Near-infrared glucose sensor

Abstract

Provided are glucose sensing luminescent dyes, polymers, and sensors. In addition, provided are systems comprising the sensors and methods of using the sensors and systems.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 690,657, filed June 27, 2018, the contents of which are hereby incorporated by reference in their entirety for all purposes. This application is related to U.S. Provisional Patent Application Nos. 62 / 439,363 and 62 / 439,364, filed December 27, 2016, U.S. Patent Application No. 15 / 855,555, filed December 27, 2017, and International Patent Application No. PCT / US17 / 68531, filed December 27, 2017, the contents of each of which are hereby incorporated by reference in their entirety. Technical Field

[0003] The present disclosure is in the field of luminescent dyes, polymers, and biosensors. Background Art

[0004] Diagnosis, treatment and management of diabetes and certain metabolic disorders require monitoring of glucose concentration in the blood. Despite many advances in minimally invasive blood glucose monitoring, currently used methods are expensive, cumbersome, time-consuming and do not provide accurate real-time blood glucose concentration information. Therefore, there is a need for better long-term minimally invasive glucose monitoring systems. It is necessary to do this in a non-invasive manner with minimal user maintenance, and in real-world user environments, a sensor life of several days to several months is critical.

[0005] This real-time continuous measurement of the glucose concentration in the blood can be achieved by using a sensor inserted or implanted into the tissue, and by measuring the signal generated by the sensor through a device located outside the body. Luminescence provides a useful tool for designing this type of sensor. Sensors that are monitored optically through the skin require highly stable dyes with excitation and emission spectra in the near-infrared (NIR) optical window of the skin. These dye properties are crucial for successfully designing luminescent sensors that can be deeply implanted into the tissue. Monitoring through the skin in a non-invasive manner requires using dyes with excitation and emission wavelengths in the optical window of the skin (about 550 to 1100 nm) to minimize light scattering and absorption, and to achieve a high signal-to-noise ratio. Currently used dyes need to be excited with light that is mostly absorbed by the skin and underlying tissue. In addition, currently available sensors are made of rigid materials that are greatly different from the mechanical properties of the tissues into which they are implanted, are bulky and inconvenient, and can induce a series of biological events after implantation, which ultimately lead to the formation of a fibrous capsule separating the sensor from the body.

[0006] There is a need for glucose sensing compositions that are near-infrared detectable, particularly in vivo, and suitable for long-term minimally invasive implantation into tissue. Summary of the Invention

[0007] Disclosed herein are luminescent dyes, polymers comprising the dyes, and sensors comprising the polymers.

[0008] One aspect pertains to compounds of Formula I-IIIH and compositions as disclosed herein.

[0009] One aspect pertains to compounds and compositions of Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB or AIII as disclosed herein.

[0010] In one aspect, the present disclosure relates to a compound of formula IV-I:

[0011]

[0012] or an isomer, tautomer, solvate or salt thereof, wherein:

[0013] R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 11 、R 12 and R 14 Each is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C 10 Heteroalkyl, halogen, -C(O)R', -COOR', -C(O)NH2, -C(O)NR'R", -CF3, -CN, -SO3H, -SO2CF3, -SO2R', -SO2NR'R", -N(R')2, -N(R')3 + , -NO2, -OR', -NHC(O)R', -OC(O)R' or phenyl, wherein R' and R" are each independently H or C1-C6 alkyl; or R' and R" together with the nitrogen atom form a 5- or 6-membered heterocyclic ring optionally containing one additional heteroatom selected from S, O or N;

[0014] R 2 and R 15 Each independently is H or C1-C6 alkyl;

[0015] R 9 and R 10 are independently H, C1-C6 alkyl or -NHC(O)C(CH3)CH2;

[0016] L 1 and L 3 is independently a bond or a linker group selected from the group consisting of: optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20 heteroalkylene, optionally substituted -(CH2CH2O) n CH2-, optionally substituted -CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O)nCH2CH2-, optionally substituted -CH2CH2(CH2CH2O) n -, optionally substituted (CH2CH2O) n -, where n is an integer between 1 and 10;

[0017] L 2 is a bond; optionally substituted phenylene; optionally substituted -alkylene-phenylene-; optionally substituted -phenylene-alkylene-; or optionally substituted 5- or 6-membered heteroarylene;

