EP3891224A1 - Chromophores ir à base de polyméthine hétérocyclyle - Google Patents

Chromophores ir à base de polyméthine hétérocyclyle

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Publication number
EP3891224A1
EP3891224A1 EP19892945.7A EP19892945A EP3891224A1 EP 3891224 A1 EP3891224 A1 EP 3891224A1 EP 19892945 A EP19892945 A EP 19892945A EP 3891224 A1 EP3891224 A1 EP 3891224A1
Authority
EP
European Patent Office
Prior art keywords
compound
alkyl
aryl
mmol
heteroaryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP19892945.7A
Other languages
German (de)
English (en)
Other versions
EP3891224A4 (fr
Inventor
Ellen M. SLETTEN
Emily D. COSCO
Anthony SPEARMAN
Monica PENGSHUNG
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of California
Original Assignee
University of California
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Filing date
Publication date
Application filed by University of California filed Critical University of California
Publication of EP3891224A1 publication Critical patent/EP3891224A1/fr
Publication of EP3891224A4 publication Critical patent/EP3891224A4/fr
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—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
    • C07D403/08—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 alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/08—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—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 four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
    • C09B23/0008—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain
    • C09B23/0016—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain the substituent being a halogen atom
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
    • C09B23/0066—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain being part of a carbocyclic ring,(e.g. benzene, naphtalene, cyclohexene, cyclobutenene-quadratic acid)
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
    • C09B23/02—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups
    • C09B23/04—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups one >CH- group, e.g. cyanines, isocyanines, pseudocyanines
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
    • C09B23/02—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups
    • C09B23/06—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups three >CH- groups, e.g. carbocyanines
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
    • C09B23/02—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups
    • C09B23/08—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines
    • C09B23/086—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines more than five >CH- groups

Definitions

  • Photomedicine broadly refers to the use of light for diagnostic or therapeutic procedures, including optical imaging, photothermal therapy (thermal ablation of cells) and photodynamic therapy (reactive oxygen species induced apoptosis or necrosis).
  • photothermal therapy thermal ablation of cells
  • photodynamic therapy reactive oxygen species induced apoptosis or necrosis.
  • NIR near-infrared
  • SWIR short-wave infrared
  • SWIR-excitable fluorophores either have low or negligible quantum yields, or are too hydrophobic to be used directly for in vivo imaging.
  • the present disclosure provides NIR and SWIR-active small molecules with improved properties for use in optical imaging, photothermal therapy, and photodynamic therapy. Accordingly, the present disclosure provides compounds of formula I or formula II:
  • a and B are each independently selected from a bicyclic, tricyclic, or tetracyclic heteroaryl; wherein A and B are each independently substituted with one or more R 7a and/or R 7b ; each instance of p is independently 0, 1, or 2;
  • X is H, halo, aryl, heteroaryl, alkyl, alkenyl, cycloalkyl, alkynyl, N(R 3 )2, P(R 3 )2, PO(R 3 )2, SR 4 , S(0)R 4 , S(0)2R 4 , OR 4 , SeR 4 , Se(0)R 4 , Se(0)2R 4 , azido, cyano, haloalkyl (such as perfluoroalkyl), hydroxyl; R 1 and R 2 are each independently selected from F, D, or T; or R 1 and R 2 together complete a cycloalkenyl ring, a heterocyclyl ring, or a polycyclyl ring system;
  • R 3 is alkyl, aryl, or heteroaryl
  • R 4 is H, alkyl, or aryl
  • each R 7a and/or R 7b is independently selected from H, alkoxy, acyl, heteroaryl,
  • sulfonate carbonate, cyano, ester, amide, halo, aryl, amino, alkylamino, Ci-6 alkyl, C3-10 cycloalkyl, haloalkyl, aralkenyl (preferably arylethenyl), aralkynyl (preferably arylethynyl), hetaralkenyl (preferably heteroarylethenyl), hetaralkynyl (preferably heteroarylethynyl), and heterocyclyl;
  • R 7a and/or R 7b groups combine to form a carbocyclic or heterocyclic ring
  • the present disclosure also provides methods of using these dyes for in vivo sensing or cargo delivery, and methods of preparing these dyes.
  • FIG. 1A shows a generalized polymethine dye scaffold.
  • FIG. IB shows the lpkic,opi for selected polymethine dyes.
  • FIG. 2 shows the normalized absorbance (solid) and photoluminescence (dotted) of 5, 7- 10 in dichloromethane.
  • FIGs. 3A shows images of vials of IR-26, IR-1061 and Flav7 with matched optical density at 808 nm in dichloromethane, excited at 808 nm, collected using an InGaAs camera (1000-1500 nm).
  • FIGs. 3B shows the average background subtracted camera intensity for ten frames normalized to exposure.
  • FIGs. 4A-4G show normalized absorption and emission spectra for exemplary compounds of the present disclosure.
  • FIG. 5 shows normalized absorption and emission spectra for exemplary compounds of the present disclosure.
  • a and B are each independently selected from a bicyclic, tricyclic, or tetracyclic heteroaryl; wherein A and B are each independently substituted with one or more R 7a and/or R 7b ; each instance of p is independently 0, 1, or 2;
  • X is H, halo, aryl, heteroaryl, alkyl, alkenyl, cycloalkyl, alkynyl, N(R 3 )2, P(R 3 )2, PO(R 3 )2, SR 4 , S(0)R 4 , S(0)2R 4 , OR 4 , SeR 4 , Se(0)R 4 , Se(0)2R 4 , azido, cyano, haloalkyl (such as perfluoroalkyl), hydroxyl;
  • R 1 and R 2 are each independently selected from F, D, or T; or R 1 and R 2 together complete a cycloalkenyl ring, a heterocyclyl ring, or a polycyclyl ring system;
  • R 3 is alkyl, aryl, or heteroaryl
  • R 4 is H, alkyl, or aryl
  • each R 7a and/or R 7b is independently selected from H, alkoxy, acyl, heteroaryl,
  • sulfonate carbonate, cyano, ester, amide, halo, aryl, amino, alkylamino, Ci-6 alkyl, C3-10 cycloalkyl, haloalkyl, aralkenyl (preferably arylethenyl), aralkynyl (preferably arylethynyl), hetaralkenyl (preferably heteroarylethenyl), hetaralkynyl (preferably heteroarylethynyl), and heterocyclyl;
  • R 7a and/or R 7b groups combine to form a carbocyclic or heterocyclic ring
  • R 1 and R 2 are the same.
  • R 1 is F. In certain embodiments, R 1 is D. In certain embodiments, R 1 is T.
  • R 2 is F. In certain embodiments, R 2 is D. In certain embodiments, R 2 is T. In certain embodiments, the present disclosure provides compounds of formula I or formula
  • a and B are each independently selected from a bicyclic, tricyclic, or tetracyclic heteroaryl; wherein A and B are each independently substituted with one or more R 7a and/or R 7b ; each instance of p is independently 0, 1, or 2;
  • X is H, halo, aryl, heteroaryl, alkyl, alkenyl, cycloalkyl, alkynyl, N(R 3 )2, P(R 3 )2, PO(R 3 )2, SR 4 , OR 4 , SeR 4 , azido, cyano, haloalkyl (such as perfluoroalkyl), or hydroxyl;
  • R 1 and R 2 together complete a cycloalkenyl ring, a heterocyclyl ring, or a polycyclyl ring system;
  • R 3 is alkyl, aryl, or heteroaryl
  • R 4 is H, alkyl, or aryl
  • each R 7a and/or R 7b is independently selected from H, alkoxy, acyl, heteroaryl,
  • sulfonate carbonate, cyano, ester, amide, halo, aryl, amino, alkylamino, Ci-6 alkyl, C3-10 cycloalkyl, haloalkyl, aralkenyl (preferably arylethenyl), aralkynyl (preferably arylethynyl), hetaralkenyl (preferably heteroarylethenyl), hetaralkynyl (preferably heteroarylethynyl), and heterocyclyl;
  • R 7a and/or R 7b groups combine to form a carbocyclic or heterocyclic ring
  • At least one of A and B is not:
  • the compounds of formulas I and II are not:
  • the compounds of formulas I and II are not:
  • the compounds of formulas I and II are none of the structural formulae depicted above.
