88A) [0368] A mixture of N-tert-butyl-4-[3-hydroxy-5-methyl-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (100 mg, 184.62 μmol, 1 eq) in DCE (1 mL) and TFA (1.00 mL) was stirred at 50°C for 2 h. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1%TFA)- ACN];gradient:15%-40% B over 8.0 min) . Compound 4-[3-hydroxy-5-methyl-2-oxo-1-[[4- (4-pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (70 mg, 110.91 μmol, 60.08% yield, TFA salt) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ 8.79 (d, J = 6.8 Hz, 2H), 8.26 (d, J = 6.8 Hz, 2H), = 8.4 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.55 - 7.51 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.0 Hz, 1H), 7.07 (s, 1H), 6.90 (d, J = 8.0 Hz, 1H), 5.06 (d, J = 4.4 Hz, 2H), 2.28 (s, 3H) MS (M + H)+ = 486.2
Example 40. Synthesis of Compound NEM-89A tert-butyl-benzenesulfonamide (3) [0369] To a solution of N-tert-butyl-4-(6-chloro-3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (150 mg, 379.87 μmol, 1 eq) and 1-bromo-4-(bromomethyl)benzene (113.93 mg, 455.84 μmol, 1.2 eq) in DMF (3 mL) was added K2CO3 (131.25 mg, 949.68 μmol, 2.5 eq), the reaction was stirred at 60°C for 3 h.3 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (10 mL*3) and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0- 35 % ethyl acetate in petroleum ether, gradient over 20 min).4-[1-[(4-bromophenyl)methyl]- 6-chloro-3-hydroxy-2-oxo-indolin-3-yl]-N-tert-butyl-benzenesulfonamide (190 mg, 336.95 μmol, 88.70% yield) was obtained as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.01 (s, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.48 (dd, J = 8.4, 14.0 Hz, 4H), 7.18 (dd, J = 6.8, 7.6 Hz, 3H), 7.07 (dd, J = 1.2, 8.0 Hz, 1H), 6.80 (d, J = 1.0 Hz, 1H), 5.00 - 4.75 (m, 2H), 4.64 (br s, 1H), 1.24 (s, 9H) Synthesis of N-tert-butyl-4-[6-chloro-3-hydroxy-2-oxo-1-[(4-pyrrolidin-1- ylphenyl)methyl]indolin-3-yl]benzenesulfonamide (4) [0370] To a solution of 4-[1-[(4-bromophenyl)methyl]-6-chloro-3-hydroxy-2-oxo- indolin-3-yl]-N-tert-butyl-benzenesulfonamide (190 mg, 336.95 μmol, 1 eq) and pyrrolidine (28.76 mg, 404.33 μmol, 33.75 μL, 1.2 eq) in 2-methylbutan-2-ol (2 mL) were added sodium;2-methylpropan-2-olate (2 M, 336.95 μL, 2 eq) and [2-(2-aminophenyl)phenyl]- methylsulfonyloxy-palladium;dicyclohexyl-[3,6-dimethoxy-2-(2,4,6- triisopropylphenyl)phenyl]phosphane (61.09 mg, 67.39 μmol, 0.2 eq), the reaction mixture was degassed with N2 for three times. The mixture was heated to 90°C and stirred for 12 h under N2 atmosphere.3 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (15 mL*3). The combined extracts was dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica, 0-30 % ethyl acetate in petroleum ether, gradient over 20 min). N- tert-butyl-4-[6-chloro-3-hydroxy-2-oxo-1-[(4-pyrrolidin-1-ylphenyl)methyl]indolin-3- yl]benzenesulfonamide (150 mg, 203.03 μmol, 60.26% yield) was obtained as a yellow oil. MS (M + H)+ = 554.4 Synthesis of 4-[6-chloro-3-hydroxy-2-oxo-1-[(4-pyrrolidin-1-ylphenyl)methyl]indolin-3- yl]benzenesulfonamide (NEM-89A) [0371] A mixture of N-tert-butyl-4-[6-chloro-3-hydroxy-2-oxo-1-[(4-pyrrolidin-1- ylphenyl)methyl]indolin-3-yl]benzenesulfonamide (150 mg, 270.71 μmol, 1 eq) in DCE (1 mL) and TFA (1.5 mL) was stirred at 50°C for 2 h. The mixture was concentrated under reduced pressure to give the crude product. The residue was purified by prep-HPLC: column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [H2O (10mM NH4HCO3)-ACN];gradient:45%-75% B over 8.0 min.4-[6-chloro-3-hydroxy-2-oxo-1-[(4- pyrrolidin-1-ylphenyl)methyl]indolin-3-yl]benzenesulfonamide (6.8 mg, 13.52 μmol, 6.66% yield) was obtained. 1HNMR (400 MHz, ACETONITRILE-d3) δ 7.87 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.18 (dd, J = 8.3, 12.2 Hz, 3H), 7.11 - 7.05 (m, 1H), 7.03 (d, J = 1.8 Hz, 1H), 6.57 (d, J = 6.8 Hz, 2H), 5.70 (s, 2H), 4.88 (s, 1H), 4.80 (d, J = 2.8 Hz, 2H), 3.30 - 3.21 (m, 4H), 2.03 - 1.99 (m, 4H). MS (M + H)+ = 498.1
Example 41. Synthesis of Compound NEM-91A a g, g, 36.58 mmol, 3.05 mL, 3 eq) in dioxane (30 mL) were added SPhos Pd G3 (951.40 mg, 1.22 mmol, 0.1 eq) and NaOtBu (2 M, 12.19 mL, 2 eq). The reaction mixture was degassed with N2 for three times. The mixture was heated to 90°C, stirred for 12 h under N2 atmosphere.40 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (50 mL*2), and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica, 0-25 % ethyl acetate in petroleum ether, gradient over 20 min).5- pyrrolidin-1-ylthiazole (2.13 g, 10.36 mmol, 84.95% yield, 75% purity) was obtained as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ 7.99 (s, 1H), 6.75 (s, 1H), 3.27 (m, 4H), 2.08 - 2.02 (m, 4H) Synthesis of 5-pyrrolidin-1-ylthiazole-2-carbaldehyde (3) [0373] To a solution of 5-pyrrolidin-1-ylthiazole (2.13 g, 10.36 mmol, 1 eq) in THF (30 mL) was added n-BuLi (2.5 M, 6.21 mL, 1.5 eq) at -70°C. The reaction mixture was degassed with N2 for three times. The mixture was stirred at -70°C for 1 h under N2 atmosphere. Then a solution of DMF (1.89 g, 25.89 mmol, 1.99 mL, 2.5 eq) in THF (10 mL) was added. The resulting mixture was stirred for 2.5 h, allowing the temperature to raise to -60°C. The mixture was quenched with NH4Cl (10 mL) at -70°C, and then diluted with H2O 20 mL and extracted with ethyl acetate (50 mL *2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give a residue.5-pyrrolidin-1-ylthiazole-2-carbaldehyde (1.9 g, crude) was obtained as a brown gum.1H NMR (400 MHz, CHLOROFORM-d) δ = 9.66 (s, 1H), 7.00 (s, 1H), 3.50 - 3.35 (m, 4H), 2.19 - 2.08 (m, 4H) Synthesis of (5-pyrrolidin-1-ylthiazol-2-yl)methanol (4) [0374] To a solution of 5-pyrrolidin-1-ylthiazole-2-carbaldehyde (1.8 g, 9.88 mmol, 1 eq) in MeOH (30 mL) was added NaBH4 (747.34 mg, 19.75 mmol, 2 eq) at 0°C, the reaction was stirred at 25°C for 1 h. The mixture was quenched with NH4Cl (10 mL) at 0°C, the mixture was extracted with ethyl acetate (20 mL*2) and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 40 g silica, 0-40 % ethyl acetate in petroleum ether, gradient over 20 min). Compound (5-pyrrolidin-1-ylthiazol-2- yl)methanol (600 mg, 3.13 mmol, 31.65% yield, 96% purity) was obtained as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 6.54 (s, 1H), 4.76 (s, 2H), 3.25 (m, 4H), 2.11 - 1.98 (m, 4H) Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[(5-pyrrolidin-1-ylthiazol-2- yl)methyl]indolin-3-yl]benzenesulfonamide [0375] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (150 mg, 416.17 μmol, 1 eq), (5-pyrrolidin-1-ylthiazol-2- yl)methanol (92.02 mg, 499.41 μmol, 1.2 eq) and 2-(tributyl-phosphanylidene) acetonitrile (200.89 mg, 832.35 μmol, 2 eq) in toluene (2 mL) was added 2-(tributyl-phosphanylidene) acetonitrile (200.89 mg, 832.35 μmol, 2 eq), the reaction mixture was bubbled with N2 for a while and stirred at 80°C for 12 h under N2 atmosphere.3 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (5 mL*2) and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0-30% ethyl acetate in petroleum ether, gradient over 20 min). Compound N-tert-butyl-4-[3- hydroxy-2-oxo-1-[(5-pyrrolidin-1-ylthiazol-2-yl)methyl]indolin-3-yl]benzenesulfonamide (200 mg, 87.34 μmol, 20.99% yield, 23% purity) was obtained as a brown oil. MS (M + H)+ = 527.3 Synthesis of 4-[3-hydroxy-2-oxo-1-[(5-pyrrolidin-1-ylthiazol-2-yl)methyl]indolin-3- yl]benzenesulfonamide [0376] A solution of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[(5-pyrrolidin-1-ylthiazol-2- yl)methyl]indolin-3-yl]benzenesulfonamide (200 mg, 87.34 μmol, 1 eq, 23% purity) in DCE (2 mL) and TFA (3.07 g, 26.92 mmol, 2 mL, 308.27 eq) was stirred at 50°C for 1 h. The reaction mixture was cooled to room temperature. The mixture was basified by sat. NaHCO3 to pH = 9.3 at 0 oC, the mixture was extracted with ethyl acetate (5 mL*2), and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC: column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)- ACN];gradient:30%-60% B over 8.0 min.4-[3-hydroxy-2-oxo-1-[(5-pyrrolidin-1-ylthiazol- 2-yl)methyl]indolin-3-yl]benzenesulfonamide (8.87 mg, 18.47 μmol, 21.15% yield, 98% purity) was obtained.1H NMR (400 MHz, ACETONITRILE-d3) δ = 7.87 - 7.76 (m, 2H), 7.57 - 7.48 (m, 2H), 7.35 (dt, J = 1.3, 7.8 Hz, 1H), 7.21 - 7.05 (m, 3H), 6.48 (s, 1H), 5.64 (s, 2H), 5.05 (d, J = 16 Hz,1H), 4.94 (d, J = 15.6 Hz,1H), 4.78 (s, 1H), 3.24 - 3.09 (m, 4H), 1.97 (td, J = 3.3, 6.8 Hz, 4H). MS (M + H)+ = 471.1. Example 42. Synthesis of Compound NEM-94A [0377] To a solution of (4-morpholinophenyl)methanol (1 g, 5.17 mmol, 1 eq), TEA (1.05 g, 10.35 mmol, 1.44 mL, 2 eq) and 4-methylbenzenesulfonyl chloride (986.57 mg, 5.17 mmol, 1 eq) in DCM (20 mL) was added DMAP (63.22 mg, 517.49 μmol, 0.1 eq) at 0 °C, the reaction was stirred at 25°C for 12 h.20 mL of water was added to the mixture, the mixture was extracted with dichloromethane (30 mL*2), the combined extracts were dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. (4-morpholinophenyl)methyl 4-methylbenzenesulfonate (1.5 g, crude) was obtained as a yellow solid. Synthesis of N-tert-butyl-4-[6-chloro-3-hydroxy-1-[(4-morpholinophenyl)methyl]-2- oxo-indolin-3-yl]benzenesulfonamide (3) [0378] To a solution of (4-morpholinophenyl)methyl 4-methylbenzenesulfonate (314.11 mg, 904.09 μmol, 2 eq) and N-tert-butyl-4-(6-chloro-3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (210 mg, 452.05 μmol, 1 eq) in DMF (10 mL) was added K2CO3 (187.43 mg, 1.36 mmol, 3 eq), the reaction was stirred at 80°C for 24 h.10 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (20 mL*2), washed with brine (5 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica, 0-25 % ethyl acetate in petroleum ether, gradient over 20 min). N-tert-butyl-4-[6-chloro-3-hydroxy-1-[(4- morpholinophenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (300 mg, 210.49 μmol, 46.56% yield) was obtained as a yellow oil. MS (M + H)+ = 570.18. Synthesis of 4-[6-chloro-3-hydroxy-1-[(4-morpholinophenyl)methyl]-2-oxo-indolin-3- yl]benzenesulfonamide (NEM-94A) [0379] A mixture of N-tert-butyl-4-[6-chloro-3-hydroxy-1-[(4- morpholinophenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (300 mg, 210.49 μmol, 1 eq) in DCE (1 mL) and TFA (1 mL) was stirred at 50°C for 1 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC: column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1% TFA)- ACN]; gradient:30%-60% B over 8.0 min.4-[6-chloro-3-hydroxy-1-[(4- morpholinophenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (10 mg, 15.76 μmol, 7.49% yield, TFA salt) was obtained.1H NMR (400 MHz, ACETONITRILE-d3) δ 7.84 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 8.0 Hz, 1H), 7.11 - 7.05 (m, 1H), 7.01-6.96 (m, 3H), 5.66 (s, 2H), 4.86-4.77 (m, 2H), 3.79 - 3.77 (m, 4H), 3.14 - 3.13 (m, 4H). MS (M + H)+ = 514.1. Example 43. Synthesis of Compound NEM-98A [0380] To a solution of 6-isoquinolylmethanol (200 mg, 1.26 mmol, 1 eq) in DCM (1 mL) was added SOCl2 (747.37 mg, 6.28 mmol, 456.27 Μl, 5 eq). The mixture was stirred at 25°C for 12 hr. The mixture was concentrated to give a residue. Compound 6- (chloromethyl)isoquinoline (200 mg, crude, HCl salt) was obtained as a white solid. MS (M + H)+ = 178.3 Synthesis of N-tert-butyl-4-[3-hydroxy-1-(6-isoquinolylmethyl)-2-oxo-indolin-3- yl]benzenesulfonamide (4) [0381] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (100 mg, 277.45 μmol, 1 eq) in DMF (2 mL) was added K2CO3 (95.86 mg, 693.62 μmol, 2.5 eq) and 6-(chloromethyl)isoquinoline (59.14 mg, 276.24 μmol, 1 eq, HCl).The mixture was stirred at 60°C for 12 hr.10 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (10 mL*2), and the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated to give a residue. Compound N-tert-butyl-4-[3-hydroxy-1-(6- isoquinolylmethyl)-2-oxo-indolin-3-yl]benzenesulfonamide (100 mg, crude) was obtained as a brown oil. MS (M + H)+ = 502.3 Synthesis of 4-[3-hydroxy-1-(6-isoquinolylmethyl)-2-oxo-indolin-3- yl]benzenesulfonamide (NEM-98A) [0382] A mixture of N-tert-butyl-4-[3-hydroxy-1-(6-isoquinolylmethyl)-2-oxo-indolin-3- yl]benzenesulfonamide (100 mg, 199.36 μmol, 1 eq) in DCE (2 mL) and TFA (1 mL). The mixture was stirred at 60°C for 2 hr. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:15%-45% B over 8.0 min) to give product. Compound 4-[3-hydroxy-1-(6-isoquinolylmethyl)-2-oxo-indolin-3- yl]benzenesulfonamide (61.9 mg, 135.82 μmol, 68.13% yield, 97.749% purity) was obtained. 1HNMR (400 MHz, METHANOL-d4) δ = 9.21 (s, 1H), 8.43 (d, J = 6.0 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.93 - 7.85 (m, 3H), 7.77 (d, J = 6.0 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.34 - 7.23 (m, 2H), 7.15 - 7.09 (m, 1H), 7.01 (d, J = 8.0 Hz, 1H), 5.26 - 5.14 (m, 2H). MS (M + H)+ = 446.1 Example 44. Synthesis of Compound NEM-99A a mg, was added SOCl2 (747.37 mg, 6.28 mmol, 456.27 μL, 5 eq). The mixture was stirred at 25°C for 12 hr. The mixture was concentrated to give a residue. Compound 6- (chloromethyl)quinoline (200 mg, crude, HCl) was obtained as a brown solid. MS (M + H)+ = 178.2 Synthesis of N-tert-butyl-4-[(3Z)-3-[(4-methoxyphenyl)methylene]-2-oxo-indolin-1- yl]benzenesulfonamide (4) [0384] To a solution of 6-(chloromethyl)quinoline (65.06 mg, 303.90 μmol, 1.2 eq, HCl) in DMF (2 mL) was added K2CO3 (87.50 mg, 633.12 μmol, 2.5 eq) and N-tert-butyl-4-(5- chloro-3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (100 mg, 253.25 μmol, 1 eq). The mixture was stirred at 60°C for 12 hr.20 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (10 mL*2), and the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated to give a residue. Compound N-tert-butyl-4-[5-chloro-3-hydroxy-2-oxo-1-(6- quinolylmethyl)indolin-3-yl]benzenesulfonamide (100 mg, crude) was obtained as a yellow solid. MS (M + H)+ = 536.1 Synthesis of 4-[5-chloro-3-hydroxy-2-oxo-1-(6-quinolylmethyl)indolin-3- yl]benzenesulfonamide (NEM-99A) [0385] A mixture of N-tert-butyl-4-[5-chloro-3-hydroxy-2-oxo-1-(6- quinolylmethyl)indolin-3-yl]benzenesulfonamide (100 mg, 186.55 μmol, 1 eq) in DCE (1 mL) and TFA (1 mL) was stirred at 60°C for 2 hr. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18100*40mm*3 um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:15%-30% B over 18.0 min) to give product. Compound 4-[5-chloro-3-hydroxy-2-oxo-1-(6- quinolylmethyl)indolin-3-yl]benzenesulfonamide (74.10 mg, 123.51 μmol, 66.21% yield, 99% purity, TFA salt) was obtained. 1 H NMR (400 MHz, METHANOL-d4) δ 9.11 - 9.03 (m, 1H), 8.86 - 8.76 (m, 1H), 8.20 - 8.11 (m, 2H), 8.04 - 7.95 (m, 1H), 7.90 (d, J = 8.4 Hz, 3H), 7.60 - 7.52 (m, 2H), 7.33 (dd, J = 2.1, 8.4 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 5.31 - 5.18 (m, 2H) MS (M + H)+ = 480.1 Example 45. Synthesis of Compound NEM-100A O O S O O N S O H N Cl (3) [0386] To a solution of 4-bromo-N-tert-butyl-benzenesulfonamide (3.22 g, 11.01 mmol, 2 eq) in THF (40 mL) was added dropwise n-BuLi (2.5 M, 8.81 mL, 4 eq) at -70°C under N2 atmosphere. After addition, the mixture was stirred at this temperature for 1 hr and then 6- chloroindoline-2,3-dione (1 g, 5.51 mmol, 1 eq) in THF (15 mL) added dropwise at -70°C. The resulting mixture was stirred at -70°C for 2 hr under N2 atmosphere. The reaction was quenched by addition of ice sat. NH4Cl (20mL) at 0°C under N2 atmosphere, extracted with ethyl acetate (15 mL*2). The combined extracts were washed with brine (15 mL), dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 40 g silica, 0-45 % ethyl acetate in petroleum ether, gradient over 20 min). N-tert-butyl-4-(6-chloro-3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (550 mg, 988.93 μmol, 17.96% yield) was obtained as a yellow solid. MS (M + H)+ = 395.1 Synthesis of N-tert-butyl-4-[6-chloro-3-hydroxy-2-oxo-1-(6-quinolylmethyl)indolin-3- yl]benzenesulfonamide (4) [0387] To a solution of 6-(chloromethyl)quinoline (76.47 mg, 430.52 μmol, 1.7 eq) and N-tert-butyl-4-(6-chloro-3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (100 mg, 253.25 μmol, 1 eq) in DMF (2 mL) were added K2CO3 (105.00 mg, 759.74 μmol, 3 eq) and KI (84.08 mg, 506.49 μmol, 2 eq), the reaction mixture was stirred at 60°C for 12 h.3 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (10 mL*3), the combined extracts was dried with anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0- 25 % ethyl acetate in petroleum ether, gradient over 15 min). N-tert-butyl-4-[6-chloro-3- hydroxy-2-oxo-1-(6-quinolylmethyl)indolin-3-yl]benzenesulfonamide (100 mg, 160.44 μmol, 89.23% yield) was obtained as a yellow oil. MS (M + H)+ = 536.1 Synthesis of 4-[6-chloro-3-hydroxy-2-oxo-1-(6-quinolylmethyl)indolin-3- yl]benzenesulfonamide (NEM-100A) [0388] A mixture of N-tert-butyl-4-[6-chloro-3-hydroxy-2-oxo-1-(6- quinolylmethyl)indolin-3-yl]benzenesulfonamide (100 mg, 186.55 μmol, 1 eq) in DCE (1 mL) and TFA (1 mL) was stirred at 50°C for 1 h. The mixture was concentrated under reduced pressure to give the crude product. The residue was purified by prep-HPLC column: Phenomenex luna C18100*40mm*3 um; mobile phase: [H2O(0.1% TFA)- ACN];gradient:10%-40% B over 18.0 min.4-[6-chloro-3-hydroxy-2-oxo-1-(6- quinolylmethyl)indolin-3-yl]benzenesulfonamide (35.7 mg, 58.90 μmol, 36.71% yield, 98% purity, TFA) was obtained. 1HNMR (400 MHz, METHANOL-d4) δ 9.04 (m, 1H), 8.79-8.77 (m, 1H), 8.16 - 8.11 (m, 2H), 7.99 (br d, J = 9.1 Hz, 1H), 7.94 - 7.78 (m, 3H), 7.55 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 1H), 7.17 - 7.05 (m, 2H), 5.30 - 5.16 (m, 2H). MS (M + H)+ = 480.0 Example 46. Synthesis of Compound NEM-101A [0389] To a solution of 2-chloro-1,1,1-trimethoxy-ethane (2.81 g, 18.16 mmol, 2.45 mL, 2 eq) and 3-aminopyridin-2-ol (1 g, 9.08 mmol, 1 eq) in DME (20 mL), the reaction was stirred at 85°C for 12 h then the mixture was added 4-methylbenzenesulfonic acid (46.92 mg, 272.45 μmol, 0.03 eq) at 25°C, the reaction was stirred at 85°C for another 12 h.10 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (20 mL*2), and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica, 0-25 % ethyl acetate in petroleum ether, gradient over 20 min).2- (chloromethyl)oxazolo[5,4-b]pyridine (300 mg, 1.78 mmol, 19.60% yield, 100% purity) was obtained as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ 8.41 (dd, J = 1.2, 6.0 Hz, 1H), 8.08 (dd, J = Hz, 1H), 7.39 (dd, J = 6.0, 8.0 Hz, 1H), 4.77 (s, 2H) + MS(M+H) = 169.10 Synthesis of N-tert-butyl-4-[3-hydroxy-1-(oxazolo[5,4-b]pyridin-2-ylmethyl)-2-oxo- indolin-3-yl]benzenesulfonamide (3) [0390] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (100 mg, 277.45 μmol, 1 eq) and 2-(chloromethyl)oxazolo[5,4- b]pyridine (93.54 mg, 554.90 μmol, 2 eq) in DMF (2 mL) were added KI (92.11 mg, 554.90 μmol, 2 eq) and K2CO3 (115.03 mg, 832.35 μmol, 3 eq), the reaction was stirred at 60°C for 12 h.3 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (5 mL*2) and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0-20 % ethyl acetate in petroleum ether, gradient over 20 min). N-tert-butyl-4-[3-hydroxy-1-(oxazolo[5,4-b]pyridin-2-ylmethyl)-2-oxo-indolin- 3yl]benzenesulfonamide (120 mg,170.54 μmol, 61.47% yield, 70% purity) was obtained as a yellow oil. MS(M+H)+ = 493.2 Synthesis of 4-[3-hydroxy-1-(oxazolo[5,4-b]pyridin-2-ylmethyl)-2-oxo-indolin-3- yl]benzenesulfonamide (NEM-101A) [0391] A mixture of N-tert-butyl-4-[3-hydroxy-1-(oxazolo[5,4-b]pyridin-2-ylmethyl)-2- oxo-indolin-3-yl]benzenesulfonamide (50 mg, 71.06 μmol, 1 eq, 70% purity) in DCE (2 mL) and TFA (1 mL) was stirred at 50°C for 1 h. The mixture was basified by slowly adding resin anion at 0°C to pH = 9. Then 3 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (5 mL*2), and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC: column: Waters Xbridge BEH C18 100*25mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient:10%-40% B over 8.0 min.4-[3-hydroxy-1-(oxazolo[5,4-b]pyridin-2-ylmethyl)-2-oxo-indolin-3- yl]benzenesulfonamide (6.3 mg, 14.43 μmol, 14.22% yield, 100% purity) was obtained. 