[0018] Y 1 Selected from -P(O)(R d )-、-Ge(R d )(R e )-or-Si(R d )(R e )-, where R d and R e Each is H, -OH, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy or C6-C 10 aryloxy;

[0019] R 20 、R 21 、R 23 and R 24 are each independently H; optionally replaced by -NH2 or -NH3 + Substituted C1-C6 alkyl; C2-C6 alkenyl; or optionally substituted by -B(OR 2 )2 substituted benzyl;

[0020] R 22 、R 25 、R 26 and R 27 Each independently is H or C1-C6 alkyl;

[0021] Alternatively, (R 21 and R 20) and / or (R 23 and R 24 ) together with the nitrogen atom to which they are attached, form a 6-, 5- or 4-membered saturated or partially saturated ring;

[0022] Alternatively, (R 21 and R 22 )、(R 24 and R 25 )、(R 23 and R 27 ) and / or (R 26 and R 20 ) together with the atoms to which they are attached form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring.

[0023] In one embodiment of the compound of formula (IV-I), Y 1 Yes-P(O)(R d )-. In one embodiment, Y 1 Yes-P(O)(R d )-, and R d It is –OH or C1-C6 alkoxy.

[0024] In one embodiment of the compound of formula (IV-I), Y 1 Yes-Ge(R d )(R e )-or-Si(R d )(R e )-, where R d and R e Each is H, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy or C6-C 10 Aryloxy.

[0025] In some embodiments of the compound of Formula (IV-I), the compound is not compounds 27, 54, 63, 64, 65, 66, 67, 69, 73, 74, 75, 76, 77, 81, 82, and 83 of Table 1.

[0026] In some embodiments of the compound of Formula (IV-I), the compound has the structure of Formula (IV-IA):

[0027]

[0028] or an isomer, tautomer, solvate or salt thereof, wherein:

[0029] R 1 、R 3 、R 4 、R 5 、R 6、R 7 、R 8 、R 11 、R 12 and R 14 Each is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C 10 Heteroalkyl, halogen, -C(O)R', -COOR', -C(O)NH2, -C(O)NR'R", -CF3, -CN, -SO3H, -SO2CF3, -SO2R', -SO2NR'R", -N(R')2, -N(R')3 + , -NO2, -OR', -NHC(O)R', -OC(O)R' or phenyl;

[0030] R' and R" are each independently H or C1-C6 alkyl; or R' and R" together with the nitrogen atom to which they are attached may form a 5- or 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains one additional heteroatom selected from S, O or N;

[0031] R d and R e Each is H, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy or C6-C 10 aryloxy;

[0032] R 2 and R 15 Each independently is H or C1-C6 alkyl;

[0033] R 9 and R 10 are independently H, C1-C6 alkyl or -NHC(O)C(CH3)CH2;

[0034] L 1 and L 3 is independently a bond or a linker group selected from the group consisting of: optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20 heteroalkylene, optionally substituted -(CH2CH2O) n CH2-, optionally substituted -CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O)nCH2CH2-, optionally substituted -CH2CH2(CH2CH2O) n -, optionally substituted (CH2CH2O) n -, where n is an integer between 1 and 5;

[0035] L 2 is a bond; optionally substituted phenylene; optionally substituted -alkylene-phenylene-; optionally substituted -phenylene-alkylene-; or optionally substituted 5- or 6-membered heteroarylene;

[0036] R 20 、R 21 、R 23 and R 24 are each independently H; optionally replaced by -NH2 or -NH3 + Substituted C1-C6 alkyl; C2-C6 alkenyl; or optionally substituted by -B(OR 2 )2 substituted benzyl;

[0037] R 22 、R 25 、R 26 and R 27 Each independently is H or C1-C6 alkyl;

[0038] Alternatively, (R 21 and R 20 ) and / or (R 23 and R 24 ) together with the nitrogen atom to which they are attached, form a 6-, 5- or 4-membered saturated or partially saturated ring;

[0039] Alternatively, (R 21 and R 22 )、(R 24 and R 25 )、(R 23 and R 27 ) and / or (R 26 and R 20 ) together with the atoms to which they are attached form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring.