  • R 1 and R 2 together complete a cycloalkenyl ring, such as a cyclohexenyl ring.
  • a and B are different.
  • A is substituted by one or more substituents independently selected from R 7a and R 7b ;
  • B is substituted by one or more substituents independently selected from R 7a and R 71 ’;
  • each instance of R 7a and R 71 ’ is independently selected from alkyl (such as haloalkyl, fluoroalkyl or sulfonatoalkyl), alkoxy (such as haloalkyloxy, fluoroalkyloxy or sulfonatoalkyloxy), acyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, N(R 6 )R 6 , sulfonate, carbonate, cyano, ester, amide, or halo; and
  • each instance of R 6 is independently selected from H, alkyl, such as fluoroalkyl or
  • A is substituted by one or more substituents independently selected from R 7a and R 71 ’;
  • B is substituted by one or more substituents independently selected from R 7a and R 71 ’;
  • each instance of R 7a and R 71 ’ is independently selected from alkyl (such as haloalkyl, fluoroalkyl or sulfonatoalkyl), alkoxy (such as haloalkyloxy, fluoroalkyloxy or sulfonatoalkyloxy), acyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, N(R 6 )R 6 , sulfonate, carbonate, cyano, ester, amide, or halo; and
  • each instance of R 6 is independently selected from H, alkyl, such as fluoroalkyl or
  • sulfonatoalkyl acyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or two instances of R 6 connected to the same N may complete a heterocyclyl.
  • A is substituted by one or more substituents independently selected from R 7a and R 7b ;
  • B is substituted by one or more substituents independently selected from R 7a and R 71 ’;
  • each instance of R 7a and R 71 ’ is independently selected from alkyl, such as fluoroalkyl or
  • sulfonatoalkyl acyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, N(R 6 )R 6 , sulfonate, or carbonate;
  • each instance of R 6 is independently selected from H, alkyl, such as fluoroalkyl or
  • sulfonatoalkyl acyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or two instances of R 6 connected to the same N may complete a heterocyclyl.
  • At least one R 7a or R 71 ’ is a water-solubilizing group, for example one capable, either alone or in combination with other water-solubilizing groups, of rendering the compound soluble in an aqueous medium.
  • the water-solubilizing group is selected from a carboxylate group, a sulfonate, an anionic-substituted alkyl, or an anionic-substituted alkyl ether.
  • the water-solubilizing group is a poly(ethylene glycol), a poly(oxazoline), or a poly(zwitterion).
  • the water-solubilizing group is a poly(ethylene glycol), or a poly(oxazoline).
  • the molecular weight of the poly(ethylene glycol), a poly(oxazoline), or a poly(zwitterion) is about 100 daltons to about 5,000 daltons. In certain embodiments, the molecular weight of the poly(ethylene glycol) or a poly(oxazoline) is about 1,000 daltons to about 5,000 daltons.
  • At least one R 7a or R 7b is an electron-withdrawing group, for example to alter the electronic and/or optical properties of the compound.
  • the electron-withdrawing group is selected from haloalkyl, cyano, sulfonate, sulfonatoalkyl, sulfonatoalkyloxy, carboxyl, ester, amide, halo, nitro, alkylammonium, amine oxide, or haloalkyl, such as trifluoromethyl.
  • At least one R 7a or R 76 is selected from fluoroalkyl, for example one capable, either alone or in combination with other water-solubilizing groups, of rendering the compound soluble in a fluorous medium.
  • at least one R 7a or R 76 is N(R 6 )R 6 .
  • a and B are independently selected from
  • W is selected from O, SO, SO2, PR 6 , PO2H, POR 6 , SeO, Se0 2 , TeO, Te0 2 , SIR 6 2 , GeR 6 2 , BH, BOH, or BR 6 ;
  • Y is selected from 0 + , S + , Se + , Te + , SiR, GeR 6 , N, NR 6+ , or NO;
  • a and B are independently optionally substituted with one or more R 7a and/or R 76 , up to the limits of valence.
  • a and B are independently selected from
  • Q is N(R 6 )R 6 OR 6 , SR 6 , SO(R 6 ) 2 , SeR 6 , SeOR 6 , SeO(R 6 ) 2 , P(R 6 )R 6 , PO(R 6 )R 6 , B(R 6 ) 2 , or halo;
  • n 0, 1 , 2, 3, 4, or 5 subject to the limits of valence, preferably 0 or 1.
  • a and B are independently selected from:
  • n 0, 1, 2, 3, 4, or 5 subject to the limits of valence, preferably 0 or 1.
  • a and B are independently selected from
  • R7ib is C(R 31 )(R 32 ), arylene, heteroarylene, cycloalkylene, or heterocyclylene; R 31 and R 32 are each independently selected from H or alkyl (e.g., methyl); n is 0, 1, 2, 3, 4, or 5 subject to the limits of valence, preferably 0 or 1; and o is 0, 1, 2, or 3.
  • R7ib is arylene, heteroarylene, cycloalkylene, or heterocyclylene
  • the recited ring(s) may be either fused to the ring in which R7ib appears, or may be in a spiro relationship to that ring.
  • R7ib is C(R 31 )(R 32 ); and R 31 and R 32 are each alkyl (e.g., methyl). In other embodiments, R7ib is arylene (e.g., phenylene).
  • a and B are independently selected from
  • o is 2.
  • the compound is or
  • At least one R 7a or R 7b is aryl, trifluoromethyl, tert-butyl, H, aralkenyl, aralkynyl, cycloalkyl, or heterocyclyl.
  • at least one R 7a or R 7b is phenyl, heterocyclyl, polycylic aromatic, aralkenyl, or aralkynyl.
  • at least one R 7a or R 71 ’ is alkyloxy (e.g., methoxy), or cycloalkyl (e.g., adamantyl).
  • At least one R 7a or R 71 ’ is substituted with one or more R 7 , wherein R 7 is selected from alkyl (such as haloalkyl, fluoroalkyl or sulfonatoalkyl), alkoxy (such as haloalkyloxy, fluoroalkyloxy or sulfonatoalkyloxy), acyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, N(R 6 )R 6 , sulfonate, carbonate, cyano, ester, amide, or halo.
  • the R 7 on the at least one R 7a or R 71 ’ is at the para position.
  • the compound is selected from:
  • Ar is aryl
  • n 0, 1, 2, 3, 4, or 5, preferably 0 or 1.
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-phenyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • R 7a and R 7b are each aryl (e.g., phenyl).
  • at least one R 7a or R 7b is substituted with one or more R 7 , wherein R 7 is selected from alkyl (such as alkyl (e.g., methyl), haloalkyl, fluoroalkyl (e.g., trifluoromethyl) or sulfonatoalkyl), alkoxy (such as methoxy, haloalkyloxy, fluoroalkyloxy or sulfonatoalkyloxy), acyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonate, carbonate, cyano, ester, amide, amino (e.g., dimethyl amino) or halo (e.g., fluoro, chloro, or bromo).
  • alkyl such as alkyl (e.g., methyl), haloalkyl, fluoroalky
  • a and B are
  • R 6 is alkyl (e.g., methyl or ethyl).
  • two instances of R 6 connected to the same N complete a heterocyclyl (e.g., azetidinyl, pyrrolidinyl, or piperidinyl).
  • two instances of R 6 connected to the same N complete a heteroaryl (e.g., carbazolyl).
  • X is Cl
  • At least one of A and B is a tricyclic moiety. In certain embodiments, at least one of A and B is carbazolyl. In certain embodiments, at least one of A and B is substituted with N(R n )R 12 , wherein R 11 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R 12 is selected from H, alkyl, acyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or wherein R 11 and R 12 together complete a heterocyclyl. In certain embodiments, at least one of A and B is substituted with a 4-8 member N-linked heterocyclyl. In certain embodiments, at least one of A and B is
  • a and B is substituted with a fluoroalkyl.
  • the compound is a compound of formula I. In other embodiments, the compound is a compound of formula II.
  • At least one of A and B is:
  • each instance of q is independently selected from 0, 1, 2, or 3.
  • X is H, halo, aryl, heteroaryl, alkyl, alkenyl, cycloalkyl, alkynyl, N(R 3 )2, P(R 3 )2, PO(R 3 )2, SR 4 , OR 4 , SeR 4 , azido, cyano, haloalkyl (such as perfluoroalkyl), or hydroxyl.