1H NMR (400 MHz, ACETONITRILE-d3) δ 8.33 (d, J = 4.8 Hz, 1H), 8.08 (dd, J = 1.6, 8.0 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.44 - 7.33 (m, 2H), 7.24 (d, J = 7.6 Hz, 1H), 7.15 - 7.08 (m, 2H), 5.65 (s, 2H), 5.36 - 5.27 (d, J = 4.8 Hz, 1H), 5.25 - 5.14 (d, J = 4.8 Hz, 1H), 4.89 (s, 1H). MS(M+H)+ = 437.10 Example 47. Synthesis of Compound NEM-102A [0392] To a solution of 3-aminopyridine-2-thiol (200 mg, 1.59 mmol, 1 eq) in EtOH (6 mL) was added 2-chloro-1,1,1-triethoxy-ethane (342.91 mg, 1.74 mmol, 332.60 μL, 1.1 eq). The mixture was stirred at 60°C for 2 h. The mixture was evaporated under reduced pressure. The crude product was purified by flash column (ISCO 2 g silica, 0~30% ethyl acetate in petroleum ether, gradient over 30 min). Compound 2-(chloromethyl)thiazolo[5,4- b]pyridine (60 mg, 324.95 μmol, 20.50% yield) was obtained as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.63 (dd, J = 1.2, 4.8 Hz, 1H), 8.27 (dd, J = 1.2, 8.4 Hz, 1H), 7.48 (dd, J = 4.8, 8.4 Hz, 1H), 4.94 (s, 2H) Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-(thiazolo[5,4-b]pyridin-2- ylmethyl)indolin-3-yl]benzenesulfonamide (3) [0393] To a solution of 2-(chloromethyl)thiazolo[5,4-b]pyridine (49.18 mg, 266.35 μmol, 1.2 eq) and N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (80 mg, 221.96 μmol, 1 eq) in DMF (2 mL) was added KI (55.27 mg, 332.94 μmol, 1.5 eq) and K2CO3 (92.03 mg, 665.88 μmol, 3 eq). The mixture was stirred at 60°C for 12 h.5 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (5 mL*2) and the combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated to give a residue. The crude product was purified by flash column (ISCO 2 g silica, 0~50% ethyl acetate in petroleum ether, gradient over 30 min). Compound N-tert-butyl-4-[3-hydroxy-2-oxo-1-(thiazolo[5,4-b]pyridin-2- ylmethyl)indolin-3-yl]benzenesulfonamide (40 mg, 78.65 μmol, 35.43% yield) was obtained as a light yellow solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.60 (br d, J = 4.6 Hz, 1H), 8.27 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 7.6 Hz, 2H), 7.49 (dd, J = 4.8, 8.0 Hz, 1H), 7.36 - 7.28 (m, 2H), 7.16 - 7.10 (m, 1H), 7.01 (d, J = 7.8 Hz, 1H), 5.51 (d, J = 16.0 Hz, 1H), 5.24 (d, J = 16.0 Hz, 1H), 4.54 (br s, 1H), 1.25 (s, 9H) Synthesis of 4-[3-hydroxy-2-oxo-1-(thiazolo[5,4-b]pyridin-2-ylmethyl)indolin-3- yl]benzenesulfonamide (NEM-102A) [0394] A mixture of N-tert-butyl-4-[3-hydroxy-2-oxo-1-(thiazolo[5,4-b]pyridin-2- ylmethyl)indolin-3-yl]benzenesulfonamide (40 mg, 78.65 μmol, 1 eq) in DCE (1 mL) and TFA (0.5 mL) was stirred at 50°C for 2 hr. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:20%-45% B over 8.0 min). Compound 4-[3-hydroxy-2-oxo-1-(thiazolo[5,4-b]pyridin-2-ylmethyl)indolin-3- yl]benzenesulfonamide (13.4 mg, 29.61 μmol, 37.65% yield, 100% purity) was obtained. 1H NMR (400 MHz, ACETONITRILE-d3) δ 8.57 (d, J = 1.6 Hz, 1H), 8.28 (d, J = 8.4 Hz, 1H), 7.90 - 7.85 (d, J = 8.8 Hz, 2H), 7.66 - 7.61 (d, J = 8.8 Hz, 2H), 7.53-7.51 (m, 1H), 7.35 (dt, J = 1.2, 8.0 Hz, 1H), 7.24 (dd, J = 1.2, 8.0 Hz, 1H), 7.15 - 7.05 (m, 2H), 5.66 (s, 2H), 5.48 - 5.24 (m, 2H). MS (M + H)+ = 453.1 Example 48. Synthesis of Compound NEM-103A silane (2) [0395] To a solution of 2-(chloromethyl)-1H-imidazo[4,5-b]pyridine;hydrochloride (300 mg, 1.47 mmol, 1 eq) and SEM-Cl (294.13 mg, 1.76 mmol, 312.24 μL, 1.2 eq) in THF (5 mL) was added DIEA (462.70 mg, 3.58 mmol, 623.58 μL, 2eq), the reaction was stirred at 25°C for 1 h.3mL of water was added to the mixture, the mixture was extracted with ethyl acetate (5 mL*2) and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0-15 % ethyl acetate in petroleum ether, gradient over 20 min).2-[[2-(chloromethyl)imidazo[4,5-b]pyridin-3-yl]methoxy]ethyl-trimethyl- silane (150 mg, 488.49 μmol, 33.23% yield, 97% purity) was obtained as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.43 (dd, J = 1.2, 4.8 Hz, 1H), 8.07 (dd, J = 1.2, 8.0 Hz, 1H), 7.29 (dd, J = 4.8, 8.0 Hz, 1H), 5.85 (s, 2H), 4.94 (s, 2H), 3.67 - 3.54 (t, 2H), 1.01 - 0.83 (t, 2H), 0.03 (s, 9H) Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[3-(2- trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]methyl]indolin-3- yl]benzenesulfonamide [0396] To a solution of 2-[[2-(chloromethyl)imidazo[4,5-b]pyridin-3-yl]methoxy]ethyl- trimethyl-silane (148.75 mg, 499.41 μmol, 2 eq) and N-tert-butyl-4-(3-hydroxy-2-oxo- indolin-3-yl)benzenesulfonamide (90 mg, 249.70 μmol, 1 eq) in DMF (1 mL) were added K2CO3 (86.28 mg, 624.26 μmol, 2.5 eq) and KI (82.90 mg, 499.41 μmol, 2 eq) ,the reaction was stirred at 60 °C for 12 h.3 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (5 mL*2) , and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0-30 % ethyl acetate in petroleum ether, gradient over 20 min). N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[3-(2- trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]methyl]indolin-3- yl]benzenesulfonamide (150 mg, 108.55 μmol, 43.47% yield, 45% purity) was obtained as a yellow. MS (M + H)+ = 622.4 Synthesis of 4-[3-hydroxy-1-(3H-imidazo[4,5-b]pyridin-2-ylmethyl)-2-oxo-indolin-3- yl]benzenesulfonamide [0397] A solution of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[3-(2- trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]methyl]indolin-3- yl]benzenesulfonamide (140 mg, 101.32 μmol, 45% purity, 1 eq) in DCE (3 mL) and TFA (1.5 mL) was stirred at 50°C for 1 h. The reaction mixture was cooled to room temperature. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC: column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:10%-40% B over 8.0 min.4-[3-hydroxy-1- (3H-imidazo[4,5-b]pyridin-2-ylmethyl)-2-oxo-indolin-3-yl]benzenesulfonamide (10.5 mg, 23.63μmol, 23.32% yield, 98% purity) was obtained.1H NMR (400 MHz, METHANOL-d4) δ 8.37 (d, J = 4.8 Hz, 1H), 8.00 (br d, J = 8.0 Hz, 1H), 7.92 - 7.81 (d, J = 8.0 Hz, 2H),7.68 - 7.58 (d, J = 8.0 Hz, 2H), 7.39 - 7.30 (m, 2H), 7.25 (d, J = 6.8 Hz, 1H), 7.16 - 7.10 (m, 1H), 7.06 (d, J = 7.9 Hz, 1H), 5.42 - 5.31 (m, 1H), 5.29 - 5.20 (m, 1H). MS (M + H)+ = 436.1 Example 49. Synthesis of Compound NEM-104A [0398] To a solution of 6-(bromomethyl)-1,3-benzoxazole (88.25 mg, 416.17 μmol, 1.5 eq) in DMF (2 mL) was added N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (100 mg, 277.45 μmol, 1 eq), KI (69.08 mg, 416.17 μmol, 1.5 eq) and K2CO3 (115.04 mg, 832.35 μmol, 3 eq). The mixture was stirred at 60°C for 5 hr.20 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (10 mL*2) and the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated to give a residue. The crude product was purified by flash column (ISCO 4 g silica, 0~50% ethyl acetate in petroleum ether, gradient over 30 min). Compound 4-[1-(1,3-benzoxazol-6-ylmethyl)-3-hydroxy-2-oxo-indolin-3-yl]-N-tert- butyl-benzenesulfonamide (100 mg, 203.43 μmol, 73.32% yield) was obtained as light yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ 8.08 (s, 1H), 7.84 (d, J= 7.6 Hz, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.52 (d, J = 5.6 Hz, 2H), 7.37 (dd, J = 1.6, 8.4 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.09 (s, 1H), 6.97 (d, J = 8.0 Hz, 1H), 5.17 - 5.01 (m, 2H), 4.66 (br s, 1H), 1.24 (s, 9H) Synthesis of 4-[1-(1,3-benzoxazol-6-ylmethyl)-3-hydroxy-2-oxo-indolin-3- yl]benzenesulfonamide (NEM-104A) [0399] A mixture of 4-[1-(1,3-benzoxazol-6-ylmethyl)-3-hydroxy-2-oxo-indolin-3-yl]- N-tert-butyl-benzenesulfonamide (50 mg, 101.72 μmol, 1 eq), Aluminum (27.44 mg, 1.02 mmol, 10 eq) and I2 (154.90 mg, 610.30 μmol, 122.94 μL, 6 eq) in acetonitrile (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 85°C for 18 hr under N2 atmosphere. The reaction was cooled to room temperature. The resultant mixture was filtered and the filter cake was rinsed with MeCN (3 mL x 3). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:15%-45% B over 8.0 min). Compound 4-[1-(1,3- benzoxazol-6-ylmethyl)-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (3 mg, 6.61 μmol, 6.50% yield) was obtained.1H NMR (400 MHz, ACETONITRILE-d3) δ 8.23 (s, 1H), 7.86 - 7.82 (d, J = 6.8 Hz, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.55 - 7.50 (d, J = 6.8 Hz, 2H), 7.40 (dd, J = 1.6, 8.0 Hz, 1H), 7.30 (dt, J = 1.6, 8.0 Hz, 1H), 7.23 - 7.19 (m, 1H), 7.10 - 7.05 (m, 1H), 6.98 (d, J = 8.0 Hz, 1H), 5.65 (s, 2H), 5.13 - 4.99 (m, 2H), 4.79 (s, 1H) MS (M + H)+ = 436.1 Example 50. Synthesis of Compound NEM-105A butyl-benzenesulfonamide (3) [0400] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (80 mg, 221.96 μmol, 1 eq) and 6-(bromomethyl)-1,3-benzothiazole (101.26 mg, 443.92 μmol, 2 eq) in DMF (1 mL) were added K2CO3 (92.03 mg, 665.88 μmol, 3 eq) and KI (73.69 mg, 443.92 μmol, 2 eq), the reaction was stirred at 60°C for 12 h.3 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (5 mL*2) and the combined extracts were dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. Compound 4-[1-(1,3-benzothiazol-6- ylmethyl)-3-hydroxy-2-oxo-indolin-3-yl]-N-tert-butyl-benzenesulfonamide (80 mg, crude) was obtained as a yellow oil which was used in next step without purification. MS (M + H)+ = 508.2 Synthesis of 4-[1-(1,3-benzothiazol-6-ylmethyl)-3-hydroxy-2-oxo-indolin-3- yl]benzenesulfonamide (NEM-105A) [0401] A mixture of 4-[1-(1,3-benzothiazol-6-ylmethyl)-3-hydroxy-2-oxo-indolin-3-yl]- N-tert-butyl-benzenesulfonamide (50 mg, 98.50 μmol, 1 eq) in DCE (1 mL) and TFA (1.54 g, 13.46 mmol, 1 mL, 136.67 eq) was stirred at 50°C for 2 h. The mixture was concentrated under reduced pressure to give the crude product. The residue was purified by prep-HPLC: column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1% TFA)- ACN];gradient:20%-50% B over 8.0 min.4-[1-(1,3-benzothiazol-6-ylmethyl)-3-hydroxy-2- oxo-indolin-3-yl]benzenesulfonamide (11 mg, 18.87 μmol, 19.15% yield, 97% purity, TFA salt) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ 9.23 (s, 1H), 8.10 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.58 (dd, J = 1.6, 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.35 - 7.28 (m, 1H), 7.23 (d, J = 6.8 Hz, 1H), 7.14 - 7.07 (m, 1H), 7.03 (d, J = 7.9 Hz, 1H), 5.16 (s, 2H). MS (M + H)+ = 452.0 Example 51. Synthesis of Compound NEM-106A and methyl 1-(2-trimethylsilylethoxymethyl)benzimidazole-5-carboxylate (2B) [0402] To a solution of methyl 3H-benzimidazole-5-carboxylate (3 g, 17.03 mmol, 1 eq) in DMF (30 mL) was added dropwise NaH (817.31 mg, 20.43 mmol, 60% purity, 1.2 eq) at 0°C. After addition, the mixture was stirred at this temperature for 0.5 hr, then SEM-Cl (3.12 g, 18.73 mmol, 3.32 mL, 1.1 eq) in DMF (10 mL) was added dropwise at 0°C. The resulting mixture was stirred at 25°C for 2 hr. The mixture was poured ice NH4Cl (5 ml) under N2. 10mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (15 mL*3) and the combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 10 g silica, 0~50% ethyl acetate in petroleum ether, gradient over 30 min). The mixture of methyl 3-(2- trimethylsilylethoxymethyl)benzimidazole-5-carboxylate and methyl 1-(2- trimethylsilylethoxymethyl)benzimidazole-5-carboxylate( 3.6 g ) were obtained as brown oil.1 H NMR (400 MHz, CHLOROFORM-d) δ 8.54 (d, J = 0.8 Hz, 1H), 8.30 (d, J = 0.8 Hz, 1H), 8.12 (s, 1H), 8.09 - 8.06 (m, 2H), 8.04 (dd, J = 1.6, 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 5.59 (s, 2H), 5.56 (s, 2H), 3.96 (s, 3H), 3.96 - 3.95 (m, 3H), 3.57 - 3.53 (m, 2H), 3.53 - 3.50 (m, 2H), 0.94 - 0.91 (m, 2H), 0.91 - 0.88 (m, 2H), 0.05 (s, 9H), 0.06 (s, 9H) Synthesis of [3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]methanol (3A) and [1- (2-trimethylsilylethoxymethyl)benzimidazol-5-yl]methanol (3B) [0403] To a solution of methyl 1-(2-trimethylsilylethoxymethyl)benzimidazole-5- carboxylate and methyl 3-(2-trimethylsilylethoxymethyl)benzimidazole-5-carboxylate (2 g, 6.52 mmol) in THF (20 mL) was added dropwise LiAlH4 (2.5 M, 2.61 mL, 2 eq) at 0°C under N2 atmosphere. The resulting mixture was stirred at 0°C for 2 h under N2 atmosphere. The mixture was quenched by H2O at 0°C and stirred for 10 min. The resultant mixture was filtered and the filter cake was rinsed with THF (15 mL x 3). The combined extracts were was extracted with Ethyl acetate (15 mL*2) and the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 5 g silica, 0~30% ethyl acetate in petroleum ether, gradient over 30 min). The mixture of [3- (2-trimethylsilylethoxymethyl)benzimidazol-5-yl]methanol and [1-(2- trimethylsilylethoxymethyl)benzimidazol-5-yl]methanol (1 g, 3.60 mmol) was obtained as brown oil.1H NMR (400 MHz, CHLOROFORM-d) δ 7.94 (br s, 1H), 7.93 (br s, 1H), 7.76 - 7.71 (m, 2H), 7.57 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.29 (s, 1H), 5.50 (s, 2H), 5.48 (s, 2H), 4.83 (s, 2H), 4.78 (s, 2H), 3.49 (t, J = 8.0 Hz, 4H), 0.89 (t, J = 8.0 Hz, 4H), 0.06 (s, 18H) Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[3-(2- trimethylsilylethoxymethyl)benzimidazol-5-yl]methyl]indolin-3-yl]benzenesulfonamide (4A) and N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[1-(2-trimethylsilyl- ethoxymethyl)benzimidazol-5-yl]methyl]indolin-3-yl]benzenesulfonamide (4B) [0404] The mixture of [3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]methanol and [1-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]methanol (139.05 mg, 499.41 μmol, 1.2 eq), N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (150 mg, 416.17 μmol, 1 eq) in Tol. (3 mL) was added 2-(tributyl-phosphanylidene)acetonitrile (200.89 mg, 832.35 μmol, 2 eq), the reaction mixture was bubbled with N2 for 1 min and stirred at 80°C for 12 h under N2 atmosphere.20 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (10 mL*2), and the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 4g silica, 0~70% ethyl acetate in petroleum ether, gradient over 10 min). The mixture of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[3-(2-trimethylsilylethoxymethyl)benzimidazol-5- yl]methyl]indolin-3-yl]benzenesulfonamide and N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[1-(2- trimethylsilylethoxymethyl)benzimidazol-5-yl]methyl]indolin-3-yl]benzenesulfonamide (190 mg, 306.04 μmol, 73.54% yield) was obtained as a white solid. MS (M + H)+ = 621.2 Synthesis of 4-[1-(3H-benzimidazol-5-ylmethyl)-3-hydroxy-2-oxo-indolin-3- yl]benzenesulfonamide (NEM-106A) [0405] A mixture of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[3-(2- trimethylsilylethoxymethyl)benzimidazol-5-yl]methyl]indolin-3-yl]benzenesulfonamide (100 mg, 161.07 μmol, 1 eq) in DCE (1 mL) and TFA (1 mL) was stirred at 50°C for 2 hr. The mixture was stirred at 50°C for 2 hr. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:5%-35% B over 8.0 min) Compound 4-[1-(3H-benzimidazol-5-ylmethyl)-3-hydroxy-2-oxo-indolin-3- yl]benzenesulfonamide (11.5 mg, 20.97 μmol, 13.02% yield, 100% purity, TFA salt) was obtained.1 H NMR (400 MHz, ACETONITRILE-d3) δ 8.82 (s, 1H), 8.07 (br s, 1H), 7.87 - 7.78 (m, 3H), 7.60 - 7.53 (m, 3H), 7.29 - 7.20 (m, 2H), 7.09 - 7.03 (m, 1H), 6.86 (d, J = 8.0 Hz, 1H), 5.72 (br s, 2H), 5.29 - 4.92 (m, 2H). MS (M + H)+ = 435.1 Example 52. Synthesis of Compound NEM-107A [0406] To a solution of methyl 2-chloroquinoline-6-carboxylate (1 g, 4.51 mmol, 1 eq) in THF (10 mL) was added dropwise LiAlH4 (2.5 M, 3.61 mL, 2 eq) at 0°C under N2 atmosphere. The resulting mixture was stirred at 0°C for 2 hr under N2 atmosphere. The mixture was quenched by Na2SO4.10H2O at 0°C and stirred for 10 min. The resultant mixture was filtered and the filter cake was rinsed with dichloromethane (5 mL x 3). Then the combined filtrates were concentrated to give crude product. Compound (2-chloro-6- quinolyl)methanol (700 mg, crude) was obtained as a yellow solid. MS (M + H)+ = 193.9 Synthesis of 2-chloro-6-(chloromethyl)quinoline (3) [0407] To a solution of (2-chloro-6-quinolyl)methanol (600 mg, 3.10 mmol, 1 eq) in DCM (1 mL) was added SOCl2 (1.84 g, 15.49 mmol, 1.13 mL, 5 eq). The mixture was stirred at 25°C for 2 hr. The mixture was evaporated under reduced pressure. Compound 2- chloro-6-(chloromethyl)quinoline (700 mg, crude) was obtained as a black solid. MS (M + H)+ = 212.2 Synthesis of N-tert-butyl-4-[1-[(2-chloro-6-quinolyl)methyl]-3-hydroxy-2-oxo-indolin-3- yl]benzenesulfonamide (4) [0408] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (830 mg, 2.30 mmol, 1 eq), 2-chloro-6-(chloromethyl)quinoline (686.80 mg, 2.76 mmol, 1.2 eq, HCl) in DMF (14 mL) was added K2CO3 (795.68 mg, 5.76 mmol, 2.5 eq). The mixture was stirred at 60°C for 12 h.20 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (10 mL*2) and the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated to give a residue. The crude product was purified by flash column (ISCO 10 g silica, 0~50% ethyl acetate in petroleum ether, gradient over 30 min). Compound N-tert- butyl-4-[1-[(2-chloro-6-quinolyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (700 mg, 1.31 mmol, 56.71% yield) was obtained as a yellow solid.1HNMR (400 MHz, CHLOROFORM-d) δ 8.05 - 7.99 (m, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.75 - 7.66 (m, 2H), 7.55 - 7.49 (m, 2H), 7.39 (d, J = 8.4 Hz, 1H), 7.30 - 7.24 (m, 2H), 7.12 - 7.07 (m, 1H), 6.84 (d, J = 8.0 Hz, 1H), 5.17 - 5.06 (m, 2H), 4.98 (br s, 1H), 1.23 (s, 9H) Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[(2-phenyl-6-quinolyl)methyl]indolin-3- yl]benzenesulfonamide (5) [0409] A mixture of N-tert-butyl-4-[1-[(2-chloro-6-quinolyl)methyl]-3-hydroxy-2-oxo- indolin-3-yl]benzenesulfonamide (120 mg, 223.86 μmol, 1 eq), phenylboronic acid (136.48 mg, 1.12 mmol, 5 eq), cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (16.38 mg, 22.39 μmol, 0.1 eq), Na2CO3 (71.18 mg, 671.59 μmol, 3 eq) in dioxane (1 mL) and H2O (0.1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 3 hr under N2 atmosphere.20 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (10 mL*2), and the combined extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated to give a residue. The crude product was purified by flash column (ISCO 10 g silica, 0~50% ethyl acetate in petroleum ether, gradient over 30 min). Compound N-tert-butyl-4-[3-hydroxy-2- oxo-1-[(2-phenyl-6-quinolyl)methyl]indolin-3-yl]benzenesulfonamide (110 mg, 190.41 μmol, 85.06% yield) was obtained as a white solid. MS (M + H)+ = 578.2 Synthesis of 4-[3-hydroxy-2-oxo-1-[(2-phenyl-6-quinolyl)methyl]indolin-3- yl]benzenesulfonamide (NEM-107A) [0410] A mixture of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[(2-phenyl-6- quinolyl)methyl]indolin-3-yl]benzenesulfonamide (110 mg, 190.41 μmol, 1 eq) in DCE (1 mL) and TFA (1.38 mL) was stirred at 50°C for 2 h. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:30%-60% B over 8.0 min). Compound 4-[3-hydroxy-2-oxo-1-[(2-phenyl-6-quinolyl)methyl]indolin-3- yl]benzenesulfonamide (38 mg, 57.99 μmol, 30.46% yield, TFA salt) was obtained.1H NMR (400 MHz, METHANOL-d4) δ 8.69 - 8.67 (m, 1H), 8.20 - 8.14 (m, 2H), 8.14 - 8.10 (m, 3H), 7.89 - 7.87 (m, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.63 (br d, J = 2.8 Hz, 3H), 7.56 (d, J = 8.4 Hz, 2H), 7.36 - 7.30 (m, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.15 - 7.06 (m, 2H), 5.24 (m, 2H). MS (M + H)+ = 522.1 Example 53. Synthesis of Compound NEM-108A [0411] To a solution of 2-amino-5-bromo-benzaldehyde (10 g, 49.99 mmol, 1 eq) in DCM (100 mL) was added Pyridine (4.35 g, 54.99 mmol, 4.44 mL, 1.1 eq), 2- chloroacetyl chloride (6.21 g, 54.99 mmol, 4.38 mL, 1.1 eq) at 0°C, the reaction was stirred at 25°C for 4 h. The mixture was filtered and the filter cake was collected and concentrated in vacuo. N-(4-bromo-2-formyl-phenyl)-2-chloro-acetamide (13 g, 37.61 mmol, 75.23% yield, 80% purity) was obtained as a yellow solid. MS (M + H)+ = 277.1 Synthesis of 6-bromoquinoline-2,3-diol (3) [0412] To a solution of N-(4-bromo-2-formyl-phenyl)-2-chloro-acetamide (7.8 g, 28.21 mmol, 1 eq) in H2O (20 mL) and MeOH (50 mL) was added KOH (1 M, 10 mL, 3.55e-1 eq), the reaction was stirred at 100°C for 2 h. The reaction was cooled to room temperature and filtered. The filter cake was collected and concentrated in vacuo to recover the starting material N-(4-bromo-2-formyl-phenyl)-2-chloro-acetamide (3 g, crude). The filtrate was removed under the reduced pressure. The residue was neutralized with a 1 M aqueous hydrochloric acid solution.10 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (20 mL*2), and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica, 0-40 % ethyl acetate in petroleum ether, gradient over 20 min).6-bromoquinoline-2,3-diol (1.37 g, 2.97 mmol, 10.52% yield, 52% purity) was obtained as a white solid. MS (M - H)+ = 237.8. Synthesis of 7-bromo-[1,3]dioxolo[4,5-b]quinoline (4) [0413] To a solution of 6-bromoquinoline-2,3-diol (400 mg, 1.67 mmol, 1 eq) in DMF (4 mL) were added CH2I2 (892.6 mg, 3.33 mmol, 268.84 μL, 2 eq) and K2CO3 (690.88 mg, 5 mmol, 3 eq) ,the reaction was stirred at 80°C for 63 h.15 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (30 mL*2), and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue.7-bromo-[1,3]dioxolo[4,5-b]quinoline (130 mg, 515.74 μmol, 30.95% yield). MS (M + H)+ = 252.1. Synthesis of [1,3]dioxolo[4,5-b]quinolin-7-ylmethanol(5) [0414] To a solution of 7-bromo-[1,3]dioxolo[4,5-b]quinoline (130 mg, 515.74 μmol, 1 eq) and tributylstannylmethanol (331.19 mg, 1.03 mmol, 2 eq) in DMF (2 mL) was added Pd(PPh3)2Cl2 (36.20 mg, 51.57 μmol, 0.1 eq), the reaction mixture was degassed with N2 for three times. The mixture was heated to 80°C and stirred for 12 h under N2 atmosphere. The mixture was filtered and the filtrate was purified directly. The residue was purified by prep-HPLC: column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:1%-35% B over 8.0 min. [1,3]dioxolo[4,5- b]quinolin-7-ylmethanol (15 mg, 73.82 μmol, 14.31% yield) was obtained as a white solid. MS (M + H)+ = 204.0. Synthesis of 7-(chloromethyl)-[1,3]dioxolo[4,5-b]quinoline (6) [0415] To a solution of [1,3]dioxolo[4,5-b]quinolin-7-ylmethanol (12 mg, 59.06 μmol, 1 eq) in DCM (1 mL) was added SOCl2 (14.05 mg, 118.11 μmol, 8.58 μL, 2 eq), the reation was stirred at 20 °C for 0.5 h. The reaction was concentrated under reduce pressure.7- (chloromethyl)-[1,3]dioxolo[4,5-b]quinoline (13 mg, crude) was obtained as a yellow gum. MS (M + H)+ = 222.0. Synthesis of N-tert-butyl-4-[1-([1,3]dioxolo[4,5-b]quinolin-7-ylmethyl)-3-hydroxy-2- oxo-indolin-3-yl]benzenesulfonamide (7) [0416] To a solution of 7-(chloromethyl)-[1,3]dioxolo[4,5-b]quinoline (12.30 mg, 55.49 μmol, 2 eq) and N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (10 mg, 27.74 μmol, 1 eq) in DMF (1 mL) were added K2CO3 (9.59 mg, 69.36 μmol, 2.5 eq) and KI (9.21 mg, 55.49 μmol, 2 eq), the reaction was stirred at 60°C for 12 hr.3 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (5 mL*2) and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. N-tert-butyl-4-[1-([1,3]dioxolo[4,5- b]quinolin-7-ylmethyl)-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (15 mg, crude) was obtained as a yellow oil. MS (M + H)+ = 546.3. Synthesis of 4-[1-([1,3]dioxolo[4,5-b]quinolin-7-ylmethyl)-3-hydroxy-2-oxo-indolin-3- yl]benzenesulfonamide (NEM-108A) [0417] A solution of N-tert-butyl-4-[1-([1,3]dioxolo[4,5-b]quinolin-7-ylmethyl)-3- hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (10 mg, 18.33 μmol, 1 eq) in DCE (1 mL) and TFA (1 mL) was stirred at 50°C for 0.25 h. The mixture was concentrated under reduced pressure to give the crude product. The residue was purified by prep-HPLC column: column: Phenomenex Luna C1875*30mm*3um; mobile phase: [H2O(0.1% TFA)- ACN];gradient:25%-55% B over 8.0 min. The residue was purified by SFC column: DAICEL CHIRALCEL OJ(250mm*30mm,10um);mobile phase: [CO2- MeOH(0.1%NH3H2O)];B%:50%, isocratic elution mode.4-[1-([1,3]dioxolo[4,5-b]quinolin- 7-ylmethyl)-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (1.2 mg, 2.44 μmol, 13.29% yield, 99.37% purity) was obtained.1H NMR (400 MHz, METHANOL-d4) δ = 7.86 (d, J = 8.4 Hz, 2H), 7.74 - 7.65 (m, 2H), 7.56 - 7.46 (m, 3H), 7.37 (s, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.13 - 7.07 (m, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.19 (s, 2H), 5.09 (s, 2H). MS (M + H)+ = 490.1. Example 54. Synthesis of Compound NEM-109A quinolyl)methyl]indolin-3-yl]benzenesulfonamide (5) [0418] To a solution of N-tert-butyl-4-[1-[(2-chloro-6-quinolyl)methyl]-3-hydroxy-2- oxo-indolin-3-yl]benzenesulfonamide (100 mg, 186.55 μmol, 1 eq) and pyrrolidine (132.68 mg, 1.87 mmol, 155.72 μL, 10 eq) in DMF (2 mL) was added K2CO3 (77.35 mg, 559.66 μmol, 3 eq) and KI (46.45 mg, 279.83 μmol, 1.5 eq). The mixture was stirred at 80°C for 12 hr.10 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (5 mL*2), and the combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated to give a residue. Compound N-tert-butyl- 4-[3-hydroxy-2-oxo-1-[(2-pyrrolidin-1-yl-6-quinolyl)methyl]indolin-3- yl]benzenesulfonamide (100 mg, crude) was obtained as a yellow solid. MS (M + H)+ = 571.3 Synthesis of 4-[3-hydroxy-2-oxo-1-[(2-pyrrolidin-1-yl-6-quinolyl)methyl]indolin-3- yl]benzenesulfonamide (NEM-109A) [0419] A mixture of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[(2-pyrrolidin-1-yl-6- quinolyl)methyl]indolin-3-yl]benzenesulfonamide (100 mg, 175.22 μmol, 1 eq) in DCE (1 mL) and TFA (1 mL) was stirred at 50°C for 2 hr. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:15%-45% B over 8.0 min). Compound 4-[3-hydroxy-2-oxo-1-[(2-pyrrolidin-1-yl-6-quinolyl)methyl]indolin-3- yl]benzenesulfonamide (41.5 mg, 65.54 μmol, 37.40% yield, TFA salt) was obtained. 1 HNMR (400 MHz, ACETONITRILE-d3) δ = 8.16 - 8.09 (m, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.76 (br s, 1H), 7.65 (td, J = 2.4, 5.2 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.30 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.11 - 6.95 (m, 3H), 5.78 (br d, J = 2.8 Hz, 2H), 5.01 (m, 2H), 3.71 (m, 4H), 2.09 (m, 4H). MS (M + H)+ = 515.2 Example 55. Synthesis of Compound NEM-110A - oxo- indolin-3-yl]benzenesulfonamide (5) [0420] To a solution of N-tert-butyl-4-[1-[(2-chloro-6-quinolyl)methyl]-3-hydroxy-2- oxo-indolin-3-yl]benzenesulfonamide (100 mg, 186.55 μmol, 1 eq) and morpholine (325.05 mg, 3.73 mmol, 328.33 μL, 20 eq) in DMA (1 mL) was added K2CO3 (77.35 mg, 559.66 μmol, 3 eq) and KI (46.45 mg, 279.83 μmol, 1.5 eq). The mixture was stirred at 80°C for 12 hr.10 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (5 mL*2) , and the combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated to give a residue. Compound N-tert-butyl- 4-[3-hydroxy-1-[(2-morpholino-6-quinolyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (100 mg, crude) was obtained as a yellow oil which was used in next step without purification. MS (M + H)+ = 587.2 Synthesis of 4-[3-hydroxy-1-[(2-morpholino-6-quinolyl)methyl]-2-oxo-indolin-3- yl]benzenesulfonamide (NEM-110A) [0421] A mixtxure of N-tert-butyl-4-[3-hydroxy-1-[(2-morpholino-6-quinolyl)methyl]-2- oxo-indolin-3-yl]benzenesulfonamide (100 mg, 170.44 μmol, 1 eq) in DCE (2 mL) and TFA (1 mL). The mixture was stirred at 50°C for 2 hr. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:15%-45% B over 8.0 min). Compound 4-[3-hydroxy-1-[(2-morpholino-6-quinolyl)methyl]-2-oxo-indolin-3- yl]benzenesulfonamide (80 mg, 117.90 μmol, 69.17% yield, TFA salt) was obtained. 1HNMR (400 MHz, METHANOL-d4) δ 8.32 (d, J = 9.6 Hz, 1H), 7.89 - 7.83 (m, 4H), 7.82 - 7.78 (m, 1H), 7.54 - 7.46 (m, 3H), 7.35 - 7.29 (m, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.15 - 7.09 (m, 1H), 7.06 (d, J = 7.6 Hz, 1H), 5.18 - 5.06 (m, 2H), 3.90 (s, 8H). MS (M + H)+ = 531.2 Example 56. Synthesis of Compound NEM-111A a g, 1 eq) in CCl4 (10 mL) was added BPO (2.12 g, 8.77 mmol, 1.5 eq) and NBS (1.56 g, 8.77 mmol, 1.5 eq), the reaction was degassed with N2 for three times. The mixture was stirred at 80 °C for 12 h under N2 atmosphere.10 mL of water was added to the mixture, the mixture was extracted with dichloromethane (20 mL*2) and the combined extracts were dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 40 g silica, 0 % ethyl acetate in petroleum ether, gradient over 20 min).4-(bromomethyl)-2,6-ditert-butyl-pyridine (800 mg, 1.83 mmol, 31.31% yield, 65% purity) was obtained as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ 7.10 (s, 2H), 4.39 (s, 2H), 1.36 (s, 18H) Synthesis of N-tert-butyl-4-[1-[(2,6-ditert-butyl-4-pyridyl)methyl]-3-hydroxy-2-oxo- indolin-3-yl]benzenesulfonamide (3) [0423] To a solution of 4-(bromomethyl)-2,6-ditert-butyl-pyridine (194.12 mg, 443.92 μmol, 2 eq) and N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (80 mg, 221.96 μmol, 1 eq) in DMF (2 mL) were added K2CO3 (61.35 mg, 443.92 μmol, 2 eq) and KI (55.27 mg, 332.94 μmol, 1.5 eq), the reaction was stirred at 60°C for 12 h.3 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (10 mL*2) and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica, 0-45 % ethyl acetate in petroleum ether, gradient over 20 min). Compound N-tert-butyl-4-[1-[(2,6-ditert-butyl-4-pyridyl)methyl]-3-hydroxy-2-oxo-indolin- 3-yl]benzenesulfonamide (120 mg, 193.70 μmol, 87.27% yield) was obtained as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.93 - 7.79 (m, 2H), 7.62 - 7.48 (m, 2H), 7.38 - 7.28 (m, 2H), 7.16 - 7.07 (m, 1H), 7.04 - 6.94 (m, 2H), 6.81 (d, J = 7.8 Hz, 1H), 5.16 (d, J = 16.1 Hz, 1H), 4.67 (br d, J = 16.1 Hz, 1H), 1.34 - 1.28 (m, 18H), 1.27 - 1.22 (m, 9H) Synthesis of 4-[1-[(2,6-ditert-butyl-4-pyridyl)methyl]-3-hydroxy-2-oxo-indolin-3- yl]benzenesulfonamide (NEM-111A) [0424] A mixture of N-tert-butyl-4-[1-[(2,6-ditert-butyl-4-pyridyl)methyl]-3-hydroxy-2- oxo-indolin-3-yl]benzenesulfonamide (120 mg, 212.86 μmol, 1 eq) in DCE (1 mL) and TFA (1.20 mL) was stirred at 50°C for 1 h. The reaction mixture was cooled to room temperature. The mixture was concentrated under reduced pressure to give a residue and the residue was purified directly. The residue was purified by prep-HPLC: column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O(0.1% TFA)-ACN];gradient:40%-80% B over 8.0 min. Compound 4-[1-[(2,6-ditert-butyl-4-pyridyl)methyl]-3-hydroxy-2-oxo-indolin-3- yl]benzenesulfonamide (31.28 mg, 50.32 μmol, 23.64% yield, 100% purity, TFA salt) was obtained.1H NMR (400 MHz, ACETONITRILE-d3) δ = 7.83 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 2H), 7.39 - 7.31 (m, 1H), 7.29 - 7.18 (m, 3H), 7.15 - 7.07 (m, 1H), 6.93 (d, J = 8.0 Hz, 1H), 5.65 (brs, 2H), 5.06 (d, J = 16.8 Hz, 1H), 4.85 (d, J = 16.8 Hz, 1H), 1.30 (s, 18H). MS (M + H)+ = 508.2. Example 57. Synthesis of Compound NEM-112A - - tert-butyl-benzenesulfonamide (2) [0425] To a solution of N-tert-butyl-4-(5-chloro-3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (150 mg, 379.87 μmol, 1 eq) in DMF (2 mL) was added K2CO3 (131.25 mg, 949.68 μmol, 2.5 eq) and 1-bromo-4-(bromomethyl)benzene (113.93 mg, 455.84 μmol, 1.2 eq). The mixture was stirred at 60°C for 3 hr.5 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (10 mL*2), and the combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 2 g silica, 0~50% ethyl acetate in petroleum ether, gradient over 30 min). Compound 4-[1-[(4-bromophenyl)methyl]-5-chloro-3-hydroxy-2-oxo-indolin- 3-yl]-N-tert-butyl-benzenesulfonamide (180 mg, 319.21 μmol, 84.03% yield) was obtained as a Light Yellow solid.1HNMR (400 MHz, CHLOROFORM-d) δ 7.81 (d, J = 8.4 Hz, 2H), 7.45 (dd, J = 8.4, 14.8 Hz, 4H), 7.26 - 7.21 (m, 2H), 7.17 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 8.4 Hz, 1H), 5.03 (br s, 1H), 4.96 - 4.78 (m, 2H), 1.24 (s, 9H) Synthesis of N-tert-butyl-4-[5-chloro-3-hydroxy-2-oxo-1-[(4-pyrrolidin-1- ylphenyl)methyl]indolin-3-yl]benzenesulfonamide (3) [0426] A mixture of 4-[1-[(4-bromophenyl)methyl]-5-chloro-3-hydroxy-2-oxo-indolin- 3-yl]-N-tert-butyl-benzenesulfonamide (150 mg, 266.01 μmol, 1 eq), pyrrolidine (22.70 mg, 319.21 μmol, 26.65 μL, 1.2 eq), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy- palladium;dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (48.23 mg, 53.20 μmol, 0.2 eq), sodium;2-methylpropan-2-olate (2 M, 266.01 μL, 2 eq) in 2- methylbutan-2-ol (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2 atmosphere.5 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (5 mL*2), and the combined extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 2 g silica, 0~50% ethyl acetate in petroleum ether, gradient over 30 min). Compound N-tert-butyl-4-[5-chloro-3-hydroxy-2-oxo-1-[(4-pyrrolidin-1- ylphenyl)methyl]indolin-3-yl]benzenesulfonamide (100 mg, 180.47 μmol, 67.84% yield) was obtained as a light yellow solid. MS (M + H)+ = 554.1 Synthesis of 4-[5-chloro-3-hydroxy-2-oxo-1-[(4-pyrrolidin-1-ylphenyl)methyl]indolin-3- yl]benzenesulfonamide (NEM-112A) [0427] To a solution of N-tert-butyl-4-[5-chloro-3-hydroxy-2-oxo-1-[(4-pyrrolidin-1- ylphenyl)methyl]indolin-3-yl]benzenesulfonamide (70 mg, 126.33 μmol, 1 eq) in DCE (1 mL) was added TFA (1.34 g, 11.78 mmol, 875.00 μL, 93.24 eq). The mixture was stirred at 50°C for 2 hr. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:40%-70% B over 8.0 min).Compound 4-[5-chloro- 3-hydroxy-2-oxo-1-[(4-pyrrolidin-1-ylphenyl)methyl]indolin-3-yl]benzenesulfonamide (17.1 mg, 33.99 μmol, 26.91% yield) was obtained.1HNMR (400 MHz, METHANOL-d4) δ = 7.87 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.30 (dd, J = 2.4, 8.4 Hz, 1H), 7.20 - 7.14 (m, 3H), 7.01 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 8.4 Hz, 2H), 4.79 - 4.73 (m, 2H), 3.24 (br t, J = 6.6 Hz, 4H), 2.00 (td, J = 3.4, 6.3 Hz, 4H). MS (M + H)+ = 498.1 Example 58. Synthesis of Compound NEM-113A [0428] To a solution of 2-chloro-5-methyl-pyrazine (500 mg, 3.89 mmol, 1 eq) in CCl4 (10 mL) were added NBS (692.22 mg, 3.89 mmol, 1 eq) and AIBN (127.73 mg, 777.85 μmol, 0.2 eq). The reaction mixture was stirred at 80°C for 12 h under N2 atmosphere. The reaction mixture was cooled to room temperature.3 mL sat sodium bisulfite was added to the mixture, the mixture was extracted with dichloromethane (5 mL*2). The combined extracts were dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 12 g silica, 0-45 % ethyl acetate in petroleum ether, gradient over 20 min).2-(bromomethyl)-5- chloro-pyrazine (360 mg, 1.74 mmol, 44.62% yield) was obtained as a yellow oil. Synthesis of N-tert-butyl-4-[1-[(5-chloropyrazin-2-yl)methyl]-3-hydroxy-2-oxo-indolin- 3-yl]benzenesulfonamide (3) [0429] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (150 mg, 416.17 μmol, 1 eq) and 2-(bromomethyl)-5-chloro- pyrazine (129.51 mg, 624.26 μmol, 1.5 eq) in DMF (3 mL) were added KI (103.63 mg, 624.26 μmol, 1.5 eq) and K2CO3 (143.79 mg, 1.04 mmol, 2.5 eq), the reaction was stirred at 60°C for 12 h.10 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (20 mL*2) and the combined extracts was dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0-45 % ethyl acetate in petroleum ether, gradient over 20 min). N-tert-butyl-4-[1-[(5-chloropyrazin-2-yl)methyl]-3-hydroxy-2-oxo- indolin-3-yl]benzenesulfonamide (134 mg, 165.10 μmol, 39.67% yield, 60% purity) was obtained as a yellow oil. MS (M + H)+ = 487.1 Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[(5-pyrrolidin-1-ylpyrazin-2- yl)methyl]indolin-3-yl]benzenesulfonamide (4) [0430] To a solution of N-tert-butyl-4-[1-[(5-chloropyrazin-2-yl)methyl]-3-hydroxy-2- oxo-indolin-3-yl]benzenesulfonamide (124 mg, 254.64 μmol, 1 eq) and pyrrolidine (90.55 mg, 1.27 mmol, 106.28 μL, 5 eq) in DMF (2 mL) were added KI (84.54 mg, 509.27 μmol, 2 eq) and K2CO3 (105.58 mg, 763.91 μmol, 3 eq). The reaction was stirred at 60°C for 12 h. 10 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (20 mL*2), and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0-35 % ethyl acetate in petroleum ether, gradient over 20 min). N- tert-butyl-4-[3-hydroxy-2-oxo-1-[(5-pyrrolidin-1-ylpyrazin-2-yl)methyl]indolin-3- yl]benzenesulfonamide (120 mg, 197.84 μmol, 77.70% yield, 86% purity) was obtained as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.13 (s, 1H), 7.93 - 7.76 (m, 3H), 7.58 (d, J = 8.4 Hz, 2H), 7.29 (s, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.09 - 6.98 (m, 2H), 5.07 (d, J = 15.2 Hz, 1H), 4.87 (d, J = 15.2 Hz, 1H), 3.57 - 3.46 (m, 4H), 2.08 - 2.03 (m, 4H), 1.24 (s, 9H) Synthesis of 4-[3-hydroxy-2-oxo-1-[(5-pyrrolidin-1-ylpyrazin-2-yl)methyl]indolin-3- yl]benzenesulfonamide [0431] A solution of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[(5-pyrrolidin-1-ylpyrazin-2- yl)methyl]indolin-3-yl]benzenesulfonamide (120 mg, 197.84 μmol, 1 eq) in DCE (1 mL) and TFA (1 mL) was stirred