[0040] In some embodiments of the compound of formula (IV-I), the compound has the structure of formula (IV-IB):

[0041]

[0042] or an isomer, tautomer, solvate or salt thereof, wherein:

[0043] R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 11 、R 12 and R14 Each is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C 10 Heteroalkyl, halogen, -C(O)R', -COOR', -C(O)NH2, -C(O)NR'R", -CF3, -CN, -SO3H, -SO2CF3, -SO2R', -SO2NR'R", -N(R')2, -N(R')3 + , -NO2, -OR', -NHC(O)R', -OC(O)R' or phenyl;

[0044] R' and R" are each independently H or C1-C6 alkyl; or optionally, R' and R" in -SO2NR'R" may form together with the nitrogen atom to which they are attached a 5- or 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains one additional heteroatom selected from S, O or N;

[0045] R d and R e Each is H, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy or C6-C 10 aryloxy;

[0046] R 2 and R 15 Each independently is H or C1-C6 alkyl;

[0047] R 9 and R 10 are independently H, C1-C6 alkyl or -NHC(O)C(CH3)CH2;

[0048] L 1 and L 3 is independently a bond or a linker group selected from the group consisting of: optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20 heteroalkylene, optionally substituted -(CH2CH2O) n CH2-, optionally substituted -CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O)nCH2CH2-, optionally substituted -CH2CH2(CH2CH2O) n -, optionally substituted (CH2CH2O) n -, where n is an integer between 1 and 5;

[0049] L 2is a bond; phenylene optionally substituted by at least one substituent selected from C1-C3 alkyl, C1-C3 alkoxy or halogen; optionally substituted -C1-C3 alkylene-phenylene-; optionally substituted -phenylene-C1-C3 alkylene-;

[0050] R 20 、R 21 、R 23 and R 24 are each independently H; optionally replaced by -NH2 or -NH3 + Substituted C1-C6 alkyl; C2-C6 alkenyl; or optionally substituted by -B(OR 2 )2 substituted benzyl;

[0051] R 22 、R 25 、R 26 and R 27 Each independently is H or C1-C6 alkyl;

[0052] Alternatively, (R 21 and R 20 ) and / or (R 23 and R 24 ) together with the nitrogen atom to which they are attached, form a 6-, 5- or 4-membered saturated or partially saturated ring;

[0053] Alternatively, (R 21 and R 22 )、(R 24 and R 25 )、(R 23 and R 27 ) and / or (R 26 and R 20 ) together with the atoms to which they are attached form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring; and

[0054] When L 2 When it is a key, R 20 、R 21 、R 23 and R 24 At least one of is optionally replaced by -B(OR 2 )2 substituted benzyl;

[0055] Provided that the compound is not compounds 27, 54, 63, 64, 65, 66, 67, 69, 73, 74, 75, 76, 77, 81, 82 and 83.

[0056] In one embodiment of the compound of Formula IV-I, IV-IA, IV-IB, IV, IVA and / or IVB, L2 is selected from a bond, an optionally substituted phenylene, an optionally substituted -alkylene-phenylene-, an optionally substituted -phenylene-alkylene-, or an optionally substituted 5- or 6-membered heteroarylene; wherein the optional substituent is halogen, C1-C3 alkyl, or C1-C3 alkoxy. In one embodiment, L 2 Select from key, In one embodiment, L 2 yes Each is optionally substituted.

[0057] In one embodiment of the compound of Formula IV-I, IV-IA, IV-IB, IV, IVA and / or IVB, L 2 is a bond, optionally substituted phenylene or optionally substituted 5- or 6-membered heteroarylene.

[0058] In one embodiment of the compound of Formula IV-I, IV-IA, IV and / or IVA, L 2 is a bond, optionally substituted phenylene or optionally substituted 5- or 6-membered heteroarylene.

[0059] In one embodiment of the compounds of Formula IV-I, IV-IB, IV and / or IVB, L 2 is a bond; phenylene optionally substituted by at least one substituent selected from C1-C3 alkyl, C1-C3 alkoxy or halogen;

[0060] In one embodiment of the compound of Formula IV-I, IV-IA, IV-IB, IV, IVA or IVB, R d and R e Each is a methyl group.

[0061] In one embodiment of the compound of Formula IV-I, IV-IA, IV-IB, IV, IVA or IVB, R 10 is -NHC(O)C(CH3)CH2. In some embodiments of the compound of Formula IV-I, IV-IA, IV-IB, IV, IVA or IVB, R 9 It is -NHC(O)C(CH3)CH2.