  • X is aryl, heteroaryl, alkyl, alkenyl, cycloalkyl, alkynyl, N(R 3 )2, P(R 3 )2, PO(R 3 )2, SR 4 , OR 4 , SeR 4 , azido, cyano, haloalkyl (such as perfluoroalkyl), or hydroxyl.
  • A is optionally substituted by one or more substituents independently selected from R 7a and/or
  • B is optionally substituted by one or more substituents independently selected from R 7a and/or
  • each instance of R 6 is independently selected from H, alkyl, such as fluoroalkyl or
  • sulfonatoalkyl acyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or two instances of R 6 connected to the same N may complete a heterocyclyl; and
  • each instance of R 7a and/or R 7b is independently selected from alkyl, such as fluoroalkyl or
  • sulfonatoalkyl acyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, N(R 6 )R 6 , sulfonate, or carbonate;
  • R 7a and/or R 7b groups combine to form a carbocyclic or heterocyclic ring
  • At least one R 7a and/or R 71 ’ is a water-solubilizing group.
  • the water-solubilizing group is selected from carboxylate group, a sulfonate, an anionic-substituted alkyl, or an anionic-substituted alkyl ether
  • at least one R 7a and/or R 71 ’ is an electron-withdrawing group.
  • the electron-withdrawing group is selected from haloalkyl, cyano, sulfonate, sulfonatoalkyl, sulfonatoalkyloxy, carboxyl, ester, amide, halo, nitro, alkylammonium, amine oxide, or haloalkyl such as trifluoromethyl.
  • at least one R 7a and/or R 71 ’ is an electron- donating group.
  • At least one R 7a and/or R 71 ’ is selected from fluoroalkyl, for instance to render the compound soluble in afluorous medium.
  • at least one R 7a and/or R 71 ’ is (CH2)3C6Fi3.
  • a and B are independently selected from carbazolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl,
  • a and B are independently optionally substituted with one or more R 7a and/or R 76 , up to the limits of valence;
  • W is O, SO, SO2, PR 6 , PO2H, POR 6 , SeO, Se0 2 , TeO, Te0 2 , SIR 6 2 , GeR 6 2 , BH, BOH, or BR 6 ;
  • Y is 0 + , S + , Se + , Te + , SiR, GeR 6 , N, NR 6+ , or NO.
  • a and B are independently selected from
  • the at least one R 7a or R 76 is substituted with one or more R 7 , wherein R 7 is selected from alkyl (such as haloalkyl, fluoroalkyl or sulfonatoalkyl), alkoxy (such as haloalkyloxy, fluoroalkyloxy or sulfonatoalkyloxy), acyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, N(R 6 )R 6 , sulfonate, carbonate, cyano, ester, amide, or halo.
  • the R 7 on the at least one R 7a or R 71 ’ is at the para position.
  • a and B are independently selected from
  • Y is 0 + .
  • W is O, SO, S0 2 , PR 6 , PO2H, POR 6 , SeO, Se0 2 , TeO, Te0 2 , SIR 6 2 , GeR 6 2 , BH, BOH, or BR 6 ; and Y is S + , Se + , Te + , SiR, GeR 6 , N, NR 6+ , or NO.
  • a and B are independently selected from carbazolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl,
  • At least one of A and B is a tricyclic or tetracyclic moiety.
  • At least one of A and B is a tricyclic moiety, e.g., at least one of A and B is carbazolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl,
  • At least one of A and B is a tetracyclic moiety, e.g., at least one of A and B is selected from
  • At least one of A and B comprises a heteroatom other than nitrogen or oxygen. In certain embodiments, at least one of A or B comprises a heteroatom selected from sulfur, silicon, or selenium. In certain embodiments of the compound of formula (I), at least one of A and B is selected from:
  • At least one of A and B is substituted with N(R n )R 12 , wherein R 11 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R 12 is selected from H, alkyl, acyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or wherein R 11 and R 12 together complete a heterocyclyl.
  • at least one of A and B is substituted with a 4-8 member N-linked heteroaryl or heterocyclyl.
  • one or both of A and B are selected from the bicyclic, tricyclic, and tetracyclic moieties disclosed in International Patent Application PCT/US 18/36099, filed June 5, 2018, which is incorporated herein by reference in its entirety.
  • one or both of A and B is ionic such that the compound of fomula (I) or formula (II) as a whole bears a charge.
  • Such compounds may be paired with any suitable counter ion of interest, for example BF4 , tetraarylborate, Cl , Br , G, CIO4 , OAc , trifluoroacetate, arylacetate, sulfonate, or phosphate.
  • compositions comprising a compound as described herein.
  • the present disclosure provides methods of delivering a compound or composition disclosed herein to a living animal, comprising administering the compound or composition to the living animal.
  • the present disclosure provides methods of obtaining an image comprising illuminating a compound disclosed herein with excitation light, thereby causing the compound to emit fluorescence; and detecting the fluorescence.
  • the image is obtained in vivo.
  • the methods further comprise administering the compound to a living animal.
  • the present disclosure provides methods of administering a therapy comprising administering a compound or composition disclosed herein, for example to an animal.
  • the methods further comprise illuminating the compound with excitation light.
  • the methods further comprise generating singlet oxygen by illuminating the compound with excitation light.
  • the present disclosure provides methods of preparing a compound as disclosed herein, comprising:
  • a and B are each independently selected from a bicyclic, tricyclic, or tetracyclic heteroaryl; wherein A and B are each independently substituted with one or more R 7a and/or R 7b ; each instance of p is independently 0, 1, or 2;
  • X is H, halo, aryl, heteroaryl, alkyl, alkenyl, cycloalkyl, alkynyl, N(R 3 )2, P(R 3 )2, PO(R 3 )2, SR 4 ,
  • R 1 and R 2 are each independently selected from F, D, or T; or R 1 and R 2 together complete a cycloalkenyl ring, a heterocyclyl ring, or a polycyclyl ring system;
  • R 3 is alkyl, aryl, or heteroaryl
  • R 4 is H, alkyl, or aryl
  • each R 7a and/or R 7b is independently selected from H, alkoxy, acyl, heteroaryl,
  • sulfonate carbonate, cyano, ester, amide, halo, aryl, amino, alkylamino, Ci-6 alkyl, C3-10 cycloalkyl, haloalkyl, aralkenyl (preferably arylethenyl), aralkynyl (preferably arylethynyl), hetaralkenyl (preferably heteroarylethenyl), hetaralkynyl (preferably heteroarylethynyl), and heterocyclyl;
  • R 7a and/or R 7b groups combine to form a carbocyclic or heterocyclic ring
  • the present disclosure provides methods of preparing a compound as disclosed herein, comprising:
  • a and B are each independently selected from a bicyclic, tricyclic, or tetracyclic heteroaryl; wherein A and B are each independently substituted with one or more R 7a and/or R 7b ;
  • each instance of p is independently 0, 1, or 2;
  • a and B are different;
  • X is H, halo, aryl, heteroaryl, alkyl, alkenyl, cycloalkyl, alkynyl, N(R 3 )2, P(R 3 )2, PO(R 3 )2, SR 4 , OR 4 , SeR 4 , azido, cyano, haloalkyl (such as perfluoroalkyl), hydroxyl;
  • R 1 and R 2 together complete a cycloalkenyl ring, a heterocyclyl ring, or a polycyclyl ring system;
  • R 3 is alkyl, aryl, or heteroaryl;
  • R 4 is H, alkyl, or aryl
  • each R 7a and/or R 7b is independently selected from H, alkoxy, acyl, heteroaryl,
  • sulfonate carbonate, cyano, ester, amide, halo, aryl, amino, alkylamino, Ci-6 alkyl, C3-10 cycloalkyl, haloalkyl, aralkenyl (preferably arylethenyl), aralkynyl (preferably
  • arylethynyl hetaralkenyl (preferably heteroarylethenyl), hetaralkynyl (preferably heteroarylethynyl), and heterocyclyl;
  • R 7a and/or R 7b groups combine to form a carbocyclic or heterocyclic ring
  • R 8 is alkyl, such as methyl.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature.
  • isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), n C, 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 C1, 82 Br, 123 I, 124 I, 129 I and 133 I, respectively. Accordingly, recitation of “hydrogen” or “H” should be understood to encompass ' H (protium), 2 H (deuterium), and 3 H (tritium) unless otherwise specified.
  • isotopic variations of a compound of the invention are useful in drug and/or substrate tissue distribution studies.
  • Tritiated and carbon- 14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • Such variants may also have advantageous optical properties arising, for example, from changes to vibrational modes due to the heavier isotope.
  • Isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.
  • SWIR small molecule chromophore To obtain a SWIR small molecule chromophore, a narrow gap between the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) must be achieved. As the HOMO-LUMO gap of chromophores decreases, their reactivity increases. Thus, stability of SWIR chromophores is a more significant challenge than for NIR chromophores. Another consequence of the small energy difference between the ground state and excited state is that there are many non-emissive pathways which can facilitate relaxation back to the ground state, resulting in low quantum yields of fluorescence (OF). Finally, for SWIR photodynamic therapy applications, the triplet energies of the photosensitizer need to be high enough to sensitize oxygen (23 kcal/mol).
  • SWIR-excitable fluorophores either have low or negligible quantum yields, or are too hydrophobic to be used directly in in vivo imaging.
  • the present disclosure provides SWIR-active small molecules with improved properties for use in optical imaging, photothermal therapy, and photodynamic therapy.
  • cyanines While cyanines have been the premier polymethine dyes for applications in the visible and NIR, their extension into the SWIR has been limited. Lengthening the polymethine chain, which is known to impart a bathochromic shift to cyanine dyes, can compromise the fluorescence quantum yield (Fr), decrease fluorophore stability, and lead to loss of electron delocalization over the entire conjugated system. Heterocycle modification can create bright, stable polymethine dyes in the SWIR. However, the photophysical changes that result from heterocyclyl modification are not straightforward. Extending heterocycle conjugation or adding electron-donating groups have been shown to bathochromically-shift polymethine dyes.
  • Dimethylamino flavylium polymethine dyes have been prepared and analyzed. Scheme 1. Synthesis of dimethylamino flavylium polymethine dyes 3 - 6.
  • Polymethine dyes can be prepared through the introduction of an activated heterocycle to an aldehyde or bis-aldehyde equivalent.
  • the requisite 7-A' A'-dimethylamino-4-methyl-flavylium heterocycle (1) was prepared in three steps from dimethylaminophenol as previously reported (Chen, J.-R.; Wong, J.-B.; Kuo, P.-Y.; Yang, D.-Y. Org. Lett. 2008, 10, 4823-4826):
  • flavylium dyes 3-6 were measured. As seen in Figure 2 and Table 1, the flavylium dyes span the long wavelength end of the visible, the NIR and enter the SWIR.
  • PCM absorption
  • the dimethylamino flavylium dyes are significantly red-shifted from classic cyanine dyes by approximately 200 nm and Flav7 absorbs ⁇ 40 nm past IR-27. Photostabilities of the Flav series were measured under continuous-wave irradiation (532 nm, 0.53 fluence). Flavl, Flav3 and Flav5 all show excellent photostabilities in dichloromethane, with Flav7 displaying reasonable stability
  • the Flavl dye absorbs at 650 nm, similar to a 5-cyanine, but has a lower absorption coefficient (s) and Fr, resulting in a low quantum efficiency (QE, defined as eFr), consistent with the short polymethine chain.
  • the Flav3 dye has similar absorption properties to the standard heptamethine indocyanine dye l,r,3,3,3’,3’-hexamethylindotricarbocyanine iodide (FUTCI, Cy7) with max.abs ⁇ 745 nm and e ⁇ 220,000 IVT'cm 1 . While HITCI has ⁇ 10-fold higher Fr than Flav3 Flav3 is 4-fold more photostable.
  • the Flav5 and Flav7 dyes are more red-shifted than indoline- containing cyanine dyes, absorbing at 862 nm and 1026 nm, respectively.
  • the Flav5 emits at 908 nm, a relatively unique wavelength for polymethine dyes, with extremely high QE (10 3 IVT'cm 1 ), desirable photostability, and the largest Stoke’ s shift of the series at 46 nm.
  • the Flav7 is a true NIR-II/SWIR fluorophore with emission at 1061 nm, Fr of 0.53%, and an impressive SWIR QE of 1,200 M ⁇ cm 1 .
  • Flav7 This family of flavylium dyes has photophysical qualities that are complementary to commonly used cyanine dyes.
  • the premier dye in the series is the Flav7 (3) as few emissive polymethine dyes exist in this region.
  • the .max.abs in dichloromethane, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, acetone exhibited minimal variation.
  • spectral broadening and accentuation of a high-energy shoulder were observed. This behavior is consistent with SWIR polymethine dyes that experience ground state symmetry breaking due to stabilization of an asymmetric electronic structure.
  • methanol an immediate color change is observed, suggestive of covalent modification of the polymethine; however, a major decomposition product could not be identified.
  • each dye’s emission was directly compared using a SWIR camera.
  • the dimethylamino flavylium dyes are notably red-shifted compared to prevalent cyanine dyes, and expand the opportunities for imaging and detection in the NIR and SWIR.
  • Certain methods for fluorescence imaging of animals are described, for instance, in U.S. Patent No. 7,383,076.
  • the stability and emission of fluorophores decrease as their absorption moves to lower energies, highlighting the challenge of achieving stable, bright fluorophores, particularly in the SWIR.
  • the three NIR polymethine dyes reported display excellent photostabilities with varying quantum yields.
  • Heptamethine Flav7 is 13-times brighter than IR-26, the current SWIR benchmark.
  • Flav7 is the superior SWIR fluorophore using a comparative imaging experiment and absolute ®F.
  • Polymethine fluorophores have other distinctive properties including narrow absorption and emission bands and the ability to be chemically fine-tuned, which poise them to be a promising fluorophore scaffold for new technologies in these underdeveloped regions of the EM spectrum.
  • further improvements beyond these dimethylaminoflavylium dyes are still possible, and are described herein.
  • the heterocycle composition of polymethine dyes has a significant effect on the photophysical properties of these chromophores.
  • the present disclosure describes polymethine fluorophores that replace the flavylium heterocycle in the dyes described above with other heterocycles, including modified flavylium heterocycles.
  • the dimethylaminoflavylium group may be extended to include other moieties that impart different physicochemical properties, or the amino may be replaced entirely with a more hydrophilic group.
  • the modifications of the dimethylaminoflavylium group described herein are designed to enhance absorption coefficient (e), fluorescence quantum yield (Fr), the singlet oxygen quantum yield
  • R may represent alkyl, such as lower alkyl, cycloalkyl, such as lower cycloalkyl, aryl, or heteroaryl. In certain embodiments, R may represent alkyl, such as lower alkyl. Analogous substitutions may be made on the other modified heterocycles disclosed herein.
  • heterocyclyl moieties when conjugated to a polymethine, such as a pentamethine or a heptamethine, may be drawn in one of two or more resonance structures, depending on the end of the polymethine to which the moiety is attached as well as the other atoms in the heterocyclyl moieties. This is illustrated for 7 below:
  • Extended aromatic systems may also be used to improve SWIR fluorophore properties, for instance, by resulting in a bathochromic shift.
  • exemplary heterocycles include carbazolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl, and the following:
  • R may represent alkyl, such as lower alkyl, cycloalkyl, such as lower cycloalkyl, aryl, or heteroaryl. In certain embodiments, R may represent alkyl, such as lower alkyl. Analogous substitutions may be made on the other modified heterocycles disclosed herein.
  • the flavylium oxygen (or the oxygen in the other heterocycles disclosed herein) may be replaced with another heteroatom, which may also be substituted as valence permits:
  • W may represent SO, SO2, PR, PO2H, POR, SeO, Se02, TeO, Te02, SiR 6 2, GeR 6 2, BH, BOH, or BR;
  • Y may represent 0 + , S + , Se + , Te + , SiR, GeR, N, NR + , or NO;
  • R may represent alkyl, such as lower alkyl, cycloalkyl, such as lower cycloalkyl, aryl, or heteroaryl. In certain embodiments, R may represent alkyl, such as lower alkyl. Analogous substitutions may be made on the other modified heterocycles disclosed herein.