at 50°C for 1 h. The reaction mixture was cooled to room temperature. The mixture was concentrated under reduced pressure to give the crude product. The residue was purified by prep-HPLC:column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:20%-55% B over 8.0 min. 4-[3-hydroxy-2-oxo-1-[(5-pyrrolidin-1-ylpyrazin-2-yl)methyl]indolin-3- yl]benzenesulfonamide (22.5 mg, 37.57 μmol, 18.99% yield, 96.78% purity, TFA salt) was obtained as a yellow solid.1H NMR (400 MHz, ACETONITRILE-d3) δ 8.05 (d, J = 3.6 Hz, 2H), 7.89 - 7.77 (d, J = 8.4 Hz, 2H), 7.61 - 7.50 (d, J = 8.0 Hz, 2H), 7.30 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.09 - 6.98 (m, 2H), 5.62 (br s, 2H), 5.01 - 4.91 (m, 1H), 4.88 - 4.77 (m, 1H), 3.46 (m, 4H), 2.04 - 1.96 (m, 4H) MS (M + H)+ = 466.1. Example 59. Synthesis of Compound NEM-114A and NEM114AI [0432] To a solution of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]- N-tert-butyl-benzenesulfonamide (100 mg, 188.88 μmol, 1 eq) and 3,3,4,4- tetrafluoropyrrolidine;hydrochloride (101.73 mg, 566.63 μmol, 3 eq) in dioxane (2 mL) were added t-BuONa (2 M, 236.10 μL, 2.5 eq), Pd2(dba)3 (17.30 mg, 18.89 μmol, 0.1 eq) and Xantphos (10.93 mg, 18.89 μmol, 0.1 eq) in the glovebox, the reaction was stirred at 90 °C for 12 h under Ar2 atmosphere.3 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (5 mL*2), and the combined extracts were dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0-35 % ethyl acetate in petroleum ether, gradient over 20 min). N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4- (3,3,4,4-tetrafluoropyrrolidin-1-yl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (120 mg, 182.55 μmol, 96.65% yield, 90% purity) was obtained as a yellow solid. MS (M + H)+ = 592.3. Synthesis of 4-[3-hydroxy-2-oxo-1-[[4-(3,3,4,4-tetrafluoropyrrolidin-1- yl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (NEM-114A) & 4-[1-[[4-(3,4- difluoropyrrol-1-yl)phenyl]methyl]-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (NEM-114AI) [0433] A solution of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(3,3,4,4- tetrafluoropyrrolidin-1-yl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (60 mg, 91.27 μmol, 1 eq) in DCE (1 mL) and TFA (1 mL) was stirred at 20°C for 1 h. The reaction mixture was cooled to room temperature. The mixture was concentrated under reduced pressure to give the crude product. The residue was purified by prep-HPLC: column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)- ACN];gradient:45%-75% B over 8.0 min to give crude product. The crude product was purified by SFC (column: ChiralPak IH, 250*30mm, 10um;mobile phase: [CO2- EtOH];B%:50%, isocratic elution mode.4-[3-hydroxy-2-oxo-1-[[4-(3,3,4,4- tetrafluoropyrrolidin-1-yl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (1 mg, 1.87 μmol, 1.84% yield, 100% purity) was obtained. 1H NMR (400 MHz, ACETONITRILE-d3) δ = 7.84 (d, J = 8.8 Hz, 2H), 7.55 - 7.47 (d, J = 8.8 Hz, 2H), 7.35 - 7.24 (m, 3H), 7.19 (dd, J = 1.2, 7.6 Hz, 1H), 7.10 - 7.02 (m, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.67 - 6.59 (J = 8.4 Hz, 2H), 5.71 - 5.56 (m, 1H), 4.84 (s, 2H), 3.89 (m, 4H). MS (M + H)+ = 536.1. 4-[1-[[4- (3,4-difluoropyrrol-1-yl)phenyl]methyl]-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (1.29 mg, 2.60 μmol, 2.57% yield, 100% purity) was obtained. 1H NMR (400 MHz, ACETONITRILE-d3) δ 7.84 (d, J = 8.8 Hz, 2H), 7.56 - 7.49 (d, J = 8.8 Hz, 2H), 7.47 - 7.41 (m, 2H), 7.39 - 7.28 (m, 3H), 7.24 - 7.18 (m, 1H), 7.13 - 7.04 (m, 1H), 7.01 - 6.92 (m, 3H), 5.79 - 5.52 (m, 1H), 5.00 - 4.87 (m, 2H), 4.82 (br s, 1H). MS (M + H)+ = 496.2. Example 60. Synthesis of Compound NEM-115A [0434] To a solution of 3,3,4,4-tetramethylpyrrolidine-2,5-dione (500 mg, 3.22 mmol, 1 eq) in THF (10 mL) was added LiAlH4 (2.5 M, 5.15 mL, 4 eq) at 0°C under N2 atmosphere. The resulting mixture was stirred at 70°C for 5 hr under N2 atmosphere. The mixture was quenched by Na2SO4.10H2O at 0°C and stirred for 10 min, the resultant mixture was filtered and the filter cake was rinsed with THF (1 mL x 3). Then the combined filtrates were concentrated under reduced pressure to give product as colorless oil. Compound 3,3,4,4- tetramethylpyrrolidine (300 mg, crude) was obtained as colorless oil which was used in next step without purification.1 H NMR (400 MHz, CHLOROFORM-d) δ 2.88 (s, 4H), 0.93 (s, 12H) Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(3,3,4,4-tetramethylpyrrolidin-1- yl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (3) [0435] A mixture of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N- tert-butyl-benzenesulfonamide (150 mg, 283.32 μmol, 1 eq), 3,3,4,4-tetramethylpyrrolidine (72.09 mg, 566.63 μmol, 2 eq), dicyclohexyl-[2-(2,6- diisopropoxyphenyl)phenyl]phosphane;methanesulfonate;[2-[2- (methylamino)phenyl]phenyl]palladium(1+) (24.09 mg, 28.33 μmol, 0.1 eq), dicesium;carbonate (184.62 mg, 566.63 μmol, 2 eq) in 2-methylbutan-2-ol (3 mL) was degassed and purged with Ar for 3 times in the glove box , and then the mixture was stirred at 90°C for 12 hr under Ar atmosphere.5 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (10 mL*2), and the combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and filtered the filtrate was concentrated under reduced pressure to give a residue. Compound N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4- (3,3,4,4-tetramethylpyrrolidin-1-yl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (90 mg, 156.32 μmol, 55.17% yield) was obtained as a yellow solid. MS (M + H)+ = 576.3 Synthesis of 4-[3-hydroxy-2-oxo-1-[[4-(3,3,4,4-tetramethylpyrrolidin-1- yl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (NEM-115A) [0436] A mixture of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-(3,3,4,4- tetramethylpyrrolidin-1-yl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (80 mg, 138.95 μmol, 1 eq) in TFA (1mL) and DCE (2 mL) was stirred at 50°C for 2 hr. The reaction was cooled to room temperature. Then the product fraction was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 55%-85% B over 8.0 min). Compound 4-[3-hydroxy-2-oxo-1-[[4-(3,3,4,4-tetramethylpyrrolidin-1- yl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (33.6 mg, 52.75 μmol, 37.96% yield, 99.48% purity, TFA salt) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ 7.85 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.30 (dt, J = 1.2, 8.0 Hz, 1H), 7.21 - 7.14 (m, 3H), 7.10 - 7.00 (m, 2H), 6.47 (br d, J = 8.4 Hz, 2H), 4.92 - 4.87 (m, 1H), 4.79 - 4.73 (m, 1H), 3.18 (s, 4H), 1.01 (s, 12H) MS (M + H)+ = 520.2 Example 61. Synthesis of Compound NEM-116A O O O O O O S S S NH Cl Cl yl]phenyl]methyl]-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (2) [0437] To a solution of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]- N-tert-butyl-benzenesulfonamide (200 mg, 377.75 μmol, 1 eq) and 3-(3,4- dichlorophenyl)pyrrolidine (244.91 mg, 1.13 mmol, 3 eq) in dioxane (2 mL) were added RuPhos Pd G4 (32.12 mg, 37.78 μmol, 0.1 eq) and Cs2CO3 (307.70 mg, 944.39 μmol, 2.5 eq), the reaction mixture was bubbled with N2 for a while and heated to 90°C and stirred for 12 h under N2 atmosphere.3 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (5 mL*2), and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0-30 % ethyl acetate in petroleum ether, gradient over 20 min). N-tert-butyl-4-[1-[[4-[3-(3,4- dichlorophenyl)pyrrolidin-1-yl]phenyl]methyl]-3-hydroxy-2-oxo-indolin-3- yl]benzenesulfonamide (140 mg, 168.51 μmol, 44.61% yield, 80% purity) was obtained as a yellow solid. MS (M + H)+ = 664.1 Synthesis of 4-[1-[[4-[3-(3,4-dichlorophenyl)pyrrolidin-1-yl]phenyl]methyl]-3-hydroxy- 2-oxo-indolin-3-yl]benzenesulfonamide (4) [0438] A solution of N-tert-butyl-4-[1-[[4-[3-(3,4-dichlorophenyl)pyrrolidin-1- yl]phenyl]methyl]-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (130 mg, 195.59 μmol, 1 eq) in DCE (1.5 mL) and TFA (2.30 g, 20.19 mmol, 1.5 mL, 103.24 eq) was stirred at 50°C for 1 h. The reaction mixture was cooled to room temperature. The mixture was concentrated under reduced pressure to give the crude product. The residue was purified by prep-HPLC:column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:55%-85% B over 8.0 min.4-[1-[[4-[3-(3,4-dichlorophenyl)pyrrolidin- 1-yl]phenyl]methyl]-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (16.60 mg, 22.97 μmol, 11.75% yield, 100% purity, TFA salt) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ 7.84 (d, J = 8.4 Hz, 2H), 7.54 - 7.39 (m, 4H), 7.34 - 7.14 (m, 5H), 7.06 (m, 2H), 6.62 (d, J = 8.4 Hz, 2H), 4.93 - 4.89 (m, 1H), 4.82 - 4.78 (m, 1H), 3.76 - 3.67 (m, 1H), 3.57 - 3.41 (m, 4H), 2.51 - 2.37 (m, 1H), 2.20 - 2.01 (m, 1H). MS (M + H)+ = 608.1.
Example 62. Synthesis of Compound NEM-117A - indolin-3-yl]benzenesulfonamide (2) [0439] A mixture of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N- tert-butyl-benzenesulfonamide (100 mg, 188.88 μmol, 1 eq), isoindoline (27.01 mg, 226.65 μmol, 25.72 μL, 1.2 eq), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy- palladium;dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (34.24 mg, 37.78 μmol, 0.2 eq), sodium; 2-methylpropan-2-olate (2 M, 188.88 μL, 2 eq) in 2-methylbutan-2-ol (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2 atmosphere.5 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (5 mL*2) and the combined extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 5 g silica, 0~50% ethyl acetate in petroleum ether, gradient over 30 min). Compound N-tert-butyl-4-[3-hydroxy-1-[(4-isoindolin-2-ylphenyl)methyl]-2-oxo- indolin-3-yl]benzenesulfonamide (70 mg, 123.31 μmol, 65.28% yield) was obtained as a yellow solid. MS (M + H)+ = 568.2 Synthesis of 4-[3-hydroxy-1-[(4-isoindolin-2-ylphenyl)methyl]-2-oxo-indolin-3- yl]benzenesulfonamide (NEM-117A) [0440] A solution of N-tert-butyl-4-[3-hydroxy-1-[(4-isoindolin-2-ylphenyl)methyl]-2- oxo-indolin-3-yl]benzenesulfonamide (70 mg, 123.31 μmol, 1 eq) in TFA (1 mL) and DCE (1 mL) was stirred at 50°C for 2 hr. The reaction was cooled to room temperature. Then the product fraction was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:45%-75% B over 8.0 min) Compound 4-[3-hydroxy-1-[(4- isoindolin-2-ylphenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (17.5 mg, 27.28 μmol, 22.13% yield, 97.53% purity, TFA salt) was obtained. 1 H NMR (400 MHz, METHANOL-d4) δ = 7.85 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.38 - 7.33 (m, 2H), 7.32 - 7.26 (m, 5H), 7.18 (d, J = 7.6 Hz, 1H), 7.10 - 7.03 (m, 2H), 6.69 (d, J = 8.4 Hz, 2H), 4.97 - 4.91 (m, 1H), 4.84-4.80 (m, 1H), 4.60 (s, 4H). MS (M + H)+ = 512.2 Example 63. Synthesis of Compound NEM-119A [0441] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (4 g, 11.10 mmol, 1 eq) and 1-bromo-4-(bromomethyl)benzene (4.16 g, 16.65 mmol, 1.5 eq) in DMF (100 mL) was added K2CO3 (4.60 g, 33.29 mmol, 3 eq), the reaction was stirred at 60°C for 12 h. The mixture was quenched by H2O (100*2 mL) at 0°C. The mixture was extracted with ethyl acetate (150 mL*3) and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 80 g silica, 0- 36 % ethyl acetate in petroleum ether, gradient over 20 min).4-[1-[(4-bromophenyl)methyl]- 3-hydroxy-2-oxo-indolin-3-yl]-N-tert-butyl-benzenesulfonamide (5.58 g, 10.22 mmol, 92.12% yield, 97% purity) was obtained as a yellow oil. Synthesis of 4-[1-[[4-(3-azabicyclo[3.1.0]hexan-3-yl)phenyl]methyl]-3-hydroxy-2-oxo- indolin-3-yl]-N-tert-butyl-benzenesulfonamide (4) – [0442] To a solution of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]- N-tert-butyl-benzenesulfonamide (170 mg, 321.09 μmol, 1 eq) and 3- azabicyclo[3.1.0]hexane (66.73 mg, 802.73 μmol, 2.5 eq) in 2-methylbutan-2-ol (2 mL) were added t-BuONa (2 M, 401.36 μL, 2.5 eq) and BrettPhos Pd G3 (29.11 mg, 32.11 μmol, 0.1 eq). The reaction mixture was degassed with N2 for three times. The mixture was heated to 90 °C and stirred for 12 h under N2 atmosphere. 10 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (20 mL*2). The combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue.4-[1-[[4-(3-azabicyclo[3.1.0]hexan-3-yl)phenyl]methyl]-3-hydroxy-2-oxo- indolin-3-yl]-N-tert-butyl-benzenesulfonamide (150 mg, crude) was obtained as a yellow oil. MS (M + H)+ = 532.4 Synthesis of 4-[1-[[4-(3-azabicyclo[3.1.0]hexan-3-yl)phenyl]methyl]-3-hydroxy-2-oxo- indolin-3-yl]benzenesulfonamide [0443] A solution of 4-[1-[[4-(3-azabicyclo[3.1.0]hexan-3-yl)phenyl]methyl]-3-hydroxy- 2-oxo-indolin-3-yl]-N-tert-butyl-benzenesulfonamide (150 mg, 282.13 μmol, 1 eq) in DCE (2 mL) and TFA (3.07 g, 26.92 mmol, 2 mL, 95.43 eq) was stirred at 50°C for 1 h. The reaction mixture was cooled to room temperature. The mixture was concentrated under reduced pressure to give the crude product. The residue was purified by prep-HPLC:column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)- ACN];gradient:25%-65% B over 8.0 min.4-[1-[[4-(3-azabicyclo[3.1.0]hexan-3- yl)phenyl]methyl]-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (2.5 mg, 5.21 μmol, 1.85% yield, 99.09% purity) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ = 7.85 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.39 - 7.23 (m, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.12 - 6.96 (m, 2H), 6.52 (d, J = 8.4 Hz, 2H), 4.91 - 4.86 (m, 1H), 4.82-4.78 (m, 1H), 3.50 (d, J = 8.4 Hz, 2H), 3.16 (br d, J = 8.4 Hz, 2H), 1.80 - 1.58 (m, 2H), 0.71 (m, 1H), 0.38 - 0.23 (m, 1H) MS (M + H)+ = 476.2 Example 64. Synthesis of Compound NEM-120A indolin-1-yl]methyl]phenyl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b]pyridine-1- carboxylate [0444] To a solution of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]- N-tert-butyl-benzenesulfonamide (200 mg, 377.75 μmol, 1 eq) and tert-butyl 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b]pyridine-1-carboxylate (102.59 mg, 453.30 μmol, 1.2 eq) in 2-methylbutan-2-ol (4 mL) were added BrettPhos Pd G3 (34.24 mg, 37.78 μmol, 0.1 eq) and t-BuONa (2 M, 472.19 μL, 2.5 eq). The reaction mixture was degassed with N2 for three times. The mixture was heated to 90°C and stirred for 12 h under N2 atmosphere. 10 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (20 mL*2) and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0-25 % ethyl acetate in petroleum ether, gradient over 20 min). tert-butyl 6-[4-[[3-[4-(tert-butylsulfamoyl)phenyl]-3-hydroxy-2-oxo-indolin-1- yl]methyl]phenyl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b]pyridine-1-carboxylate (134 mg, 123.11 μmol, 32.59% yield, 62% purity) was obtained as a yellow solid. MS (M + H)+ = 675.3 Synthesis of 4-[1-[[4-(1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6- yl)phenyl]methyl]-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide [0445] A solution of tert-butyl 6-[4-[[3-[4-(tert-butylsulfamoyl)phenyl]-3-hydroxy-2- oxo-indolin-1-yl]methyl]phenyl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b]pyridine-1- carboxylate (125 mg, 185.23 μmol, 1 eq) in DCE (1 mL) and TFA (1 mL) was stirred at 50°C for 1 h. The reaction mixture was cooled to room temperature. The mixture was concentrated under reduced pressure to give the crude product. The residue was purified by prep-HPLC: column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:5%-45% B over 8.0 min.4-[1-[[4-(1,2,3,4,4a,5,7,7a- octahydropyrrolo[3,4-b]pyridin-6-yl)phenyl]methyl]-3-hydroxy-2-oxo-indolin-3- yl]benzenesulfonamide (24.7 mg, 38.91 μmol, 21.01% yield, 99.66% purity, TFA salt) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ 7.83 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.38 - 7.20 (m, 3H), 7.18 (d, J = 6.8 Hz, 1H), 7.11 - 7.04 (m, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.60 (d, J = 8.4 Hz, 2H), 4.96 - 4.89 (m, 1H), 4.84-4.81 (m, 1H), 3.90 (t, J = 4.5 Hz, 1H), 3.59 (br dd, J = 1.8, 4.6 Hz, 1H), 3.53 - 3.34 (m, 3H), 3.27 (br s, 1H), 3.04 (br d, J = 2.0 Hz, 1H), 2.83 (br dd, J = 4.4, 9.1 Hz, 1H), 2.01 - 1.89 (m, 2H), 1.89 - 1.69 (m, 2H). MS (M + H)+ = 519.2 Example 65. Synthesis of Compound NEM-121A
