WO2025259601A1 - Inhibiteurs d'enzyme anhydrase carbonique et leurs procédés d'utilisation - Google Patents

Inhibiteurs d'enzyme anhydrase carbonique et leurs procédés d'utilisation

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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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English (en)
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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/fr
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    • C07D401/00—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
    • 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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    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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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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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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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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    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • 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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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux composés, tels qu'un composé de formule I, ainsi que des compositions comprenant les nouveaux composés de l'invention. Les composés sont généralement des inhibiteurs d'anhydrase carbonique et sont utiles pour le traitement prophylactique ou thérapeutique d'une maladie ou d'un état à médiation par une enzyme anhydrase carbonique.
PCT/US2025/032875 2024-06-10 2025-06-09 Inhibiteurs d'enzyme anhydrase carbonique et leurs procédés d'utilisation Pending WO2025259601A1 (fr)

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