  • heterocycles include:
  • R may represent alkyl, such as lower alkyl, cycloalkyl, such as lower cycloalkyl, aryl, or heteroaryl. In certain embodiments, R may represent alkyl, such as lower alkyl.
  • cycloalkyl such as lower cycloalkyl, aryl, or heteroaryl.
  • R may represent alkyl, such as lower alkyl.
  • W may represent O, SO, SO2, PR, PO2H, POR, SeO, Se02, TeO, Te02, SiR 6 2, GeR 6 2 , BH, BOH, or BR;
  • Y may represent 0 + , S + , Se + , Te + , SiR, GeR, N, NR + , or NO;
  • R may represent alkyl, such as lower alkyl, cycloalkyl, such as lower cycloalkyl, aryl, or heteroaryl; and R A may represent an electron-withdrawing group such as haloalkyl, cyano, sulfonate, sulfonatoalkyl, sulfonatoalkyloxy, carboxyl, ester, amide, halo, nitro, alkylammonium, amine oxide, or haloalkyl, such as trifluoromethyl.
  • R A may represent sulfonate, sulfonatoalkyl, or sulfonatoalkyloxy, preferably sulfonate or a sulfonatoalkyl such as sulfonatoethyl.
  • R A may represent an electron-donating group such as alkoxy, alkyl, or aryl.
  • R may represent alkyl or lower alkyl. Analogous substitutions may be made on the other modified heterocycles disclosed herein.
  • Dimethylamino flavylium cyanine 3 is hydrophobic, which hinders its ability to be employed for in vivo imaging.
  • the present disclosure provides variants that are hydrophilic and/or fluorophilic.
  • Hydrophilicity may be imparted to polymethine dyes by incorporating ionic groups such as sulfonates, as described above, or carboxylates.
  • Carboxylates can also facilitate conjugation of biomolecules.
  • Exemplary heterocycles include:
  • any R group may independently be anionic-substituted alkyl, such as sulfonatoethyl.
  • R may be a nonionic alkyl and R’ may be a carboxylate group, a sulfonate, an anionic-substituted alkyl, or an anionic substituted alkyl ether.
  • R’ may be located at any position on the aryl ring and one or more R’ substituents may be present. Analogous substitutions may be made on the other modified heterocycles disclosed herein.
  • a fluorinated alkyl chain such as (CH2)3C6Fi3.
  • fluorophibc dyes can be used to localize the dyes inside perfluorocarbon nanoemulsions.
  • the fluorous phase despite requiring a nanomaterial scaffold, has significant advantages for imaging in the SWIR, including the protection of cyanine dyes from biomolecules, increased quantum yields, and increased photostabilities.
  • Exemplary heterocycles include:
  • R may be a fluorinated alkyl, such as (CH2)3C6Fi3 .
  • R may be a fluorinated alkyl or fluorinated alkoxy, such as (CH2)3C6Fi3 or 0(CH2)3C6Fi3 .
  • R’ may be located at any position on the aryl ring and one or more R’ substituents may be present. Analogous substitutions may be made on the other modified heterocycles disclosed herein.
  • Heterocycles 1, 7, and 8 may be produced according to a thermally promoted condensation between a 3 -amino phenol derivative and ethyl benzoyl acetate, followed by Grignard addition of methyl magnesium bromide and treatment with HX to promote dehydration and install the counter ion (X) of interest. (Scheme 3 A, route 1). Any suitable counter ion of interest may be used, for example BFF, tetraarylborate, Cl , Br , G, CIOT, OAC , trifluoroacetate, arylacetate, sulfonate, or phosphate.
  • 7-amino flavylium heterocycle derivatives may be obtained from the commercial 7-hydroxyflavone which can undergo triflation with trifluoromethane sulfonic anhydride to produce a species reactive towards cross-coupling reactions.
  • the 7-triflate flavone can then undergo Buchwald-Hartwig cross-coupling reactions with a variety of primary and secondary amines and amides (Scheme 3 A, route 2) to produce the 7-amino functionalized flavone.
  • This flavone is similarly reactive towards Grignard conditions to yield the functionalized flavylium heterocycle.
  • 7-amino functionalized derivatives may be obtained beginning with the commercial 7-amino flavone which can undergo nucleophilic addition reactions or reductive amination reactions to yield the functionalized flavone (Scheme 3A, route 3).
  • Heterocycles 11B, l lC, and 11D may be obtained by Grignard addition of methyl magnesium bromide to the corresponding flavones (Scheme 3B), which are either commercially available or can be obtained from previously reported routes (see, e.g., Foroozesh, M. J. Med. Chem. 2015, 58, 6481-6493.).
  • Scheme 3B
  • Heterocycle 11 A may be produced by a 1,4-addition into butynophenone and subsequent internal nucleophilic attack by the phenol oxygen into the pendant carbonyl, followed by dehydration.
  • the route through a Michael reaction, exemplified in Scheme 3C may be achieved by lithiation of the ortho-bromophenol or brominated naphthalene precursors.
  • the dimethylamino thiaflavylium heterocycle 1013 can arise from minor adaptations of the syntheses of the related thiaflavylium, where several routes are available.
  • One option is condensation of the intermediate 1016 with phosphorous chloride and subsequent treatment with perchloric acid.
  • Intermediate 1016 can be achieved thorough 1,4-addition of the dimethylamino benzenethiol into styryl methyl ketone.
  • the sulfone 1014 will be accessed by oxidation of heterocycle 1013 (Scheme 3D).
  • Various pentamethine dyes can be accessed through the base catalyzed condensation of malonaldehyde bis(phenylimine) mono hydrochloride or similar, as was described for the synthesis of Flav5 (4).
  • Trimethine dyes can be accessed through the introduction of a one-carbon electrophile such as formaldehyde, paraformaldehyde, or triethyl orthoformate, as was described for the synthesis of Flav3 (5).
  • Asymmetric dyes i.e., dyes containing two different heterocycles
  • the half-dye can be prepared by treating the activated flavylium heterocycle with 1 equivalent of bis-imine or aldehyde equivalent (such as N-[(3-(anilinomethylene)-2-chloro-l-cyclohexen-l- yl)methylene] aniline hydrochloride) in basic conditions in an appropriate solvent (see Pisoni, D. S.; Ce, A.; Borges, A.; Petzhold, C. L.; Rodembusch, F. S.; Campo, L. F. J. Org. Chem. 2014,
  • bis-imine or aldehyde equivalent such as N-[(3-(anilinomethylene)-2-chloro-l-cyclohexen-l- yl)methylene] aniline hydrochloride
  • Asymmetric polymethine dye comprising the heterocycles disclosed herein, or other suitable heterocycles, may be prepared by these and other suitable methods.
  • the following exemplary asymmetric polymethine dyes may be prepared by the methods disclosed herein:
  • agent is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues.
  • Agents include, for example, agents whose structure is known, and those whose structure is not known. The ability of such agents to inhibit AR or promote AR degradation may render them suitable as“therapeutic agents” in the methods and compositions of this disclosure.
  • A“patient,”“subject,” or“individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).
  • Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results.
  • treatment is an approach for obtaining beneficial or desired results, including clinical results.
  • Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • preventing is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.
  • a condition such as a local recurrence (e.g., pain)
  • a disease such as cancer
  • a syndrome complex such as heart failure or any other medical condition
  • prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount.
  • administering or“administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art.
  • a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct).
  • a compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent.
  • Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
  • a compound or an agent is administered orally, e.g., to a subject by ingestion.
  • the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.
  • the phrase“conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents).
  • the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially.
  • an individual who receives such treatment can benefit from a combined effect of different therapeutic agents.
  • A“therapeutically effective amount” or a“therapeutically effective dose” of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect.
  • the full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a therapeutically effective amount may be administered in one or more administrations.
  • the precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.
  • acyl is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.
  • acylamino is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydroearbylC(0)NH-.
  • acyloxy is art-recognized and refers to a group represented by the general formula hydrocarbylC(0)0-, preferably alkylC(0)0-.
  • alkoxy refers to an alkyl group having an oxygen attached thereto.
  • Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
  • alkyl refers to saturated aliphatic groups, including straight- chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C i-30 for straight chains, C3-30 for branched chains), and more preferably 20 or fewer.