Synthesis of 4-[1-[[4-(7-azabicyclo[2.2.1]heptan-7-yl)phenyl]methyl]-3-hydroxy-2-oxo- indolin-3-yl]-N-tert-butyl-benzenesulfonamide (2) [0446] A mixture of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N- tert-butyl-benzenesulfonamide (23.15 mg, 43.73 μmol, 1 eq), 7-azabicyclo[2.2.1]heptane (7.01 mg, 52.48 μmol, 1.2 eq, HCl), sodium;2-methylpropan-2-olate (2 M, 87.46 μL, 4 eq), dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane;methanesulfonate;(2- phenylanilino)palladium(1+) (3.41 mg, 4.37 μmol, 0.1 eq) in 2-methylbutan-2-ol (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 h under N2 atmosphere.3 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (3 mL*2), and the combined extracts were washed with brine (3 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. Compound 4-[1-[[4-(7-azabicyclo[2.2.1]heptan-7- yl)phenyl]methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N-tert-butyl-benzenesulfonamide (20 mg, crude) was obtained as a black brown solid which was used in next step without purification. MS (M + H)+ = 546.4 Synthesis of 4-[1-[[4-(7-azabicyclo[2.2.1]heptan-7-yl)phenyl]methyl]-3-hydroxy-2-oxo- indolin-3-yl]benzenesulfonamide [0447] A solution of 4-[1-[[4-(7-azabicyclo[2.2.1]heptan-7-yl)phenyl]methyl]-3- hydroxy-2-oxo-indolin-3-yl]-N-tert-butyl-benzenesulfonamide (40 mg, 73.30 μmol, 1 eq) in TFA (0.5 mL) and DCE (1 mL) was stirred at 50°C for 2 hr. The reaction was cooled to room temperature and was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:10%-40% B over 8.0 min). Compound 4-[1-[[4-(7- azabicyclo[2.2.1]heptan-7-yl)phenyl]methyl]-3-hydroxy-2-oxo-indolin-3- yl]benzenesulfonamide (6.8 mg, 11.27 μmol, 15.37% yield, 100% purity, TFA salt) was obtained.1H NMR (400 MHz, METHANOL-d4) δ 7.85 (d, J = 8.4 Hz, 2H), 7.53 - 7.45 (m, 6H), 7.33 (dt, J = 1.2, 8.0 Hz, 1H), 7.23 (d, J = 6.8 Hz, 1H), 7.13 (dt, J = 1.2, 8.0 Hz, 1H), 7.03 (d, J = 7.6, 1H), 5.00 (d, J = 2.0 Hz, 2H), 4.71 (br s, 2H), 1.98-1.93 (m, 4H), 1.82-1.80 (m, 4H). MS (M + H)+ = 490.1 Example 66. Synthesis of Compound NEM-122A - oxo- [0448] A mixture of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N- tert-butyl-benzenesulfonamide (150 mg, 283.32 μmol, 1 eq), (3S,4R)-3-fluoro-4-methoxy- pyrrolidine (40.50 mg, 339.98 μmol, 1.2 eq), [2-(2-aminophenyl)phenyl]- methylsulfonyloxy-palladium;dicyclohexyl-[3,6-dimethoxy-2-(2,4,6- triisopropylphenyl)phenyl]phosphane (51.36 mg, 56.66 μmol, 0.2 eq), sodium;2- methylpropan-2-olate (2.5 M, 226.65 μL, 2 eq) in 2-methylbutan-2-ol (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2 atmosphere.10 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (10 mL*2) and the combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 4 g silica, 0~60% ethyl acetate in petroleum ether, gradient over 30 min). Compound N-tert-butyl-4-[1-[[4-[(3S,4R)- 3-fluoro-4-methoxy-pyrrolidin-1-yl]phenyl]methyl]-3-hydroxy-2-oxo-indolin-3- yl]benzenesulfonamide (100 mg, 176.16 μmol, 62.18% yield) was obtained as a yellow solid. MS (M + H)+ = 568.3 Synthesis of 4-[1-[[4-[(3S,4R)-3-fluoro-4-methoxy-pyrrolidin-1-yl]phenyl]methyl]-3- hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (NEM-122A) [0449] A mixture of N-tert-butyl-4-[1-[[4-[(3S,4R)-3-fluoro-4-methoxy-pyrrolidin-1- yl]phenyl]methyl]-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (80 mg, 140.93 μmol, 1 eq) in TFA (1 mL) and DCE (2 mL) was stirred at 50°C for 2 hr. The reaction was cooled to room temperature. Then the product fraction was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:30%-60% B over 8.0 min). Compound 4-[1-[[4-[(3S,4R)-3-fluoro-4-methoxy-pyrrolidin-1-yl]phenyl]methyl]-3- hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (21.2 mg, 33.10 μmol, 23.49% yield, 97.668% purity, TFA salt) was obtained. 1 H NMR (400 MHz, METHANOL-d4) δ = 7.84 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.29 (dt, J = 1.2, 7.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 2H), 7.19 - 7.15 (m, 1H), 7.09 - 7.00 (m, 2H), 6.52 (d, J = 8.4 Hz, 2H), 5.38 - 5.20 (m, 1H), 4.92 - 4.88 (m, 1H), 4.81 - 4.76 (m, 1H), 4.16 - 4.03 (m, 1H), 3.66 - 3.43 (m, 6H), 3.21 (t, J = 8.7 Hz, 1H) MS (M + H)+ = 512.1 Example 67. Synthesis of Compound NEM-123A Synthesis of tert-butyl 2-[4-[[3-[4-(tert-butylsulfamoyl)phenyl]-3-hydroxy-2-oxo- indolin-1-yl]methyl]phenyl]-2,8-diazaspiro[4.5]decane-8-carboxylate (2) [0450] A mixture of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N- tert-butyl-benzenesulfonamide (150 mg, 283.32 μmol, 1 eq), tert-butyl 2,8- diazaspiro[4.5]decane-8-carboxylate (81.71 mg, 339.98 μmol, 1.2 eq), [2-(2- aminophenyl)phenyl]-methylsulfonyloxy-palladium;dicyclohexyl-[3,6-dimethoxy-2-(2,4,6- triisopropylphenyl)phenyl]phosphane (51.36 mg, 56.66 μmol, 0.2 eq), sodium;2- methylpropan-2-olate (2 M, 283.32 μL, 2 eq) in 2-methylbutan-2-ol (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2 atmosphere.5 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (5 mL*2) and the combined extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 10 g silica, 0~50% ethyl acetate in petroleum ether, gradient over 30 min). Compound tert-butyl 2-[4-[[3-[4-(tert- butylsulfamoyl)phenyl]-3-hydroxy-2-oxo-indolin-1-yl]methyl]phenyl]-2,8- diazaspiro[4.5]decane-8-carboxylate (70 mg, 101.62 μmol, 35.87% yield) was obtained as a yellow solid. MS (M + H)+ = 689.4 Synthesis of 4-[1-[[4-(2,8-diazaspiro[4.5]decan-2-yl)phenyl]methyl]-3-hydroxy-2-oxo- indolin-3-yl]benzenesulfonamide (NEM-123A) [0451] A solution of tert-butyl 2-[4-[[3-[4-(tert-butylsulfamoyl)phenyl]-3-hydroxy-2- oxo-indolin-1-yl]methyl]phenyl]-2,8-diazaspiro[4.5]decane-8-carboxylate (70 mg, 101.62 μmol, 1 eq) in TFA (1 mL) and DCE (1 mL) was stirred at 50°C for 2 hr. The reaction was cooled to room temperature. Then the product fraction was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:10%-35% B over 8.0 min). Compound 4-[1-[[4-(2,8-diazaspiro[4.5]decan-2-yl)phenyl]methyl]-3-hydroxy-2-oxo- indolin-3-yl]benzenesulfonamide (31.9 mg, 47.54 μmol, 46.78% yield, 96.370% purity, TFA salt) was obtained. 1 H NMR (400 MHz, METHANOL-d4) δ 7.83 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.30 (dt, J = 1.2, 8.0 Hz, 1H), 7.23 - 7.15 (m, 3H), 7.11 - 7.01 (m, 2H), 6.55 (d, J = 8.4 Hz, 2H), 4.95 - 4.89 (m, 1H), 4.78 - 4.72 (m, 1H), 3.38 (t, J = 7.0 Hz, 2H), 3.27 - 3.20 (m, 6H), 2.04 - 1.96 (m, 2H), 1.91 - 1.78 (m, 4H). MS (M + H)+ = 533.2 Example 68. Synthesis of Compound NEM-124A c]pyrrol-5-yl]phenyl]methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N-tert-butyl- benzenesulfonamide (2) [0452] A mixture of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N- tert-butyl-benzenesulfonamide (150 mg, 283.32 μmol, 1 eq), (3aR,6aS)-2,2-dimethyl- 4,5,6,6a-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrole (81.13 mg, 566.63 μmol, 2 eq), [2-(2- aminophenyl)phenyl]-methylsulfonyloxy-palladium;dicyclohexyl-[3,6-dimethoxy-2-(2,4,6- triisopropylphenyl)phenyl]phosphane (51.36 mg, 56.66 μmol, 0.2 eq), tBuONa (2.5 M, 226.65 μL, 2 eq) in 2-methylbutan-2-ol (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2 atmosphere.5 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (3 mL*2) and the combined extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 4 g silica, 0~50% ethyl acetate in petroleum ether, gradient over 30 min). Compound 4-[1-[[4-[(3aR,6aS)-2,2-dimethyl-3a,4,6,6a- tetrahydro-[1,3]dioxolo[4,5-c]pyrrol-5-yl]phenyl]methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N- tert-butyl-benzenesulfonamide (50 mg, 84.50 μmol, 29.83% yield) was obtained as a yellow solid. MS (M + H)+ = 592.4 Synthesis of 4-[1-[[4-[(3aR,6aS)-2,2-dimethyl-3a,4,6,6a-tetrahydro-[1,3]dioxolo[4,5- c]pyrrol-5-yl]phenyl]methyl]-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (NEM- 124A) [0453] A mixture of 4-[1-[[4-[(3aR,6aS)-2,2-dimethyl-3a,4,6,6a-tetrahydro- [1,3]dioxolo[4,5-c]pyrrol-5-yl]phenyl]methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N-tert-butyl- benzenesulfonamide (40 mg, 67.60 μmol, 1 eq) in TFA (0.5 mL) and DCE (1 mL) was stirred at 50°C for 2 hr. The reaction was cooled to room temperature. Then the mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)- ACN];gradient:35%-65% B over 8.0 min). Compound 4-[1-[[4-[(3aR,6aS)-2,2-dimethyl- 3a,4,6,6a-tetrahydro-[1,3]dioxolo[4,5-c]pyrrol-5-yl]phenyl]methyl]-3-hydroxy-2-oxo- indolin-3-yl]benzenesulfonamide (6 mg, 10.87 μmol, 16.07% yield, 97% purity) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ 7.85 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.29 (dt, J = 1.2, 8.0 Hz, 1H), 7.25 - 7.15 (m, 3H), 7.10 - 6.99 (m, 2H), 6.67 (d, J = 8.8 Hz, 2H), 4.93 - 4.87 (m, 3H), 4.82 - 4.77 (m, 1H), 3.66 - 3.60 (m, 2H), 3.06 - 2.98 (m, 2H), 1.42 (s, 3H), 1.34 (s, 3H) MS (M + H)+ = 536.2 Example 69. Synthesis of Compound NEM-125A [0454] To a solution of 5-bromo-1,2,3-trifluoro-benzene (800 mg, 3.79 mmol, 452.74 μL, 1 eq) and tert-butyl 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole- 1-carboxylate (1.68 g, 5.69 mmol, 1.5 eq) in H2O (5 mL) and THF (20 mL) were added K3PO4 (1.61 g, 7.58 mmol, 2 eq) and XPHOS-PD-G2 (298.34 mg, 379.18 μmol, 0.1 eq), the reaction mixture was degassed with N2 for three times. The mixture was heated to 80°C and stirred for 12 h under N2 atmosphere.20 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (30 mL*2) and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica, 0-20 % ethyl acetate in petroleum ether, gradient over 20 min). Compound tert-butyl 3-(3,4,5-trifluorophenyl)- 2,5-dihydropyrrole-1-carboxylate (1.37 g, 3.66 mmol, 96.58% yield, 80% purity) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.51 - 7.46 (m, 2H), 6.54 (br d, J = 10.4 Hz, 1H), 4.38 (m, 2H), 4.21 (m, 2H), 1.44 (d, J = 5.6 Hz, 9H) Synthesis of tert-butyl 3-(3,4,5-trifluorophenyl)pyrrolidine-1-carboxylate (4) [0455] To a solution of Pd/C (75.19 mg, 70.66 μmol, 10% purity, 2.64e-2 eq) in MeOH (10 mL) under Ar2 atmosphere was added tert-butyl 3-(3,4,5-trifluorophenyl)-2,5- dihydropyrrole-1-carboxylate (800 mg, 2.67 mmol, 1 eq) and degassed and purged with H2 for 3 times and then the mixture was stirred at 25°C for 2 h under H2 atmosphere at 15 Psi. The resultant mixture was filtered and the filter cake was rinsed with MeOH (5 mL x 3). Then the combined filtrates were concentrated under reduced pressure to give product as yellow oil. The crude product was purified by flash column (ISCO 4 g silica, 0~30% ethyl acetate in petroleum ether, gradient over 30 min). Compound tert-butyl 3-(3,4,5- trifluorophenyl)pyrrolidine-1-carboxylate (500 mg, 1.66 mmol, 62.08% yield) was obtained as yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 6.88 - 6.82 (m, 2H), 3.88 - 3.21 (m, 5H), 2.27-2.22 (m, 1H), 2.00 - 1.83 (m, 1H), 1.48 (s, 9H) Synthesis of 3-(3,4,5-trifluorophenyl)pyrrolidine (5) [0456] A solution of tert-butyl 3-(3,4,5-trifluorophenyl)pyrrolidine-1-carboxylate (200 mg, 663.78 μmol, 1 eq) in HCl/EtOAc (2 mL) was stirred at 25 °C for 1hr. The mixture was concentrated under reduced pressure. MeOH (2mL) was added and it was basified by slowly adding weak anion resin at 0 oC to pH = 9, dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give the crude product. Compound 3- (3,4,5-trifluorophenyl)pyrrolidine (100 mg, crude) was obtained as a pink solid which was used in next step without purification. MS (M + H)+ = 202.1 Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-[3-(3,4,5-trifluorophenyl)pyrrolidin- 1-yl]phenyl]methyl]indolin-3-yl]benzenesulfonamide (6) [0457] A mixture of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N- tert-butyl-benzenesulfonamide (100 mg, 188.88 μmol, 1 eq), 3-(3,4,5- trifluorophenyl)pyrrolidine (45.60 mg, 226.65 μmol, 1.2 eq), Cs2CO3 (123.08 mg, 377.75 μmol, 2 eq) and dicyclohexyl-[2-(2,6- diisopropoxyphenyl)phenyl]phosphane;methanesulfonate;[2-[2- (methylamino)phenyl]phenyl]palladium(1+) (16.06 mg, 18.89 μmol, 0.1 eq) in dioxane (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2 atmosphere.5 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (3 mL*2), and the combined extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 4 g silica, 0~40% ethyl acetate in petroleum ether, gradient over 30 min). Compound N-tert-butyl-4-[3- hydroxy-2-oxo-1-[[4-[3-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]phenyl]methyl]indolin-3- yl]benzenesulfonamide (70 mg, 107.74 μmol, 57.04% yield) was obtained as a white solid. MS (M + H)+ = 650.3 Synthesis of 4-[3-hydroxy-2-oxo-1-[[4-[3-(3,4,5-trifluorophenyl)pyrrolidin-1- yl]phenyl]methyl]indolin-3-yl]benzenesulfonamide (NEM-125A) [0458] A mixture of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-[3-(3,4,5- trifluorophenyl)pyrrolidin-1-yl]phenyl]methyl]indolin-3-yl]benzenesulfonamide (70 mg, 107.74 μmol, 1 eq) in TFA (1 mL) and DCE (1 mL) was stirred at 50°C for 2 hr. The reaction was cooled to room temperature. Then the product fraction was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:40%- 80% B over 8.0 min). Compound 4-[3-hydroxy-2-oxo-1-[[4-[3-(3,4,5- trifluorophenyl)pyrrolidin-1-yl]phenyl]methyl]indolin-3-yl]benzenesulfonamide (17.8 mg, 29.99 μmol, 27.83% yield, 100% purity) was obtained. 1 H NMR (400 MHz, METHANOL- d4) δ = 7.85 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.30 (dt, J = 1.2, 8.0 Hz, 1H), 7.25 - 7.15 (m, 3H), 7.13 - 7.00 (m, 4H), 6.57 (d, J = 8.8 Hz, 2H), 4.93 - 4.88 (m, 1H), 4.81 - 4.75 (m, 1H), 3.71 - 3.64 (m, 1H), 3.57 - 3.44 (m, 2H), 3.42 - 3.35 (m, 1H), 3.29 - 3.23 (m, 1H), 2.46 - 2.36 (m, 1H), 2.10-2.05 (m, 1H) MS (M + H)+ = 594.1 Example 70. Synthesis of Compound NEM-126A - hydroxy-2-oxo-indolin-3-yl]-N-tert-butyl-benzenesulfonamide (2) [0459] A mixture of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N- tert-butyl-benzenesulfonamide (150 mg, 283.32 μmol, 1 eq), 3,3a,4,5,6,6a-hexahydro-1H- furo[3,4-c]pyrrole (38.47 mg, 339.98 μmol, 1.2 eq), [2-(2-aminophenyl)phenyl]- methylsulfonyloxy-palladium;dicyclohexyl-[3,6-dimethoxy-2-(2,4,6- triisopropylphenyl)phenyl]phosphane (51.36 mg, 56.66 μmol, 0.2 eq), sodium;2- methylpropan-2-olate (2 M, 283.32 μL, 2 eq) in 2-methylbutan-2-ol (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2 atmosphere.5 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (5 mL*2), and the combined extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 10 g silica, 0~60% ethyl acetate in petroleum ether, gradient over 30 min). Compound 4-[1-[[4-(1,3,3a,4,6,6a- hexahydrofuro[3,4-c]pyrrol-5-yl)phenyl]methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N-tert- butyl-benzenesulfonamide (120 mg, 213.64 μmol, 75.41% yield) was obtained as a yellow solid. MS (M + H)+ = 562.2 Synthesis of 4-[1-[[4-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)phenyl]methyl]-3- hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (NEM-126A) [0460] A solution of 4-[1-[[4-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5- yl)phenyl]methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N-tert-butyl-benzenesulfonamide (120 mg, 213.64 μmol, 1 eq) (70 mg, 101.62 μmol, 1 eq) in TFA (1 mL) and DCE (1 mL) was stirred at 50°C for 2 hr. The reaction was cooled to room temperature. Then the product fraction was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:20%-60% B over 8.0 min). Compound 4-[1-[[4- (1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)phenyl]methyl]-3-hydroxy-2-oxo-indolin-3- yl]benzenesulfonamide (32.5 mg, 64.28 μmol, 30.09% yield, 100% purity) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ 7.84 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.29 (dt, J = 1.2, 7.6 Hz, 1H), 7.23 - 7.15 (m, 3H), 7.09 - 6.99 (m, 2H), 6.64 (d, J = 8.4 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 4.92 - 4.86 (m, 1H), 4.81 - 4.73 (m, 1H), 4.00-3.97 (m, 1H), 3.97 - 3.92 (m, 0.5H), 3.64 (dd, J = 2.8, 8.8 Hz, 0.5H), 3.53 (dd, J = 7.3, 10.5 Hz, 1H), 3.47 (ddd, J = 2.2, 6.2, 8.3 Hz, 1H), 3.39 - 3.33 (m, 1H), 3.19 (br d, J = 9.6 Hz, 0.5H), 3.11 (br t, J = 8.6 Hz, 1H), 3.06 - 3.00 (m, 0.5H), 2.62 - 2.50 (m, 1H). MS (M + H)+ = 506.2 Example 71. Synthesis of Compound NEM-127A indolin-1-yl]methyl]phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (2) [0461] A mixture of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N- tert-butyl-benzenesulfonamide (150 mg, 283.32 μmol, 1 eq), tert-butyl 3,8- diazabicyclo[3.2.1]octane-3-carboxylate (72.17 mg, 339.98 μmol, 1.2 eq), [2-(2- aminophenyl)phenyl]-methylsulfonyloxy-palladium;dicyclohexyl-[3,6-dimethoxy-2-(2,4,6- triisopropylphenyl)phenyl]phosphane (51.36 mg, 56.66 μmol, 0.2 eq), sodium;2- methylpropan-2-olate (2 M, 283.32 μL, 2 eq) in 2-methylbutan-2-ol (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2 atmosphere.10 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (5 mL*2), and the combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 4 g silica, 0~50% ethyl acetate in petroleum ether, gradient over 30 min). Compound tert-butyl 8-[4-[[3-[4-(tert- butylsulfamoyl)phenyl]-3-hydroxy-2-oxo-indolin-1-yl]methyl]phenyl]-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (40 mg, 60.53 μmol, 21.37% yield) was obtained as a white solid. MS (M + H)+ = 661.2 Synthesis of 4-[1-[[4-(3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl]methyl]-3-hydroxy-2- oxo-indolin-3-yl]benzenesulfonamide (NEM-127A) [0462] A solution of tert-butyl 8-[4-[[3-[4-(tert-butylsulfamoyl)phenyl]-3-hydroxy-2- oxo-indolin-1-yl]methyl]phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (30 mg, 45.40 μmol, 1 eq) in TFA (0.5 mL) and DCE (1 mL) was stirred at 50°C for 2 hr. The reaction was cooled to room temperature. Then the mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:5%-35% B over 8.0 min) to give crude product and then was further purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:20%- 55% B over 8.0 min). Compound 4-[1-[[4-(3,8-diazabicyclo[3.2.1]octan-8- yl)phenyl]methyl]-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (4.4 mg, 8.48 μmol, 18.67% yield, 97.2% purity) was obtained. 1 H NMR (400 MHz, METHANOL-d4) δ = 7.84 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H), 7.32 (dt, J = 1.2, 8.0 Hz, 1H), 7.27 - 7.16 (m, 3H), 7.11 - 7.03 (m, 2H), 6.82 (d, J = 8.8 Hz, 2H), 4.92 - 4.88 (m, 1H), 4.83 - 4.77 (m, 1H), 4.12 (br s, 2H), 3.09 (d, J = 12.4 Hz, 2H), 2.52 (br d, J = 12.4 Hz, 2H), 2.07 - 1.89 (m, 4H) MS (M + H)+ = 505.2 Example 72. Synthesis of Compound NEM-128A O O O O S O O S N S O Synthesis of N-tert-butyl-4-[3-hydroxy-1-[[4-(2-oxa-7-azaspiro[3.4]octan-7- yl)phenyl]methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (2) [0463] A mixture of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N- tert-butyl-benzenesulfonamide (200 mg, 377.75 μmol, 1 eq), 2-oxa-7-azaspiro[3.4]octane (51.29 mg, 453.30 μmol, 1.2 eq), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy- palladium;dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (68.49 mg, 75.55 μmol, 0.2 eq), sodium;2-methylpropan-2-olate (2 M, 377.75 μL, 2 eq) in 2- methylbutan-2-ol (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12 hr under N2 atmosphere.10 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (5 mL*2), and the combined extracts were washed with brine (10 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 4 g silica, 0~60% ethyl acetate in petroleum ether, gradient over 30 min). Compound N-tert-butyl-4-[3-hydroxy-1-[[4-(2-oxa-7-azaspiro[3.4]octan-7- yl)phenyl]methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (120 mg, 213.64 μmol, 56.56% yield) was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.83 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.31 - 7.27 (m, 1H), 7.26 - 7.20 (m, 3H), 7.08 - 7.03 (m, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.68 (br d, J = 8.4 Hz, 2H), 4.98 (d, J = 15.2 Hz, 1H), 4.78 - 4.60 (m, 6H), 3.60 (s, 2H), 3.37 (t, J = 6.8 Hz, 2H), 2.37 (t, J = 6.8 Hz, 2H), 1.24 (s, 9H). MS (M + H)+ = 562.3 Synthesis of 4-[3-hydroxy-1-[[4-(2-oxa-7-azaspiro[3.4]octan-7-yl)phenyl]methyl]-2-oxo- indolin-3-yl]benzenesulfonamide (NEM-128A) [0464] A mixture of N-tert-butyl-4-[3-hydroxy-1-[[4-(2-oxa-7-azaspiro[3.4]octan-7- yl)phenyl]methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (50 mg, 89.02 μmol, 1 eq) in DCE (2 mL) and TFA (1 mL) was stirred at 25°C for 8 hr. The product fraction was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)- ACN];gradient:30%-60% B over 8.0 min). Compound 4-[3-hydroxy-1-[[4-(2-oxa-7- azaspiro[3.4]octan-7-yl)phenyl]methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (5.5 mg, 10.88 μmol, 12.22% yield, 100% purity) was obtained.1H NMR (400 MHz, ACETONITRILE-d3) δ 7.83 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.29 (dt, J = 1.2, 8.0 Hz, 1H), 7.22 - 7.14 (m, 3H), 7.10 - 7.01 (m, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.53 (d, J = 8.8 Hz, 2H), 5.64 (br s, 2H), 4.79 (s, 2H), 4.74 - 4.69 (m, 1H), 4.61 - 4.53 (m, 4H), 3.49 (s, 2H), 3.26 (t, 2H), 2.26 (t, 2H). MS (M + H)+ = 506.2 Example 73. Synthesis of Compound NEM-129A O O O O O O S O O S S O Synthesis of methyl (2S)-1-[4-[[3-[4-(tert-butylsulfamoyl)phenyl]-3-hydroxy-2-oxo- indolin-1-yl]methyl]phenyl]pyrrolidine-2-carboxylate (2) [0465] A mixture of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N- tert-butyl-benzenesulfonamide (100 mg, 188.88 μmol, 1 eq), methyl (2S)-pyrrolidine-2- carboxylate (62.56 mg, 377.75 μmol, 2 eq, HCl salt), [2-(2- aminophenyl)phenyl]palladium(1+);2-(2-dicyclohexylphosphanylphenyl)-N1,N1,N3,N3- tetramethyl-benzene-1,3-diamine;methanesulfonate (15.23 mg, 18.89 μmol, 0.1 eq), Cs2CO3 (246.16 mg, 755.51 μmol, 4 eq) in dioxane (2 mL) was degassed and purged with N2 for 3 times