  • alkyl as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc.
  • Cx- y or“Cx-C y ”, when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain.
  • Coalkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.
  • a Ci-6alkyl group for example, contains from one to six carbon atoms in the chain.
  • alkylamino refers to an amino group substituted with at least one alkyl group.
  • alkylthio refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.
  • amide refers to a group
  • R 9 and R 10 each independently represent a hydrogen or hydrocarbyl group, or R 9 and R 10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • amine and“amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by
  • R 9 , R 10 , and R 10 ’ each independently represent a hydrogen or a hydrocarbyl group, or R 9 and R 10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • aminoalkyl refers to an alkyl group substituted with an amino group.
  • aralkyl refers to an alkyl group substituted with an aryl group.
  • aryl as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
  • the ring is a 5- to 7-member ed ring, more preferably a 6-membered ring.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
  • R 9 and R 10 independently represent hydrogen or a hydrocarbyl group.
  • carbocyclylalkyl refers to an alkyl group substituted with a carbocycle group.
  • carbocycle refers to a non aromatic saturated or unsaturated ring in which each atom of the ring is carbon.
  • a carbocycle ring contains from 3 to 10 atoms, more preferably from 5 to 7 atoms.
  • carbocyclylalkyl refers to an alkyl group substituted with a carbocycle group.
  • carbonate is art-recognized and refers to a group -OCO2-.
  • ester refers to a group -C(0)0R 9 wherein R 9 represents a hydrocarbyl group.
  • ether refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.
  • halo and“halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.
  • haloalkyl and“heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.
  • heteroaryl and“hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heteroaryl and“hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
  • heterocyclylalkyl refers to an alkyl group substituted with a heterocycle group.
  • heterocyclyl refers to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heterocyclyl and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
  • Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group.
  • lower when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer.
  • acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).
  • each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
  • sulfate is art-recognized and refers to the group -OSC H, or a pharmaceutically acceptable salt thereof.
  • R 9 and R 10 independently represents hydrogen or hydrocarbyl.
  • sulfoxide is art-recognized and refers to the group-S(O)-.
  • sulfonate is art-recognized and refers to the group SC H, or a pharmaceutically acceptable salt thereof.
  • substitution or“substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substitution or“substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substitution or“substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substitution is contemplated to include all permissible substituents
  • the permissible substituents 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 alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic mo
  • thioalkyl refers to an alkyl group substituted with a thiol group.
  • thioester refers to a group -C(0)SR 9 or -SC(0)R 9
  • R 9 represents a hydrocarbyl
  • thioether is equivalent to an ether, wherein the oxygen is replaced with a sulfur.
  • R 9 and R 10 independently represent hydrogen or a hydrocarbyl.
  • module includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity.
  • pharmaceutically acceptable is art-recognized.
  • the term includes compositions, excipients, adjuvants, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable salt” or“salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients.
  • pharmaceutically acceptable acid addition salt means any non toxic organic or inorganic salt of any base compounds represented by Formula I or Formula II.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form.
  • mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sul
  • the acid addition salts of compounds of Formula I or Formula II are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
  • the selection of the appropriate salt will be known to one skilled in the art.
  • Other non-pharmaceutically acceptable salts e.g., oxalates, may be used, for example, in the isolation of compounds of Formula I or Formula II for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable basic addition salt means any non toxic organic or inorganic base addition salt of any acid compounds represented by Formula I or Formula II or any of their intermediates.
  • Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide.
  • Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art.
  • stereogenic center in their structure.
  • This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30.
  • the disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01/062726.
  • Prodrug or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form the compound of the present disclosure (e.g., compounds of Formula I or Formula II).
  • Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety of the active compound.
  • Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound.
  • prodrugs using ester or phosphoramidate as biologically labile or cleavable (protecting) groups are disclosed in U.S. Patents 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference.
  • the prodrugs of this disclosure are metabolized to produce a compound of Formula I or Formula II.
  • the present disclosure includes within its scope, prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in“Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.
  • phrases“pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter, diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use.
  • log of solubility is used in the art to quantify the aqueous solubility of a compound.
  • the aqueous solubility of a compound significantly affects its absorption and distribution characteristics. A low solubility often goes along with a poor absorption.
  • LogS value is a unit stripped logarithm (base 10) of the solubility measured in mol/liter.
  • deuterium-containing compound of general formula (I) or (II)” and“tritium- containing compound of general formula (I) or (II)” are defined as a compound of general formula (I) or (II), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium and/or tritium atom(s) and in which the abundance of deuterium or tritium at each deuterated or triterated position of the compound of general formula (I) or (II) is higher than the natural abundance of deuterium, which is about 0.015%, or tritium, which is about 1 x 10 18 %.
  • the abundance of deuterium or tritium at each deuterated or triterated position of the compound of general formula (I) or (II) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s). It is understood that the abundance of deuterium or tritium at each deuterated or triterated position is independent of the abundance of deuterium or tritium at other deuterated or triterated position(s).
  • the selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) or (II) may alter the physicochemical properties (such as for example acidity [C. L. Perrin, et al, J. Am. Chem. Soc., 2007, 129, 4490; A. Streitwieser et al, J. Am. Chem. Soc., 1963, 85, 2759;], basicity [C. L. Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641; C. L. Perrin, et al, J. Am. Chem. Soc., 2003, 125, 15008; C. L.
  • deuterium- containing compound of general formula (I) or (II) can have important consequences with respect to the pharmacodynamics, tolerability and efficacy of a deuterium- containing compound of general formula (I) or (II).
  • deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (e.g., Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102).
  • the major effect of deuteration is to reduce the rate of systemic clearance.
  • Deuterated drugs showing this effect may have reduced dosing requirements (e.g., lower number of doses or lower dosage to achieve the desired effect) and/or may produce lower metabolite loads.
  • deuterated or triturated compounds of the disclosure may have other advantageous features, such as an increased quantum yield. This may result from alterations to the available molecular vibrational modes that can reduced coupling between optical and vibrational transitions, thus reducing the rate of intersystem conversion.
  • deuterated reagents and synthetic building blocks are commercially available from companies such as for example C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA. Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA. Further information on the state of the art with respect to deuterium-hydrogen exchange is given for example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990; R. P. Hanzlik et al., Biochem. Biophys. Res. Commun.
  • compositions and methods of the present invention may be utilized to treat an individual in need thereof.
  • the individual is a mammal such as a human, or a non-human mammal.
  • the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as an eye drop.
  • a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • the choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
  • the preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self- microemulsifying drug delivery system.
  • the pharmaceutical composition also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention.
  • Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin, or as an eye drop).
  • routes of administration including, for example, orally (for example, drenches as in aqueous or
  • the compound may also be formulated for inhalation.
  • a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient (e.g., dye) which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients.
  • an active compound such as a compound of the invention
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • Compositions or compounds may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents,
  • pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above- described excipients.
  • Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art,
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds (e.g., dyes) with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • active compounds e.g., dyes
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment.
  • compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine.
  • Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the active compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
  • Exemplary ophthalmic formulations are described in U.S. Publication Nos. 2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference.
  • liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatible with such fluids.
  • a preferred route of administration is local administration (e.g ., topical administration, such as eye drops, or administration via an implant).
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
  • active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Methods of introduction may also be provided by rechargeable or biodegradable devices.
  • Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals.
  • a variety of biocompatible polymers including hydrogels, including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • therapeutically effective amount is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention.
  • a larger total dose can be delivered by multiple administrations of the agent.
  • Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).
  • a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.
  • the patient receiving this treatment is any animal in need, including primates, in particular humans; and other mammals such as equines, cattle, swine, sheep, cats, and dogs; poultry; and pets in general.
  • compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.
  • contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra- alkyl ammonium salts.
  • contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, lH-imidazole, lithium, L-lysine, magnesium, 4-(2- hydroxyethyljmorpholine, piperazine, potassium, 1 -(2-hydroxy ethyljpyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts.
  • contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, 1 -hydroxyl- naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4- acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, 1-ascorbic acid, 1-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane
  • the pharmaceutically acceptable acid-addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared.