and then the mixture was stirred at 110°C for 12 h under N2 atmosphere.5 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (3 mL*2) and the combined extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 4 g silica, 0~50% ethyl acetate in petroleum ether, gradient over 30 min). Compound methyl (2S)-1-[4-[[3-[4-(tert- butylsulfamoyl)phenyl]-3-hydroxy-2-oxo-indolin-1-yl]methyl]phenyl]pyrrolidine-2- carboxylate (60 mg, 103.86 μmol, 54.99% yield) was obtained. MS (M + H)+ = 578.1 Synthesis of methyl (2S)-1-[4-[[3-hydroxy-2-oxo-3-(4-sulfamoylphenyl)indolin-1- yl]methyl]phenyl]pyrrolidine-2-carboxylate (NEM-129AI) [0466] A solution of methyl (2S)-1-[4-[[3-[4-(tert-butylsulfamoyl)phenyl]-3-hydroxy-2- oxo-indolin-1-yl]methyl]phenyl]pyrrolidine-2-carboxylate (50 mg, 86.55 μmol, 1 eq) in TFA (0.5 mL) and DCE (1 mL) was stirred at 50°C for 1.5 hr. The reaction was cooled to room temperature. The mixture was adjusted pH = 9 by adding saturated NaHCO3 aqueous solution slowly at 0°C. The mixture was diluted by water (2 mL), extracted with dichloromethane (2 mL * 2). The combined organics were washed with brine (3 mL), dried over Na2SO4, filtered and the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18100*25mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:25%- 60% B over 8.0 min). Compound methyl (2S)-1-[4-[[3-hydroxy-2-oxo-3-(4- sulfamoylphenyl)indolin-1-yl]methyl]phenyl]pyrrolidine-2-carboxylate (13.9 mg, 26.65 μmol, 30.79% yield, 100% purity) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ 7.87 - 7.81 (m, 2H), 7.51 - 7.44 (m, 2H), 7.32 - 7.26 (m, 1H), 7.24 - 7.15 (m, 3H), 7.09 - 6.99 (m, 2H), 6.48 (d, J = 8.8 Hz, 2H), 4.91 - 4.87 (m, 1H), 4.82 - 4.74 (m, 1H), 4.29 - 4.23 (m, 1H), 3.69 (d, J = 5.2 Hz, 3H), 3.54 - 3.47 (m, 1H), 3.37 - 3.34 (m, 1H), 2.37 - 2.25 (m, 1H), 2.16 - 2.02 (m, 3H) MS (M + H)+ = 522.1 Example 74. Synthesis of Compound NEM-134A [0467] To a solution of 3-bromo-1,8-naphthyridine (200 mg, 956.74 μmol, 1 eq) and tributylstannylmethanol (921.59 mg, 2.87 mmol, 3 eq) in dioxane (5 mL) was added XPHOS-PD-G2 (75.28 mg, 95.67 μmol, 0.1 eq). The reaction mixture was degassed with N2 for three times. The mixture was heated to 80 °C and stirred for 12 h under N2 atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product.10 mL of water was added to the mixture, the mixture was extracted with dichloromethane (15 mL*2), and the combined extracts were dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue.1,8-naphthyridin-3-ylmethanol (60 mg, 187.30 μmol, 19.58% yield, 50% purity) was obtained as a yellow oil. MS(M+H)+ = 161.3 Synthesis of 3-(chloromethyl)-1,8-naphthyridine (3) [0468] To a solution of 1,8-naphthyridin-3-ylmethanol (20 mg, 62.43 μmol, 1 eq, 50% purity) in DCM (1 mL) was added SOCl2 (29.71 mg, 249.73 μmol, 18.14 μL, 2 eq), the reaction was stirred at 20°C for 1 h. The reaction was concentrated under reduce pressure.3- (chloromethyl)-1,8-naphthyridine (20 mg, crude) was obtained as a yellow oil. MS(M+H)+ =179.0 Synthesis of N-tert-butyl-4-[3-hydroxy-1-(1,8-naphthyridin-3-ylmethyl)-2-oxo-indolin- 3-yl]benzenesulfonamide (4) [0469] To a solution of 3-(chloromethyl)-1,8-naphthyridine (19.82 mg, 110.98 μmol, 2 eq) and N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (20 mg, 55.49 μmol, 1 eq) in DMF (1 mL) were added KI (13.82 mg, 83.23 μmol, 1.5 eq) and K2CO3 (19.17 mg, 138.72 μmol, 2.5 eq), the reaction was stirred at 60 °C for 12 h.3 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (5 mL*2) and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. N-tert-butyl-4-[3-hydroxy-1-(1,8- naphthyridin-3-ylmethyl)-2-oxo-indolin-3-yl]benzenesulfonamide (27 mg, crude) was obtained as a yellow solid. MS(M+H)+ = 503.3 Synthesis of 4-[3-hydroxy-1-(1,8-naphthyridin-3-ylmethyl)-2-oxo-indolin-3- yl]benzenesulfonamide (NEM-134A) [0470] A solution of N-tert-butyl-4-[3-hydroxy-1-(1,8-naphthyridin-3-ylmethyl)-2-oxo- indolin-3-yl]benzenesulfonamide (20 mg, 39.79 μmol, 1 eq) in DCE (1 mL) and TFA (0.5 mL) was stirred at 50°C for 0.5 h. The reaction mixture was cooled to room temperature. The mixture was concentrated under reduced pressure to give the crude product. The residue was purified by prep-HPLC: column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:10%-40% B over 8.0 min]. The residue was purified by SFC: column: DAICEL CHIRALCEL OD(250mm*30mm,10um);mobile phase: [CO2- IPA];B%:50%, isocratic elution mode.4-[3-hydroxy-1-(1,8-naphthyridin-3-ylmethyl)-2-oxo- indolin-3-yl]benzenesulfonamide (5.52 mg, 12.36 μmol, 31.07% yield, 100% purity) was obtained.1H NMR (400 MHz, ACETONITRILE-d3) δ 9.15 - 9.01 (m, 2H), 8.37 - 8.19 (m, 2H), 7.85 (d, J = 6.4 Hz, 2H), 7.64 - 7.49 (m, 3H), 7.33 (dt, J = 1.2, 8.0 Hz, 1H), 7.24 (d, J = 6.4 Hz, 1H), 7.16 - 6.98 (m, 2H), 5.67 (br s, 1H), 5.22-5.10 (m, 2H), 4.84 (s, 1H). MS(M+H)+ = 447.1
Example 75. Synthesis of Compound NEM-135A [0471] A mixture of 6-bromoquinazoline (1 g, 4.78 mmol, 1 eq), tributylstannylmethanol (1.84 g, 5.74 mmol, 1.2eq), [2-(2-aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)- butyl-phosphane;methanesulfonate (348.38 mg, 478.37 μmol, 0.1 eq) in dioxane (20 mL) was degassed and purged with N2 for 3 times and then the mixture was stirred at 110°C for 12 hr under N2 atmosphere. The resultant mixture was filtered and the filter cake was rinsed with dioxane (5 mL x 3). Then the combined filtrates were concentrated under reduced pressure to give product as brown oil. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18250*50mm*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:1%-20% B over 10.0 min). Compound quinazolin-6-ylmethanol (670 mg, 4.18 mmol, 87.44% yield) was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 9.39 (s, 1H), 9.32 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.96 - 7.91 (m, 2H), 4.96 (br d, J = 3.6 Hz, 2H), 2.45 (br t, 1H) MS (M + H)+ = 161.1 Synthesis of 6-(chloromethyl)quinazoline (3) [0472] To a solution of quinazolin-6-ylmethanol (100 mg, 624.33 μmol, 1 eq) in DCM (2 mL) was added SOCl2 (371.38 mg, 3.12 mmol, 226.73 μL, 5 eq). The mixture was stirred at 0°C for 2hr. The product fraction was evaporated under reduced pressure. Compound 6- (chloromethyl)quinazoline (100 mg, crude) was obtained as a white solid which was used in next step without purification. MS (M + H)+ = 179.0 Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-(quinazolin-6-ylmethyl)indolin-3- yl]benzenesulfonamide (5) [0473] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (70 mg, 194.21 μmol, 1 eq), 6-(chloromethyl)quinazoline (41.63 mg, 233.06 μmol, 1.2 eq) in DMF (1 mL) was added K2CO3 (67.10 mg, 485.54 μmol, 2.5 eq). The mixture was stirred at 60°C for 12hr.5 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (3 mL*2) and the combined extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 4 g silica, 0~60% ethyl acetate in petroleum ether, gradient over 30 min). Compound N-tert-butyl-4-[3-hydroxy-2-oxo-1-(quinazolin-6-ylmethyl)indolin-3-yl]benzenesulfonamide (90 mg, 179.07 μmol, 92.20% yield) was obtained as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 9.20 - 9.16 (m, 2H), 7.96 - 7.92 (m, 1H), 7.90 - 7.84 (m, 3H), 7.81 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.37 - 7.30 (m, 2H), 7.19 - 7.12 (m, 1H), 6.91 (d, J = 7.6 Hz, 1H), 5.22 - 5.04 (m, 2H), 1.25 (s, 9H) MS (M + H)+ = 503.1 Synthesis of 4-[3-hydroxy-2-oxo-1-(quinazolin-6-ylmethyl)indolin-3- yl]benzenesulfonamide (NEM-135A) [0474] A mixture of N-tert-butyl-4-[3-hydroxy-2-oxo-1-(quinazolin-6-ylmethyl)indolin- 3-yl]benzenesulfonamide (80 mg, 159.18 μmol, 1 eq) in TFA (0.5 mL) and DCE (1 mL) was stirred at 50°C for 2 hr. The reaction was cooled to room temperature. Then the mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)- ACN];gradient:15%-45% B over 8.0 min). Compound 4-[3-hydroxy-2-oxo-1-(quinazolin-6- ylmethyl)indolin-3-yl]benzenesulfonamide (14.1 mg, 31.30 μmol, 19.66% yield, 99.1% purity) was obtained.1 H NMR (400 MHz, METHANOL-d4) δ = 9.48 (s, 1H), 9.24 (s, 1H), 8.11 (s, 1H), 8.03 (d, J = 1.2 Hz, 2H), 7.88 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.8 Hz, 2H), 7.31 (t, 1H), 7.25 (d, 1H), 7.11 (t, 1H), 7.05 (d, 1H), 5.29 - 5.16 (m, 2H). MS (M + H)+ = 447.1
Example 76. Synthesis of Compound NEM-136A [0475] A mixture of 6-bromo-1H-quinolin-2-one (500 mg, 2.23 mmol, 1 eq), tributylstannylmethanol (859.84 mg, 2.68 mmol, 1.2 eq), [2-(2- aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl-phosphane;methanesulfonate (162.52 mg, 223.16 μmol, 0.1 eq) in dioxane (13 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110°C for 12hr under N2 atmosphere. The solid was collected by filtration, washed with dioxane (5 mL * 3) and dried under reduced pressure to give a black solid, then dissolved in a small amount of DMSO. The crude product was purified by flash column (ISCO 4 g silica, 0~30% MeOH in petroleum ether, gradient over 20 min). Compound 6-(hydroxymethyl)-1H-quinolin-2-one (150 mg, 856.24 μmol, 38.37% yield) was obtained as a white solid.1 H NMR (400 MHz, DMSO-d6) δ = 11.70 (br s, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.57 (s, 1H), 7.44 (dd, J = 1.6, 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.47 (d, J = 9.2 Hz, 1H), 5.22 (t, J = 5.6 Hz, 1H), 4.51 (d, J = 4.8 Hz, 2H) MS (M + H)+ = 176.0 Synthesis of 6-(chloromethyl)-1H-quinolin-2-one (3) [0476] To a solution of 6-(hydroxymethyl)-1H-quinolin-2-one (90 mg, 513.75 μmol, 1 eq) in DCM (1 mL) was added SOCl2 (305.60 mg, 2.57 mmol, 186.57 μL, 5 eq). The mixture was stirred at 25°C for 2hr. The product fraction was evaporated under reduced pressure. Compound 6-(chloromethyl)-1H-quinolin-2-one (100 mg, crude) was obtained as a white solid which was used in next step without purification. MS (M + H)+ = 194.2 Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[(2-oxo-1H-quinolin-6- yl)methyl]indolin-3-yl]benzenesulfonamide (5) [0477] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (100 mg, 277.45 μmol, 1 eq), 6-(chloromethyl)-1H-quinolin-2-one (80.58 mg, 416.17 μmol, 1.5 eq) in DMF (2 mL) was added K2CO3 (115.03 mg, 832.35 μmol, 3 eq). The mixture was stirred at 60°C for 12 hr.5 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (5 mL*2), and the combined extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 4 g silica, 0~80% ethyl acetate in petroleum ether, gradient over 30 min). Compound N-tert-butyl-4-[3-hydroxy-2-oxo-1-[(2-oxo-1H-quinolin-6- yl)methyl]indolin-3-yl]benzenesulfonamide (50 mg, 96.60 μmol, 34.82% yield) was obtained as a yellow solid. MS (M + H)+ = 518.3 Synthesis of 4-[3-hydroxy-2-oxo-1-[(2-oxo-1H-quinolin-6-yl)methyl]indolin-3- yl]benzenesulfonamide (NEM-136A) [0478] A solution of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[(2-oxo-1H-quinolin-6- yl)methyl]indolin-3-yl]benzenesulfonamide (40 mg, 77.28 μmol, 1 eq) in TFA (1 mL) and DCE (2 mL) was stirred at 50°C for 2hr. The reation was cooled to room temperature. Then the product fraction was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C1880*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:15%-45% B over 8.0 min). Compound 4-[3-hydroxy-2- oxo-1-[(2-oxo-1H-quinolin-6-yl)methyl]indolin-3-yl]benzenesulfonamide (9.6 mg, 20.80 μmol, 26.92% yield, 100% purity) was obtained.1H NMR (400 MHz, METHANOL-d4) δ 7.92 - 7.84 (m, 3H), 7.68 (d, J = 1.2 Hz, 1H), 7.59 - 7.50 (m, 3H), 7.37 - 7.29 (m, 2H), 7.22 (d, J = 7.4 Hz, 1H), 7.13 - 7.07 (m, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 9.6 Hz, 1H), 5.09 - 4.99 (m, 2H) MS (M + H)+ = 462.1
Example 77. Synthesis of Compound NEM-138A [0479] To a solution of methyl 2-chloroquinoline-6-carboxylate (1 g, 4.51 mmol, 1 eq) in THF (20 mL) was added LiAlH4 (2.5 M, 3.61 mL, 2 eq) at 0°C under N2 atmosphere. The resulting mixture was stirred at 0°C for 2 hr under N2 atmosphere. The mixture was quenched by Na2SO4.10H2O at 0°C and stirred for 10 min. The resultant mixture was filtered and the filter cake was rinsed with dichloromethane (5 mL x 3). Then the combined filtrates were concentrated under reduced pressure to give as yellow solid. (2- chloro-6-quinolyl)methanol (870 mg, crude) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.44 (d, J = 8.4 Hz, 1H), 8.01 - 7.84 (m, 2H), 7.77 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 5.48 (t, J = 5.6 Hz, 1H), 4.70 (d, J = 5.6 Hz, 2H) Synthesis of 2-chloro-6-(chloromethyl)quinoline (3) [0480] To a solution of (2-chloro-6-quinolyl)methanol (870 mg, 4.49 mmol, 1 eq) in DCM (10 mL) was added SOCl2 (2.67 g, 22.47 mmol, 1.63 mL, 5 eq), the reaction was stirred at 25°C for 2 h. The reaction was concentrated under reduce pressure.2-chloro- 6-(chloromethyl)quinoline (1 g, crude) was obtained as a yellow solid. Synthesis of N-tert-butyl-4-[1-[(2-chloro-6-quinolyl)methyl]-3-hydroxy-2-oxo-indolin-3- yl]benzenesulfonamide (5) [0481] To a solution of 2-chloro-6-(chloromethyl)quinoline (423.65 mg, 2.00 mmol, 1.2 eq) and N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (600 mg, 1.66 mmol, 1 eq) in DMF (10 mL) was added K2CO3 (575.17 mg, 4.16 mmol, 2.5 eq), the reaction was stirred at 60°C for 12 h.10 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (20 mL*2), and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 12 g silica, 0-35 % ethyl acetate in petroleum ether, gradient over 20 min). N-tert-butyl-4-[1-[(2-chloro-6-quinolyl)methyl]-3- hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (900 mg, 839.49 μmol, 50.43% yield, 50% purity) was obtained as a yellow oil. Synthesis of N-tert-butyl-4-[1-[[2-(dimethylamino)-6-quinolyl]methyl]-3-hydroxy-2- oxo-indolin-3-yl]benzenesulfonamide (6) [0482] To a solution of N-tert-butyl-4-[1-[(2-chloro-6-quinolyl)methyl]-3-hydroxy-2- oxo-indolin-3-yl]benzenesulfonamide (150 mg, 139.91 μmol, 1 eq, 50% purity) and N- methylmethanamine (2 M in THF, 1.40 mL, 20 eq) in DMF (3 mL) were added K2CO3 (48.34 mg, 349.79 μmol, 2.5 eq) and KI (34.84 mg, 209.87 μmol, 1.5 eq), the reaction was stirred at 60°C for 12 hr.3 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (5 mL*2), and the combined extracts was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 4 g silica, 0-35 % ethyl acetate in petroleum ether, gradient over 20 min). N-tert-butyl-4-[1-[[2-(dimethylamino)-6-quinolyl]methyl]-3- hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (70 mg, 64.26 μmol, 45.93% yield, 50% purity) was obtained as a yellow solid. Synthesis of 4-[1-[[2-(dimethylamino)-6-quinolyl]methyl]-3-hydroxy-2-oxo-indolin-3- yl]benzenesulfonamide (NEM-138A) [0483] A solution of N-tert-butyl-4-[1-[[2-(dimethylamino)-6-quinolyl]methyl]-3- hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (70 mg, 128.52 μmol, 1 eq, 50% purity) in DCE (1 mL) and TFA (1.54 g, 13.46 mmol, 1 mL, 104.75 eq) was stirred at 60°C for 12 hr. The mixture was concentrated under reduced pressure to give the crude product. The residue was purified by prep-HPLC: column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:25%-55% B over 8.0 min.4-[1-[[2-(dimethylamino)-6-quinolyl]methyl]-3-hydroxy-2-oxo-indolin-3- yl]benzenesulfonamide (1.5 mg, 3.07 μmol, 2.39% yield, 100% purity) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ = 7.98 - 7.81 (m, 3H), 7.69 - 7.58 (m, 2H), 7.54-7.51 (m, 3H), 7.38 - 7.26 (m, 1H), 7.22 (d, J = 6.4 Hz, 1H), 7.14 - 6.97 (m, 3H), 5.06 (d, J = 3.8 Hz, 2H), 3.22 (s, 6H) MS (M + H)+ = 489.2. Example 78. Synthesis of Compound NEM-141A O O S N O O O O H S S HO N NH H NH - oxo- yl]methyl]indole-1-carboxylate (2) [0484] To a solution of tert-butyl 5-(hydroxymethyl)indole-1-carboxylate (82.33 mg, 332.94 μmol, 1.2 eq), N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (100 mg, 277.45 μmol, 1 eq) in Tol. (2 mL) was added 2-(tributyl- phosphanylidene)acetonitrile (133.92 mg, 554.90 μmol, 2 eq) in the glove box, the reaction mixture was stirred at 80°C for 12 h under Ar2 atmosphere.5 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (3 mL*2), and the combined extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 4g silica, 0~50% ethyl acetate in petroleum ether, gradient over 10 min). Compound tert-butyl 5-[[3-[4-(tert-butylsulfamoyl)phenyl]-3-hydroxy-2-oxo-indolin- 1-yl]methyl]indole-1-carboxylate (150 mg, 254.37 μmol, 91.68% yield) was obtained as yellow oil. MS (M - H)- = 588.2 Synthesis of 4-[3-hydroxy-1-(1H-indol-5-ylmethyl)-2-oxo-indolin-3- yl]benzenesulfonamide (NEM-141A) [0485] A mixture of tert-butyl 5-[[3-[4-(tert-butylsulfamoyl)phenyl]-3-hydroxy-2-oxo- indolin-1-yl]methyl]indole-1-carboxylate (20 mg, 33.92 μmol, 1 eq), I2 (51.65 mg, 203.49 μmol, 40.99 μL, 6 eq), Aluminum (9.15 mg, 339.16 μmol, 10 eq) in acetonitrile (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 85°C for 12 hr under N2 atmosphere. The reaction was cooled to room temperature. The resultant mixture was filtered and the filter cake was rinsed with acetonitrile (3 mL x 3). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18100*25mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:10%-40% B over 8.0 min). Compound 4-[3- hydroxy-1-(1H-indol-5-ylmethyl)-2-oxo-indolin-3-yl]benzenesulfonamide (1 mg, 2.24 μmol, 6.60% yield, 97% purity) was obtained. 1 H NMR (400 MHz, ACETONITRILE-d3) δ 9.41 - 9.23 (m, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.58 (s, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.30 - 7.24 (m, 2H), 7.20 - 7.10 (m, 2H), 7.07 - 6.99 (m, 2H), 6.44 (t, J = 2.1 Hz, 1H), 5.74 - 5.54 (m, 2H), 4.99 (s, 2H), 4.74 (br s, 1H) MS (M - H)- = 432.2 Example 79. Synthesis of Compound NEM-142A [0486] A mixture of 4-bromo-1,2-difluoro-benzene (800 mg, 4.15 mmol, 1 eq), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (2.45 g, 8.29 mmol, 2 eq), K2CO3 (1.43 g, 10.36 mmol, 2.5 eq), Pd(dppf)Cl2 (303.31 mg, 414.53 μmol, 0.1 eq) in dioxane (24 mL) and H2O (6 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 12hr under N2 atmosphere.20 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (10 mL*2), and the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 10 g silica, 0~30% ethyl acetate in petroleum ether, gradient over 10 min) Compound tert-butyl 3-(3,4-difluorophenyl)-2,5- dihydropyrrole-1-carboxylate (1.1 g, 3.91 mmol, 94.33% yield) was obtained as a white solid.1 H NMR (400 MHz, CHLOROFORM-d) δ 7.24 - 7.05 (m, 3H), 6.10 (br d, J = 18.0 Hz, 1H), 4.49 - 4.20 (m, 4H), 1.52 (s, 9H) Synthesis of tert-butyl 3-(3,4-difluorophenyl)pyrrolidine-1-carboxylate (4) [0487] To a solution of Pd/C (100 mg, 93.97 μmol, 10% purity, 2.64e-2 eq) in MeOH (10 mL) was added tert-butyl 3-(3,4-difluorophenyl)-2,5-dihydropyrrole-1-carboxylate (1 g, 3.55 mmol, 1 eq) under Ar atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 25°C for 2 hr. The resultant mixture was filtered and the filter cake was rinsed with MeOH (5 mL x 3). Then the combined filtrates were concentrated under reduced pressure to give product as yellow oil. Compound tert-butyl 3-(3,4-difluorophenyl)pyrrolidine-1-carboxylate (1 g, crude) was obtained as yellow oil which was used in next step without purification. MS (M-56+H)+ = 228.1 Synthesis of 3-(3,4-difluorophenyl)pyrrolidine (5) [0488] A solution of tert-butyl 3-(3,4-difluorophenyl)pyrrolidine-1-carboxylate (200 mg, 705.93 μmol, 1 eq) in HCl/EtOAc (2 mL) was stirred at 25°C for 1hr. The mixture was concentrated under reduced pressure. MeOH (2 mL) was added and basified by slowly adding weak anion resin at 0oC to pH = 9, dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give the crude product. Compound 3- (3,4-difluorophenyl)pyrrolidine (100 mg, crude) was obtained as yellow oil which was used in next step without purification. MS (M + H)+ = 184.1 Synthesis of N-tert-butyl-4-[1-[[4-[3-(3,4-difluorophenyl)pyrrolidin-1- yl]phenyl]methyl]-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (7) [0489] A mixture of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N- tert-butyl-benzenesulfonamide (80 mg, 151.10 μmol, 1 eq), 3-(3,4- difluorophenyl)pyrrolidine (33.22 mg, 181.32 μmol, 1.2 eq), Cs2CO3 (98.46 mg, 302.20 μmol, 2 eq), dicyclohexyl-[2-(2,6- diisopropoxyphenyl)phenyl]phosphane;methanesulfonate;[2-[2- (methylamino)phenyl]phenyl]palladium(1+) (12.85 mg, 15.11 μmol, 0.1 eq) in dioxane (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 12hr under N2 atmosphere.5 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (5 mL*2), and the combined extracts were washed with brine (5 mL) dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 4 g silica, 0~40% ethyl acetate in petroleum ether, gradient over 30 min). Compound N-tert-butyl-4-[1- [[4-[3-(3,4-difluorophenyl)pyrrolidin-1-yl]phenyl]methyl]-3-hydroxy-2-oxo-indolin-3- yl]benzenesulfonamide (70 mg, 110.81 μmol, 73.33% yield) was obtained as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.85 - 7.78 (m, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.31 - 7.28 (m, 1H), 7.25 - 7.19 (m, 3H), 7.15 - 7.02 (m, 3H), 6.99-6.97 (m, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.55 (d, J = 8.4 Hz, 2H), 5.01-4.97 (m, 1H), 4.77 - 4.70 (m, 2H), 3.72 - 3.64 (m, 1H), 3.55 - 3.24 (m, 4H), 2.48 - 2.33 (m, 1H), 2.13 - 2.06 (m, 1H), 1.254 (s, 9H). MS (M + H)+ = 632.4 Synthesis of 4-[1-[[4-[3-(3,4-difluorophenyl)pyrrolidin-1-yl]phenyl]methyl]-3-hydroxy- 2-oxo-indolin-3-yl]benzenesulfonamide (NEM-142A) [0490] A solution of N-tert-butyl-4-[1-[[4-[3-(3,4-difluorophenyl)pyrrolidin-1- yl]phenyl]methyl]-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (50 mg, 79.15 μmol, 1 eq) in TFA (1 mL) and DCE (1 mL) was stirred at 50°C for 2 hr. The reation was cooled to room temperature. Then the mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C1880*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:45%-75% B over 8.0 min). Compound 4-[1-[[4-[3- (3,4-difluorophenyl)pyrrolidin-1-yl]phenyl]methyl]-3-hydroxy-2-oxo-indolin-3- yl]benzenesulfonamide (26.4 mg, 38.28 μmol, 48.37% yield, 100% purity, TFA salt) was obtained.1 H NMR (400 MHz, METHANOL-d4) δ 7.84 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.33 - 7.27 (m, 1H), 7.27 - 7.15 (m, 5H), 7.13 - 7.01 (m, 3H), 6.64 (br d, J = 7.6 Hz, 2H), 4.94 - 4.89 (m, 1H), 4.83 - 4.77 (m, 1H), 3.76 - 3.38 (m, 5H), 2.49 - 2.39 (m, 1H), 2.17 - 2.04 (m, 1H) MS (M + H)+ = 576.1 Example 80. Synthesis of Compound NEM-143A yl]benzenesulfonamide (3) [0491] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3- yl)benzenesulfonamide (300 mg, 832.35 μmol, 1 eq), 5-(bromomethyl)-2-chloro-pyridine (206.22 mg, 998.82 μmol, 1.2 eq) in DMF (5 mL) was added K2CO3 (287.59 mg, 2.08 mmol, 2.5 eq). The mixture was stirred at 60 °C for 12hr.10 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (10 mL*2) and the combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by flash column (ISCO 10 g silica, 0~60% ethyl acetate in petroleum ether, gradient over 10 min). Compound N-tert-butyl-4-[1-[(6-chloro-3-pyridyl)methyl]-3-hydroxy-2-oxo-indolin-3- yl]benzenesulfonamide (400 mg, 691.38 μmol, 83.06% yield, 84% purity) was obtained as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ 8.44 (d, J = 2.4 Hz, 1H), 7.89 - 7.82 (m, 2H), 7.62 (dd, J = 2.5, 8.3 Hz, 1H), 7.51 - 7.46 (m, 2H), 7.39 - 7.28 (m, 3H), 7.16 - 7.10 (m, 1H), 6.84 (d, J = 7.9 Hz, 1H), 5.01 - 4.86 (m, 2H), 4.53 (br s, 1H),1.25 (s, 9H) MS (M + H)+ = 486.2 Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[(6-pyrrolidin-1-yl-3- pyridyl)methyl]indolin-3-yl]benzenesulfonamide (4) [0492] To a solution of N-tert-butyl-4-[1-[(6-chloro-3-pyridyl)methyl]-3-hydroxy-2-oxo- indolin-3-yl]benzenesulfonamide (200 mg, 411.54 μmol, 1 eq), pyrrolidine (292.69 mg, 4.12 mmol, 343.53 μL, 10 eq) in DMA (1 mL) was added KI (102.47 mg, 617.31 μmol, 1.5 eq) and K2CO3 (170.63 mg, 1.23 mmol, 3 eq). The mixture was stirred at 80°C for 12 hr.5 mL of water was added to the mixture, the mixture was extracted with Ethyl acetate (5 mL*2) and the combined extracts were washed with brine (5 mL), dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure to give a residue. Compound N-tert-butyl-4-[3-hydroxy-2-oxo-1-[(6-pyrrolidin-1-yl-3-pyridyl)methyl]indolin- 3-yl]benzenesulfonamide (200 mg, crude) was obtained as a brown solid which was used in next step without purification. MS (M + H)+ = 521.2 Synthesis of 4-[3-hydroxy-2-oxo-1-[(6-pyrrolidin-1-yl-3-pyridyl)methyl]indolin-3- yl]benzenesulfonamide (NEM-143A) [0493] A mixture of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[(6-pyrrolidin-1-yl-3- pyridyl)methyl]indolin-3-yl]benzenesulfonamide (200 mg, 384.14 μmol, 1 eq) in TFA (2 mL) and DCE (3 mL) was stirred at 50°C for 2 hr. The reaction was cooled to room temperature. Then the mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:5%-35% B over 8.0 min). Compound 4-[3- hydroxy-2-oxo-1-[(6-pyrrolidin-1-yl-3-pyridyl)methyl]indolin-3-yl]benzenesulfonamide (84.5 mg, 146.05 μmol, 38.02% yield, 100% purity, TFA salt) was obtained.1H NMR (400 MHz, METHANOL-d4) δ 7.96 - 7.89 (m, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.39 (dt, J = 1.3, 7.8 Hz, 1H), 7.26 - 7.22 (m, 1H), 7.20 - 7.12 (m, 2H), 7.07 (d, J = 9.4 Hz, 1H), 4.92 (s, 2H), 3.58-3.55 (m, 4H), 2.15 - 2.10 (m, 4H). MS (M + H)+ = 465.1 Example 81. Synthesis of Compound NEM-1D - - butanoate (2) [0494] To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoic acid (370.59 mg, 1.71 mmol, 2 eq) in DCM (3 mL) was added DMAP (10.42 mg, 85.29 μmol, 0.1 eq) and DCC (527.92 mg, 2.56mmol, 517.56μL, 3eq) and N-tert-butyl-4-[3-hydroxy-2- oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (450 mg, 852.87 μmol, 1 eq). The mixture was stirred at 20°C for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column (ISCO 20 g silica, 0-20 % ethyl acetate in petroleum ether, gradient over 20 min). Compound [3-[4-(tert- butylsulfamoyl)phenyl]-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3-yl] (2S)-2-(tert- butoxycarbonylamino)-3-methyl-butanoate (450 mg, 569.56 μmol, 66.78% yield, 92% purity) was obtained as a white solid.1H NMR (400 MHz, CHLOROFORM-d) δ 8.66 (br d, J = 5.0 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H), 7.54 - 7.42 (m, 6H), 7.34 - 7.29 (m, 1H), 7.21 (br d, J = 7.6 Hz, 1H), 7.15 - 7.09 (m, 1H), 6.79 (br d, J = 7.8 Hz, 1H), 5.06 - 4.90 (m, 3H), 4.49 (br s, 1H), 4.47 - 4.38 (m, 1H), 3.55 - 3.44 (m, 1H), 2.43 - 2.20 (m, 1H), 1.98 - 1.90 (m, 2H), 1.70 (td, J = 3.8, 13.4 Hz, 2H), 1.61 (td, J = 3.6, 13.0 Hz, 1H), 1.44 (d, J = 16.1 Hz, 9H), 1.26 (s, 9H) Synthesis of [2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]-3-(4-sulfamoylphenyl)indolin-3-yl] (2S)-2-amino-3-methyl-butanoate (NEM-1D) [0495] To a solution of [3-[4-(tert-butylsulfamoyl)phenyl]-2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]indolin-3-yl] (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoate (400 mg, 550.30 μmol, 1 eq) in DCM (3 mL) was added TFA (2.05 g, 17.95 mmol, 1.33 mL, 32.62 eq). The mixture was stirred at 40°C for 1h. The reaction mixture was concentrated under reduced presssure. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*40mm*3um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:15%- 45% B over 8.0 min); to give crude product which was further purified by prep-HPLC column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:20%-60% B over 8.0 min. Compound [2-oxo-1-[[4-(4- pyridyl)phenyl]methyl]-3-(4-sulfamoylphenyl)indolin-3-yl] (2S)-2-amino-3-methyl- butanoate (34 mg, 47.66 μmol, 8.66% yield, 95.98% purity, TFA salt) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ 8.62 - 8.58 (m, 2H), 7.94 (d, J = 8.4 Hz, 2H), 7.81 - 7.73 (m, 4H), 7.64 - 7.59 (m, 2H), 7.58 - 7.53 (m, 2H), 7.43 - 7.36 (m, 1H), 7.35 - 7.29 (m, 1H), 7.21 - 7.14 (m, 1H), 7.02 - 6.97 (m, 1H), 5.18 - 5.11 (m, 1H), 5.05 - 5.00 (m, 1H), 3.62 - 3.54 (m, 1H), 2.34 - 2.12 (m, 1H), 1.15 - 1.10 (m, 2H), 1.07 (d, J = 7.0 Hz, 2H), 0.97 (d, J = 6.8 Hz, 2H). MS (M + H)+ = 571.2 Example 82. Synthesis of Compound NEM-1A mL) was added K2CO3 (563.61 mg, 4.08 mmol, 1.2 eq) and KI (112.83 mg, 679.67 umol, 0.2 eq). The mixture was cooled in an ice-water bath and 1-(chloromethyl)-4-methoxy- benzene (585.43 mg, 3.74 mmol, 509.07 uL, 1.1 eq) was added drop wise. The reaction mixture was heated at 110 °C for 3. LC-MS showed the starting material was consumed completely and one main peak with desired mass was detected. After cooling to room temperature, the mixture was poured into ice water and 1 M hydrochloric acid (4 mL) was added. The separated solid was collected by filtration. The crude product 1-[(4- methoxyphenyl)methyl]indoline-2,3-dione (700 mg, crude) was obtained as a red solid which was used into the next step without further purification. LCMS (ESI) m/z: 268.1 [M+H]+ [0497] A mixture of (4-sulfamoylphenyl)boronic acid (293.30 mg, 1.46 mmol, 1.3 eq), 1-[(4-methoxyphenyl)methyl]indoline-2,3-dione (300 mg, 1.12 mmol, 1 eq), tritert- butylphosphonium;tetrafluoroborate (9.77 mg, 33.67 umol, 0.03 eq), K2CO3 (7.76 mg, 56.12 umol, 0.05 eq) and diacetoxyrhodium (4.96 mg, 11.22 umol, 0.01 eq) in DME (3 mL) and H2O (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 5 hr under N2 atmosphere. LC-MS showed the starting material was consumed completely and one main peak desired mass was detected. The reaction mixture was cooled to room temperature and diluted by water (15 mL), extracted with ethyl acetate (20 mL * 2). The combined organics were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in DCM (20 mL) and 1 g of silica gel was added. The resultant mixture was evaporated under reduced pressure to give a flowing solid, and then submitted for purification by flash chromatography on silica gel (Petroleum ether/ EtOAc =10:1~1:1) to give 4-[3-hydroxy-1- [(4-methoxyphenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (250 mg, 588.97 umol, 52.47% yield) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ 7.82 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 7.31 - 7.28 (m, 3H), 7.21 (d, J = 7.4 Hz, 1H), 7.10 - 7.04 (m, 1H), 6.91 - 6.86 (m, 3H), 5.08 (s, 2H), 5.02 - 4.77 (m, 1H), 4.83 - 4.78 (m, 1H), 4.05 (s, 1H), 3.80 (s, 3H). LCMS (ESI) m/z: 425.1 [M+H]+ [0498] To a solution of 4-[3-hydroxy-1-[(4-methoxyphenyl)methyl]-2-oxo-indolin-3- yl]benzenesulfonamide (100 mg, 235.59 umol, 1 eq) in DCM (1 mL) was added TEA (35.76 mg, 353.38 umol, 49.19 uL, 1.5 eq), acetyl acetate (28.86 mg, 282.71 umol, 26.48 uL, 1.2 eq) and DMAP (5.76 mg, 47.12 umol, 0.2 eq). The mixture was stirred at 20 °C for 2 h. The reaction mixture was cooled to room temperature and diluted with water (15 mL), extracted with ethyl acetate (20 mL *2). The combined organics were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex C18 80*30mm*3um;mobile phase: [water(TFA)-ACN];B%: 35%-65%,8min). Compound N-[4- [3-hydroxy-1-[(4-methoxyphenyl)methyl]-2-oxo-indolin-3-yl]phenyl]sulfonylacetamide (7.68 mg, 16.28 umol, 6.91%) was obtained. 1H NMR (400 MHz, METHANOL-d4) δ = 7.95 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 7.33 - 7.27 (m, 3H), 7.20 (d, J = 6.8 Hz, 1H), 7.11 - 7.07 (m, 1H), 7.01 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 4.89 (d, J = 4.0 Hz, 2H), 3.77 (s, 3H), 1.95 (s, 3H); LCMS (ESI) m/z: 467.0 [M+H]+ Biological Example 1. Biological Evaluation Materials and Methods [0499] Stopped-flow: IC50 values were established using an SX20 stopped-flow spectrometer from Applied Biophysics. In one syringe of the SX20, recombinant human Car1 was kept at a concentration of 9 µM in a sodium phosphate buffer and inhibitors were added to this solution at 0 nM, 10 nM, 20 nM, 80 nM and 100 nM. In a second syringe, a saturated CO2 solution was mixed with 0.2 mM phenol red. This series of dilutions allow for the evaluation of how quickly Car1 can metabolize the CO2 in the absence of an inhibitor and for the determination of whether that process is inhibited as increasing concentrations of compounds are added. [0500] In vitro Mast Cell development: Briefly, 1 x 106 bone marrow-resident progenitor cells were isolated from the femur of mice and cultured in complete media supplemented with 10 ng/mL of rIL-3 for a period of 5 days. Mast cells were identified by their expression of the surface molecules FcεRIα and c-Kit via flow cytometric analysis. In addition to IL-3, cultures were treated with vehicle or increasing concentrations of Car enzyme inhibitors at the indicated concentrations. [0501] Trichinella spiralis infection: Mice were infected with 500 T. spiralis muscle stage larvae by oral gavage and were treated with vehicle (1:5, DMSO/PBS), 10-120 mg/kg MZ, or a test compound at 10-40 mg/kg, i.p. daily; mice were sacrificed between on day 10- post infection and mast cell responses in the small intestine were evaluated by esterase staining as described previously (Henry, E.K., et al., J Exp Med, 2016.213(9): p.1663-73). [0502] The capabilities of compounds herein in inhibiting mast cell development were primarily tested using an established mast cell culture assay (Henry, E.K., et al., J Exp Med, 2016.213(9): p.1663-73). As a positive control for mast cell development, bone marrow cells were isolated from the femur of mice and cultured in the presence of 10 ng/mL of IL-3 and vehicle (1:10, DMSO/RPMI complete media) for seven days and mast cells were identified by flow cytometric analysis as (c-Kit+ FceRIa+ CD49b- cells). To determine mast cell inhibitory capacity, cultures were treated with increasing doses of compounds herein. MZ was used as a positive control at 30 ug/mL (126.97 uM) (its peak effective range based on a previous study (Henry, E.K., et al., J Exp Med, 2016.213(9): p.1663-73)). Treatment with IL-3 resulted in increased mast cell numbers compared to media treated controls. Further, while vehicle alone showed no effects, treatment with MZ resulted in significantly decreased mast cell numbers as previously reported (Henry, E.K., et al., J Exp Med, 2016. 213(9): p.1663-73). [0503] Efficacies of compounds in inhibiting Car1 enzyme activity can be tested using the sopped-flow assay herein. MZ was used as a control in this assay. Exemplary compounds of this disclosure were evaluated with the stopped-flow assay, and were found to inhibit Car1 enzyme activity. [0504] Efficacies of compounds in inhibiting in vivo mast cell responses can be tested using a model of Trichinella spiralis-induced mastocytosis. Briefly, mice were infected with T. spiralis and treated with either vehicle, MZ or a test compound and intestinal mast cells were quantified via esterase staining and histological analysis (Henry, E.K., et al., J Exp Med, 2016.213(9): p.1663-73). As reported previously, mice infected with T. spiralis exhibit significantly increased mast cell responses in the presence of vehicle (Henry, E.K., et al., J Exp Med, 2016.213(9): p.1663-73). [0505] To evaluate the ability of representative compounds of the invention to effectively inhibit mast cell development, in vitro mast cell cultures were performed as previously described (Henry et al), and the percent inhibition at 10 µm was measured. Representative compounds were tested in the mast cell culture assay, and the results were shown in percent of inhibition (POI) based on MC numbers. Results are shown in Table 1. Table 1. POI of further Car enzyme inhibitors at 10 uM* POI on MC# POI on MC# Compound # 10 uM Compound # 10 uM NEM-77A 58.00 NEM-141A 35.00 NEM-78A 100.00 NEM-142A 97.00 up to 100%. As used herein, “uM” refers to micromolar or µM. Some of the compounds tested show a POI of 0 or a negative value; most of these compounds when tested in higher concentrations, show a positive POI. ** CAR-037 is 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide, shown here for comparison purposes. *** The POI for this compound was based on testing concentration of 5 uM instead of 10 uM. Discussion [0506] As new technologies and techniques are developed, our ability to understand hematopoiesis and lineage commitment events continues to advance. As a result, recent studies are beginning to reshape traditional models of stem cell development and are identifying previously unappreciated therapeutic targets. Previous studies identified a mast cell progenitor that is defined by its high expression of the enzyme Car1 (Henry, E.K., et al., J Exp Med, 2016.213(9): p.1663-73; Inclan-Rico, J.M., et al., PLoS Pathogens, 2020. 16(5): p. e1008579). These studies also demonstrated that inhibition of Car1 is sufficient to prevent mast cell development. Determining the developmental check points of mast cells is of great scientific and clinical relevance. Mast cells are strategically positioned at barrier surfaces and are robust producers of inflammatory molecules in response to diverse stimuli (Voehringer, D., Nat Rev Immunol, 2013.13(5): p.362-75). As a result, mast cells are critical players in several disease states including allergies, asthma, mastocytosis, mast cell activation syndrome and deadly anaphylaxis reactions (Henry, E.K., et al., J Exp Med, 2016. 