  • the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha- tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • Dye 6 was purified via silica gel chromatography and reverse-phase HPLC. Via silica gel chromatography, dye 6 was eluted with a DCM/MeOH solvent gradient of 400: 1, 200: 1, 167: 1, 143: 1, 125: 1, 111 : 1, 67: 1, and 33: 1. The most pure fractions were further purified in aliquots by HPLC in a water/MeCN with 0.1% TFA solvent mixture. The method used is as follows: 70:30 for 2 m, gradient to 30:70 over 60 m, gradient to 5:90 over 20 m, followed by a hold for 5 m and subsequent re-equilibration to 70:30 for 10 m.
  • the absorbance spectra in Figure 2 and Figures 4A-4G were obtained in DCM on a JASCO V-770 UV-Visible/NIR spectrophotometer with a 2000 nm/min or 4000 nm/mm scan rate. Plotted are the baseline corrected and normalized data.
  • the emission spectra in Figure 2 were taken in DCM on either a Horiba Instruments PIT QuantaMaster Series fluorometer (6), a Fluoromax-3 spectrofluorometer (1, 3 - 5), or home-built InGaAs array detector (Princeton Instruments). For 6 the following parameters were used: ex.
  • Flav 7 3, IR-26, and IR-1061 were diluted in DCM until matching absorbance was achieved at 808 nm.
  • Spatially dispersed 808nm illumination was used to image lml samples in 2.5 mL cuvettes of the SWIR dyes alongside a DCM blank. Each dye was compared at the same position to ensure consistent camera illumination.
  • SWIR images were collected on an InGaAs camera (Princeton Instruments, NIRvana 640) with a lOOOnm long-pass filter. The camera was cooled to -80 °C, the analog to digital (AD) conversion rate set to 2 MHz, the gain set to high, and different exposure times used to achieve sufficient signal and/or frame rates.
  • AD analog to digital
  • Symmetric polymethine dyes may be prepared from their respective heterocycles, for example, by the procedure of Schemes 4-5 (Angew. Chemie Int. Ed. 2017, 56, 13126-13129; Chem. Eur. J. 2017, 23, 9306-9312; ChemPhysChem. 2010, 11, 130-138).
  • Azetidine (0.034 mL, 0.50 mmol, 2.8 equiv.) was added by two 0.017 mL portions, initially and after 2.5 h.
  • the reaction mixture was extracted with dichloromethane/water, dried with MgSCL, filtered, and evaporated.
  • the crude product was purified with a 10: 1 to 2: 1 hexanes/EtOAc solvent gradient to yield a yellow solid (26.7 mg, 0.100 mmol, 63%).
  • Rf 0.5 in 1 : 1 hexanes/EtOAc.
  • the reaction mixture was freeze-pump-thawed x3, and heated to 100 °C for 10 min.
  • the crude mixture was evaporated onto silica gel and purified via column chromatography with a gradient of dicholoromethane plus 0.5-6% ethanol, followed by chromatography with dichloromethane plus 1-2% ethanol.
  • the procedure yielded an iridescent maroon solid (4.6 mg, 0.0059 mmol, 37%).
  • Rf 0.5 in 9: 1 DCM/EtOH.
  • reaction mixture was quenched with several drops of fluoroboric acid (5%, aqueous), extracted with dichloromethane after adding more 5% HBF 4 , quickly washed with brine, dried with NaiSCh, filtered, and evaporated.
  • fluoroboric acid 5%, aqueous
  • dichloromethane 5%, aqueous
  • the crude product was purified by trituration and filtration from cold EtOAc, yielding a dark purple solid (140 mg, 0.347 mmol, 74%).
  • Acetic anhydride (4.0 mL) was added and the solution was freeze-pump-thawed x3 before heating to 100 °C for 60 min. The reaction was cooled, ⁇ 10 mL of toluene was added, and the product was collected by vacuum filtration. The product was rinsed with toluene until filtrate runs clear, followed by a water rinse. The product was further purified by column chromatography, after dry-loading onto silica, in a three-way gradient of 1 : 1 toluene/dichloromethane plus 1% ethanol to 0: 1 toluene/dichloromethane plus 20% ethanol.
  • reaction mixture was quenched with fluoroboric acid (5%, aqueous, -1.5 mL), extracted with dichloromethane/water, dried with Na2S04, filtered, and evaporated.
  • fluoroboric acid 5%, aqueous, -1.5 mL
  • dichloromethane/water extracted with dichloromethane/water
  • Na2S04 filtered
  • evaporated The crude product was purified by trituration in EtOAc to yield a dark red solid (104 mg, 0.275 mmol, 81%).
  • a-naptho-4-methyl flavylium tetrafluoroborate (4-methyl-2-phenylbenzo[/?]chromen- 1 -ium tetrafluoroborate): a-napthoflavone (2-phenyl-4//-benzo[/?]chromen-4-one) (201.4 mg, 0.740 mmol, 1.0 equiv.) was added to a flame-dried 50 mL 2 neck flask and dissolved in THF (7 mL) under a N2 atmosphere and cooled to 0 °C.
  • Methylmagesium bromide (1.15 M, 1.6 mL, 2.5 equiv.) was added dropwise, the solution was warmed to room temperature and it was stirred overnight. The reaction was quenched with 4 mL of 5% HBF4 and the resulting filtrate was filtered and rinsed with ethyl acetate to yield a lime green solid (242.9 mg, 0.678 mmol, 92%).
  • tetrafluoroborate a-naptho-4-methyl flavylium tetrafluoroborate (40.1 mg, 0.112 mmol, 1.0 equiv.), A'-[(3-(anilinomethylene)-2-chloro- l - cyclohexen-l-yl)methylene]aniline hydrochloride (19.6 mg, 0.055 mmol, 0.49 equiv.), and 2,6-di-/er/-butyl-4-methylpyridine (60.9 mg, 0.297 mg, 2.7 equiv.) were added to a flame-dried 25 mL Schlenk flask under N2 atmosphere.
  • Polymethine dyes disclosed herein are characterized with respect to their photophysics including absorption, emission, extinction coefficient, quantum yields, and fluorescence lifetime. All quantum yields values obtained are absolute quantum yields values measured using an integrating sphere. Photostabilities are evaluated by sample irradiation with high powered LEDs. Additionally, solvatochromism, solvent compatibility, and stability are assessed.
  • Example 5 Further Exemplary Preparation of Dimethylaminoflavylium Dyes
  • Triflic anhydride (0.14 mL, 0.8 mmol, 4 eq) was added slowly dropwise to a solution of 5- hydroxyflavone (50 mg, 0.2 mmol, 1 eq) in anhydrous pyridine (1.0 mL, 12 mmol, 60 eq) at 0 °C.
  • the reaction was warmed to room temperature and left to stir for 1 hr.
  • the solution was quenched with saturated NaHCC (5 mL), extracted with ethyl acetate (3 x 10 mL), dried over NaSCL, filtered and evaporated to give a yellow crystalline solid.
  • the crude filtrate was purified via silica gel chromatography with dichloromethane: ethanol (99.5: 0.5 -> 99.25: 0.75 -> 99: 1 ->99.75: 1.25) to afford pure 5-Flav7 as a dark green-brown soild.
  • Triflic anhydride (0.25 mL, 4.4 mmol, 4 eq) was added slowly dropwise to a solution of 6- hydroxyflavone (150 mg, 1.0 mmol, 1 eq) in anhydrous pyridine (3.0 mL, 36 mmol, 60 eq) at 0 °C.
  • the reaction was warmed to room temperature and left to stir for 1 hr.
  • the solution was quenched with saturated NaHCC (5 mL), extracted with ethyl acetate (3 x 10 mL), dried over NaSCL, filtered and evaporated to give an orange solid.
  • 6-(dimethylamino)-2-phenyl-4H-chromen-4-one 2a 50 mg, 0.35 mmol, 1 eq was dissolved in anhydrous THF (4.1 mL)and cooled to 0 °C.
  • MeMgBr 1.0 M in THF, 0.7 mL, 0.7 mmol, 2 eq was added dropwise over 30 min turning the solution from yellow to orange brown. Reaction was warmed to room temperature and left to stir overnight.
  • the crude product was purified via silica gel chromatography with dichloromethane: ethanol (99.25: 0.75 -> 99: 1 -> 98.75: 1.25 ->98.5: 1.5) to afford pure 6-Flav7 as a dark purple- black solid.
  • Ethyl 3-oxo-3-(4-(trifluoromethyl)phenyl)propanoate la 160 mg, 0.63 mmol, 1.8 equiv.
  • 3-(dimethylamino)phenol 49 mg, 0.36 mmol, 1.0 equiv.
  • the solution was cooled to rt and evaporated onto silica gel.
  • the crude product was purified via column chromatography, eluting with a 20: 1 hexanes/EtOAc gradient to yield a yellow solid (55 mg, 0.17 mmol, 46 %).
  • Flavone 2a (203 mg, 0.61 mmol, 1.0 equiv.) was dissolved in THF (5.9 mL) in a 25 mL double-neck round bottom flask and cooled to 0 °C. Methylmagnesium bromide was added dropwise (1.5 mL, 1.0 M in THF, 2.5 equiv.) and the solution was warmed to rt and stirred for 24 h.
  • Flavone 2b (117 mg, 0.340 mmol, 1.0 equiv.) was dissolved in THF (3.3 mL) in a 15 mL double-neck round bottom flask and cooled to 0 °C. Methylmagnesium bromide was added dropwise (0.85 mL, 1.0 M in THF, 2.5 equiv.) and the solution was warmed to rt and stirred for 24 h. The reaction was quenched by dropwise addition of 5% HBF4 on ice, extracted with dichloromethane, dried with Na2SC>4, filtered, and evaporated.
  • Flavone 2c (95 mg, 0.32 mmol, 1.0 equiv.) was dissolved in THF (3.1 mL) in a 15 mL double-neck round bottom flask and cooled to 0 °C. Methylmagnesium bromide was added dropwise (0.79 mL, 1.0 M in THF, 2.5 equiv.) and the solution was warmed to rt and stirred for 24 h. The reaction was quenched by dropwise addition of 5% HBF4 on ice, extracted with dichloromethane, dried with Na2SC>4, filtered, and evaporated.
  • Flavone 2d (80 mg, 0.28 mmol, 1.0 equiv.) was dissolved in THF (2.8 mL) in a 15 mL double-neck round bottom flask and cooled to 0 °C. Methylmagnesium bromide was added dropwise (0.71 mL, 1.0 M in THF, 2.5 equiv.) and the solution was warmed to rt and stirred for 24 h. The reaction was quenched by dropwise addition of 5% HBF4 on ice, extracted with dichloromethane, dried with Na2SC>4, filtered, and evaporated.
  • Flavone 2e (87 mg, 0.33 mmol, 1.0 equiv.) was dissolved in THF (3.1 mL) in a 15 mL double-neck round bottom flask and cooled to 0 °C. Methylmagnesium bromide was added dropwise (0.78 mL, 1.0 M in THF, 2.5 equiv.) and the solution was warmed to rt and stirred for 24 h. The reaction was quenched by dropwise addition of 5% HBF4 on ice, extracted with dichloromethane, dried with Na2SC>4, filtered, and evaporated. The crude product was triturated with ice cold ethyl acetate and vacuum filtered to produce a purple solid (77 mg, 0.21 mmol, 67 %). Absorbance (CH2CI2): 513 nm.
  • Flavone 2f (25 mg, 0.084 mmol, 1.0 equiv.) was dissolved in THF (0.82 mL) in a 15 mL double-neck round bottom flask and cooled to 0 °C. Methylmagnesium bromide was added dropwise (0.21 mL, 1.0 M in THF, 2.5 equiv.) and the solution was warmed to rt and stirred for 24 h. The reaction was quenched by dropwise addition of 5% HBF4 on ice, extracted with dichloromethane, dried with Na2SC>4, filtered, and evaporated.
  • Flavone 2g (21 mg, 0.068 mmol, 1.0 equiv.) was dissolved in THF (0.63 mL) in a 15 mL double-neck round bottom flask and cooled to 0 °C. Methylmagnesium bromide was added dropwise (0.17 mL, 1.0 M in THF, 2.5 equiv.) and the solution was warmed to rt and stirred for 24 h.
  • Flavylium 3a 31 mg, 0.074 mmol, 1.0 equiv.
  • A'-[(3-(anilinomethylene)-2-chloro- l - cyclohexen-l-yl)methylene]aniline hydrochloride (12.7 mg, 0.035 mmol, 0.48 equiv.)
  • sodium acetate (18 mg, 0.22 mmol, 3 equiv.) were dissolved in a mixture of «-butanol (0.47 mL) and toluene (0.2 mL) in a 25 mL Schlenk flask and heated to 105 °C for 30 minutes. The solution was cooled to rt and evaporated onto silica gel.
  • Flavylium 3f (18 mg, 0.047 mmol, 1.0 equiv.), /V-[(3-(anilinomethylene)-2-chloro-l- cyclohexen-l-yl)methylene]aniline hydrochloride (8 mg, 0.002 mmol, 0.48 equiv.), and sodium acetate (12 mg, 0.14 mmol, 3.0 equiv.) were dissolved in a mixture of «-butanol (0.3 mL) and toluene (0.1 mL) in a 25 mL Schlenk flask and heated to 105 °C for 20 minutes. The solution was cooled to rt and evaporated onto silica gel.
  • Flavylium 3g (10 mg, 0.03 mmol, 1.0 equiv.), /V-[(3-(anilinomethylene)-2-chloro-l- cyclohexen-l-yl)methylene]aniline hydrochloride (4 mg, 0.01 mmol, 0.48 equiv.), and sodium acetate (6 mg, 0.08 mmol, 3 equiv.) were dissolved in a mixture of «-butanol (205 pL) and toluene (86 pL) in a 25 mL Schlenk flask and heated to 100 °C for 35 minutes. The solution was cooled to rt and evaporated onto silica gel.
  • 3-(dimethylamino)phenol (299 mg, 2.18 mmol, 1.00 equiv.) and ethyl pivaloylacetate (700 pL, 3.93 mmol, 1.00 equiv.) were combined in an oven-dried 1 dram vial and heated at 180 °C for 40 h. The solution was cooled to room temperature, evaporated onto silica, and purified via column chromatography with a 10: 1 to 4: 1 hexanes/EtOAc gradient.
  • the product was extracted into dicholormethane with the addition of 5% fluoroboric acid, dried with Na2S04, filtered, and evaporated.
  • the product was purified by precipitation upon addition of cold EtOAc, filtration and rinsing with cold EtOAc to obtain a magenta solid (268 mg, 0.669 mmol, 81%).
  • DMSO-d6 d 156.1, 155.3, 154.1, 148.9, 145.5, 131.5, 131.1, 129.1, 126.0, 125.8, 115.3, 113.1,
  • Acetic anhydride (3.5 mL) was added and the solution was freeze-pump-thawed x3 before heating to 120 °C for 60 min. The reaction was cooled, ⁇ 14 mL of toluene was added, and the product was collected by vacuum filtration. The product was rinsed with toluene until filtrate runs clear, followed by a water rinse. The product was further purified by column chromatography, after dry-loading onto silica, in a three-way gradient of 1 : 1 toluene/dichloromethane plus 1% ethanol to 0: 1 toluene/dichloromethane plus 12% ethanol.
  • Acetic anhydride (3.5 mL) was added and the solution was freeze-pump-thawed x3 before heating to 100 °C for 60 min. The reaction was cooled, ⁇ 10 mL of toluene was added, and the product was collected by vacuum filtration. A bronze solid resulted (111 mg, 0.155 mmol, 81%).
  • Toluene (2.1 mL) and n-butanol (4.8 mL) were added and the solution was freeze-pump-thawed x3 before heating to 100 °C for 3 h. The reaction was cooled and evaporated. The product was precipitated in toluene and collected by vacuum filtration, washing with -200 mL toluene, -50 mL trifluorotoluene, -50 mL cold THF. The product was further purified by column chromatography after dry-loading onto silica in dichloromethane plus a gradient of 0.5-5% ethanol.

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Abstract

La présente invention concerne des colorants à base de polyméthine à petites molécules à activité SWIR et NIR ayant des propriétés améliorées pour une utilisation dans l'imagerie optique, la thérapie photothermique, la thérapie photodynamique.
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