213(9): p.1663-73; Voehringer, D., Nat Rev Immunol, 2013.13(5): p.362-75). Collectively, these studies suggest that Car1 inhibitors can be employed to treat several forms of mast cell-mediated inflammation. [0507] Previous studies have demonstrated that the Car enzyme inhibitor MZ can prevent both murine and human mast cell development. PCT/US2023/082927 shows that 4- (3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide’s capacity to inhibit Car1 correlated with its potent potential to inhibit mast cell responses both in vitro and in vivo. As exemplified in the table above, representative compounds herein are effective in inhibiting Car1 enzyme activation and can inhibit mast cell development at lower doses compared to MZ and/or CAR-037. [0508] The following illustrate representative pharmaceutical dosage forms, containing a compound of Formula I, II, or III, e.g., any of the subformulae or specific compounds according to Formula I, II, or III, as defined herein ('Compound X'), for therapeutic or prophylactic use in humans. (i) Tablet 1 mg/tablet Compound X= 100.0 Lactose 77.5 Povidone 15.0 Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesium stearate 3.0 300.0 (ii) Tablet 2 mg/tablet Compound X= 20.0 Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0 500.0 (iii) Capsule mg/capsule Compound X= 10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 600.0 (iv) Injection 1 (1 mg/ml) mg/ml Compound X= (free acid form) 1.0 Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0 N Sodium hydroxide solution (pH adjustment to 7.0-7.5) q.s. Water for injection q.s. ad 1 mL (v) Injection 2 (10 mg/ml) mg/ml Compound X= (free acid form) 10.0 Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethylene glycol 400 200.0 1.0 N Sodium hydroxide solution (pH adjustment to 7.0-7.5) q.s. Water for injection q.s. ad 1 mL (vi) Aerosol mg/can Compound X= 20.0 Oleic acid 10.0 Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane 10,000.0 Dichlorotetrafluoroethane 5,000.0 [0509] The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. [0510] The Summary and Abstract sections may set forth one or more but not all exemplary embodiments of the present invention as contemplated by the inventor(s), and thus, are not intended to limit the present invention and the appended claims in any way. [0511] The present invention has been described above with the aid of functional building blocks illustrating the implementation of specified functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternate boundaries can be defined so long as the specified functions and relationships thereof are appropriately performed. [0512] With respect to aspects of the invention described as a genus, all individual species are individually considered separate aspects of the invention. If aspects of the invention are described as "comprising" a feature, embodiments also are contemplated "consisting of” or "consisting essentially of” the feature. [0513] The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying knowledge within the skill of the art, readily modify and/or adapt for various applications such specific embodiments, without undue experimentation, without departing from the general concept of the present invention. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance. [0514] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments. [0515] All of the various aspects, embodiments, and options described herein can be combined in any and all variations. [0516] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall govern. [0517] The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims

WHAT IS CLAIMED IS: 1. A compound of Formula I, or a pharmaceutically acceptable salt thereof: , wherein: R1 is hydrogen, OH, or O-R1A, wherein R1A is an optionally substituted alkanoyl; R2 is hydrogen or an optionally substituted alkanoyl; n is 0, 1, 2, 3, or 4, preferably, 0 or 1, R3 at each occurrence is independently halogen, C1-4 alkyl optionally substituted with halogen, C1-4 alkoxy optionally substituted with halogen, NH2, NH(C1-4 alkyl), or N(C1-4 alkyl)(C1-4 alkyl); R4 and R5 are each independently hydrogen or C1-4 alkyl optionally substituted with halogen; or R4 and R5 together represent oxo (=O); X is N, CH, or CR7; R6 is an optionally substituted group selected from phenyl, 5 or 6-membered heteroaryl, or a 5-10 membered heterocyclic ring; j is 0, 1, 2, or 3, preferably, 0 or 1; and R7 at each occurrence is independently halogen, C1-4 alkyl optionally substituted with halogen, or C1-4 alkoxy optionally substituted with halogen.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having a stereochemistry according to Formula I-E1: , Formula I-E1.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having a stereochemistry according to Formula I-E2: ,
4. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula I-1: , wherein: k is 0, 1, 2, 3, or 4; and RA at each occurrence is independently F, OH, NH2, COOH, CONH2, GA, C(O)-GA, O-GA, NH-GA, N(C1-4 alkyl)-GA, C(O)-O-GA, C(O)-NH-GA, or C(O)-N(C1-4 alkyl)-GA; wherein GA at each occurrence is independently C1-4 alkyl or a 3-10 membered ring (more preferably, 3-8 membered ring, such as phenyl ring), wherein the C1-4 alkyl or 3-10 membered ring is optionally substituted, for example, with 1-3 substituents each independently a halogen, CN, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, C1-4 alkoxy optionally substituted with 1-3 fluorine, or a 3-6 membered ring optionally substituted with 1-3 G1, wherein G1 at each occurrence is independently halogen, oxo, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, or C1-4 alkoxy optionally substituted with 1-3 fluorine.
5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein RA at each occurrence is independently F, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, or C1-4 alkoxy optionally substituted with 1-3 fluorine.
6. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein k is 0.
7. The compound of claim 4, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula I-1a: , wherein: k1 is 0, 1, 2, 3, or 4; and G2 at each occurrence is independently halogen, CN, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, C1-4 alkoxy optionally substituted with 1-3 fluorine, or C3-4 cycloalkyl optionally substituted with 1 or 2 substituents each independently F or methyl.
8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein k1 is 1- 3, and G2 at each occurrence is independently F, Cl, or C1-4 alkyl optionally substituted with 1-3 fluorine.
9. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R6 is a fused, spiro, or bridged 6-10 membered bicyclic heterocyclic ring having 1-3 ring heteroatoms each independently N, S, or O, wherein the bicyclic heterocyclic ring is optionally substituted, for example, with 1-3 substituents each independently a halogen, CN, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, C1-4 alkoxy optionally substituted with 1-3 fluorine, or a 3-5 membered ring optionally substituted with 1-3 G1, wherein G1 at each occurrence is independently halogen, oxo, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, or C1-4 alkoxy optionally substituted with 1-3 fluorine.
10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R6 is selected from the following: , .
11. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R6 is phenyl or pyridyl, which is optionally substituted with 1-3 substituents independently selected from halogen (e.g., F), OH, C1-4 alkyl, C1-4 alkoxy, C1-4 heteroalkyl, or 3-6 membered ring, wherein the C1-4 alkyl, C1-4 alkoxy, C1-4 heteroalkyl or 3-6 membered ring is optionally substituted with one or more substituents each independently halogen, CN, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, C1-4 alkoxy optionally substituted with 1-3 fluorine, or C3-4 cycloalkyl optionally substituted with 1 or 2 substituents each independently F or methyl.
12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R6 is selected from , wherein: k2 is 0, 1, 2, or 3, and G3 at each occurrence is independently F, Cl, C1-4 alkyl optionally substituted with 1-3 fluorine, C1-4 alkoxy optionally substituted with 1-3 fluorine, or C3-4 cycloalkyl optionally substituted with 1 or 2 substituents each independently F or methyl.
13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein k2 is 0.
14. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein k2 is 1 or 2, and each G3 is independently F, Cl, or methyl optionally substituted with 1-3 fluorine.
15. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R6 is pyrrolyl, which is optionally substituted, for example, with substituents independently selected from halogen (e.g., F), C1-4 alkyl optionally substituted with 1-3 fluorine, or a 3-6 membered ring optionally substituted with one or more substituents each independently halogen, CN, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, C1-4 alkoxy optionally substituted with 1-3 fluorine, or C3-4 cycloalkyl optionally substituted with 1 or 2 substituents each independently F or methyl.
16. The compound of any of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R1 is OH.
17. The compound of any of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.
18. The compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein n is 0.
19. The compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein n is 1, and R3 is halogen, C1-4 alkyl optionally substituted with halogen, C1-4 alkoxy optionally substituted with halogen, or N(C1-4 alkyl)(C1-4 alkyl).
20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein R3 is F, Cl, methyl optionally substituted with F, or methoxy optionally substituted with F.
21. The compound of any of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen or methyl.
22. The compound of any of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen or methyl.
23. The compound of any of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein both R4 and R5 are hydrogen.
24. The compound of any of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein R4 and R5 together represent oxo (=O).
25. The compound of any of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein X is CH or CR7, e.g., CH or CF.
26. The compound of any of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein X is N.
27. The compound of any of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein j is 0 or 1.
28. The compound of any of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein R7 at each occurrence is independently F, Cl, C1-4 alkyl optionally substituted with F, or C1-4 alkoxy optionally substituted with F.
29. A compound of Formula II, or a pharmaceutically acceptable salt thereof: , wherein: R1 is hydrogen, OH, or O-R1A, wherein R1A is an optionally substituted alkanoyl; R2 is hydrogen or an optionally substituted alkanoyl; n is 0, 1, 2, 3, or 4, preferably, 0 or 1, R3 at each occurrence is independently halogen, C1-4 alkyl optionally substituted with halogen, C1-4 alkoxy optionally substituted with halogen, NH2, NH(C1-4 alkyl), or N(C1-4 alkyl)(C1-4 alkyl); R10 and R11 are each independently hydrogen, halogen, OH, NH2, GA, O-GA, NH-GA, or N(C1-4 alkyl)-GA; wherein GA at each occurrence is independently C1-4 alkyl or a 3-10 membered ring, wherein the C1-4 alkyl or 3-10 membered ring is optionally substituted, for example, with 1-3 substituents each independently a halogen, CN, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, C1-4 alkoxy optionally substituted with 1-3 fluorine, or a 3-6 membered ring optionally substituted with 1-3 substituents each independently halogen, oxo, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, or C1-4 alkoxy optionally substituted with 1-3 fluorine; m is 0, 1, 2, or 3, preferably, 0 or 1; and R12 at each occurrence is independently halogen, C1-4 alkyl optionally substituted with halogen, or C1-4 alkoxy optionally substituted with halogen.
30. A compound of Formula III, or a pharmaceutically acceptable salt thereof: , Formula III, wherein: R1 is hydrogen, OH, or O-R1A, wherein R1A is an optionally substituted alkanoyl; R2 is hydrogen or an optionally substituted alkanoyl; n is 0, 1, 2, 3, or 4, preferably, 0 or 1, R3 at each occurrence is independently halogen, C1-4 alkyl optionally substituted with halogen, C1-4 alkoxy optionally substituted with halogen, NH2, NH(C1-4 alkyl), or N(C1-4 alkyl)(C1-4 alkyl); R4 and R5 are each independently hydrogen or C1-4 alkyl optionally substituted with halogen; or R4 and R5 together represent oxo (=O); Ring E is a 5-membered heteroaryl ring, a 6-membered heteroaryl ring having 1 or 2 ring nitrogen, a bicyclic heteroaryl ring, or a 5-14 membered heterocyclic ring; j2 is 0, 1, 2, 3, or 4, as valency permits, preferably, 0 or 1; and R20 at each occurrence is independently halogen, OH, NH2, COOH, CONH2, GB, C(O)-GB, O-GB, NH-GB, N(C1-4 alkyl)-GB, C(O)-O-GB, C(O)-NH-GB, or C(O)-N(C1-4 alkyl)-GB; wherein GB at each occurrence is independently C1-4 alkyl or a 3-10 membered ring, wherein the C1-4 alkyl or 3-10 membered ring is optionally substituted, for example, with 1-3 substituents each independently a halogen, CN, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, C1-4 alkoxy optionally substituted with 1-3 fluorine, or a 3-6 membered ring optionally substituted with 1-3 substituents each independently halogen, oxo, OH, C1-4 alkyl optionally substituted with 1-3 fluorine, or C1-4 alkoxy optionally substituted with 1-3 fluorine.
31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein Ring E, together with the optional substituent(s) (R20)j2, are selected from the following: ,
,
32. The compound of claim 30 or 31, or a pharmaceutically acceptable salt thereof, wherein j2 is 0 or 1.
33. The compound of claim 30, or a pharmaceutically acceptable salt thereof, characterized as having a structure according to Formula III-1: , wherein: R21 is hydrogen or R20 as defined in claim 30, for example, R21 is hydrogen or an optionally substituted phenyl or 5 or 6 membered heteroaryl.
34. The compound of any of claims 29-33, or a pharmaceutically acceptable salt thereof, wherein R1 is OH.
35. The compound of any of claims 29-34, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.
36. The compound of any of claims 29-35, or a pharmaceutically acceptable salt thereof, wherein n is 0.
37. The compound of any of claims 29-35, or a pharmaceutically acceptable salt thereof, wherein n is 1, and R3 is halogen, C1-4 alkyl optionally substituted with halogen, C1-4 alkoxy optionally substituted with halogen, or N(C1-4 alkyl)(C1-4 alkyl).
38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R3 is F, Cl, methyl optionally substituted with F, or methoxy optionally substituted with F.
39. The compound of any of claims 30-38, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen or methyl.
40. The compound of any of claims 30-39, or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen or methyl.
41. The compound of any of claims 30-40, or a pharmaceutically acceptable salt thereof, wherein both R4 and R5 are hydrogen.
42. The compound of any of claims 30-38, or a pharmaceutically acceptable salt thereof, wherein R4 and R5 together represent oxo (=O).
43. A compound selected from any of the compounds described in Table A herein, or a pharmaceutically acceptable salt thereof.
44. A compound selected from: O O S O O S NH 2 HO p p y , p y, ast 90% ee, at least 95% ee, at least 98% ee, at least 99% ee, or 99.5% ee or higher.
45. A pharmaceutical composition comprising a compound as described in any one of claims 1-44 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
46. A method of inhibiting a carbonic anhydrase enzyme in vitro or in vivo comprising contacting the carbonic anhydrase enzyme with an effective amount of a compound as described in any one of claims 1-44 or a pharmaceutically acceptable salt thereof.
47. A method of treating a disease or condition mediated by a carbonic anhydrase enzyme in a mammal (e.g., a human), comprising administering a compound as described in any one of claims 1-44, or a pharmaceutically acceptable salt thereof, to the mammal.
48. The method of claim 47, further comprising administering one or more additional therapeutic agent(s).
49. The method of claim 48, wherein the one or more additional therapeutic agent(s) is an anti-histamine, a steroid, a decongestant, a bronchodilator, a mast cell stabilizer, a leukotriene modifier, a prostaglandin antagonist, a blocking/neutralizing antibody, and/or an immunotherapy.
50. The method of claim 49, wherein the one or more additional therapeutic agent(s) is an anti-histamine.
51. The method of claim 50, wherein the anti-histamine is acrivastine, azelastine, bilastine, brompheniramine, buclizine, bromodiphenhydramine, carbinoxamine, cetirizine (Zyrtec; metabolite of hydroxyzine, its prodrug), chlorpromazine, cimetidine, cyclizine, chlorphenamine, chlorodiphenhydramine, clemastine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimetindene, diphenhydramine (Benadryl), ebastine, embramine, famotidine, fexofenadine (Allegra), hydroxyzine (Vistaril), lafutidine, levocetirizine, loratadine (Claritin), nizatidine, olopatadine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, ranitidine, roxatidine, rupatadine, tiotidine, tripelennamine, or triprolidine.
52. The method of any one of claims 47-51, wherein the mammal is a human, mouse, rat, dog, cat, hamster, guinea pig, rabbit or livestock.
53. The method of any one of claims 47-52, wherein the disease or condition mediated by a carbonic anhydrase enzyme is an allergic disease, a bacterial infection, a fungal infection, a viral infection, mastocytosis or mast cell-mediated inflammation.
54. The method of any one of claims 47-52, wherein the disease or condition mediated by a carbonic anhydrase enzyme is an allergic disease.
55. The method of claim 54, wherein the allergic disease is asthma (e.g., fungal asthma), atopic dermatitis, contact dermatitis, chronic itch (pruritus), urticaria, hay fever, allergic conjunctivitis, allergic rhinitis, anaphylaxis, eosinophilic esophagitis, a food allergy(ies) or allergen-induced mastocytosis.
56. The method of claim 54, wherein the allergic disease is asthma.
57. The method of claim 54, wherein the allergic disease is a food allergy.
58. The method of any one of claims 47-52, wherein the disease or condition mediated by a carbonic anhydrase enzyme is a bacterial infection.
59. The method of any one of claims 47-52, wherein the disease or condition mediated by a carbonic anhydrase enzyme is a fungal infection.
60. The method of any one of claims 47-52, wherein the disease or condition mediated by a carbonic anhydrase enzyme is a viral infection.
61. The method of any one of claims 47-52, wherein the disease or condition mediated by a carbonic anhydrase enzyme is mastocytosis.
62. The method of any one of claims 47-52, wherein the disease or condition mediated by a carbonic anhydrase enzyme is mast cell-mediated inflammation.
63. The method of any one of claims 47-52, wherein the disease or condition mediated by a carbonic anhydrase enzyme is osteoarthritis.
64. The method of any one of claims 47-52, wherein the disease or condition mediated by a carbonic anhydrase enzyme is ankylosing spondylitis.
65. The method of any one of claims 47-52, wherein the disease or condition mediated by a carbonic anhydrase enzyme is neuropathic pain.
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