[0062] In one embodiment of the compound of Formula IV-I, IV-IA, IV-IB, IV, IVA or IVB, L 1 It is C1-C 10 Alkylene, C2-C 20Heteroalkylene, -(CH2CH2O) n CH2-, -(CH2CH2O) n CH2CH2- or -(CH2CH2O) n In some embodiments of the compound of Formula IV-I, IV-IA, IV-IB, IV, IVA or IVB, L 3 It is C1-C 10 Alkylene, C2-C 20 Heteroalkylene, -CH2(CH2CH2O) n -、-CH2CH2-(CH2CH2O) n 、-(CH2CH2O) n CH2-, -(CH2CH2O) n CH2CH2- or -(CH2CH2O) n In some embodiments of the compound of Formula IV-I, IV-IA, IV-IB, IV, IVA or IVB, L 1 and L 3 It is –CH2-CH2-CH2- or -(CH2CH2O)4CH2CH2-.

[0063] In one embodiment of the compound of Formula IV-I, IV-IA, IV-IB, IV, IVA or IVB, R 11 、R 14 and R 12 is H. In some embodiments of the compound of Formula IV-I, IV-IA, IV-IB, IV, IVA or IVB, R 22 、R 25 、R 26 and R 27 It’s H.

[0064] In one embodiment of the compound of Formula IV-I, IV-IA, IV-IB, IV, IVA or IVB, R 3 、R 4 、R 7 and R 8 is selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, -SO2NR'R", -CN and -NO2. In some embodiments of the compound of Formula IV-I, IV-IA, IV-IB, IV, IVA or IVB, R 3 、R 4 、R 7 and R 8 At least one of the following is selected from methyl, -CF3, methoxy, halogen, -SO2N(Me)2, -SO2NHMe, -CN, -NO2 and In some embodiments of the compound of Formula IV-I, IV-IA, IV-IB, IV, IVA, or IVB, R 2 and R 15 Each is H.

[0065] In one embodiment of the compound of Formula IV-I, IV-IA, IV-IB, IV, IVA or IVB, R 20 、R 21 、R 23 and R 24 are each independently H; optionally replaced by -NH2 or -NH3 + substituted C1-C4 alkyl; C2-C4 alkenyl; or optionally substituted by -B(OR 2 )2 substituted benzyl; or alternatively, (R 21 and R 22 )、(R 24 and R 25 )、(R 23 and R 27 ) and / or (R 26 and R 20 ) together with the atoms to which they are attached form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring.

[0066] In one embodiment of the compound of Formula IV-I, IV-IA, IV-IB, IV, IVA or IVB, R 20 、R 21 、R 23 and R 24 are each independently H, C1-C6 alkyl or optionally substituted by -B(OR 2 )2-substituted benzyl.

[0067] In one embodiment of the compound of Formula IV-I, IV-IA, IV-IB, IV, IVA and / or IVB, the compound is selected from Table 1. In one embodiment of the compound of Formula IV-I, IV-IA, IV-IB, IV, IVA and / or IVB, the compound is selected from Table 2. In one embodiment of the compound of Formula IV-I, IV-IA, IV-IB, IV, IVA and / or IVB, the compound is selected from Table 3.

[0068] In one aspect, the disclosure relates to a composition comprising a compound of Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, AIIIE, IV-I, IV-IA, IV-IB, IV, IVA and / or IVB.

[0069] Exemplary NIR dye moieties of the compounds disclosed herein are selected from cyanine, hemicyanine, fluorone, oxazine, phenanthidine, rhodamine, rosamine, indolium, quinolinium, benzophenoxazine, benzopyrylium, bisindolylmaleimide, boron-dipyrromethene, boron-aza-dipyrromethene, carbopyronin, perylene, porphyrin, ruthenium complex, lanthanide complex, benzoxanthenium, xanthene, fluorescein, squarylium, coumarin, anthracene, tetracene, pentacene, and pyrene dyes.

[0070] In some cases, the NIR dye moiety has a structure selected from the group consisting of:

[0071]

[0072] where R N1 and R N2 is independently a C1-C ... 10 Alkyl, and the wavy line indicates L 2 connection point.

[0073] In other embodiments, the NIR dye moiety has the structure:

[0074]

[0075] wherein R' at each occurrence is independently H, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl or optionally substituted C2-C 20 Heteroalkyl.

[0076] In other embodiments, the NIR dye moiety has the structure:

[0077]

[0078] where Y 1 is selected from O, P(O)R', SiR'R", and NR', wherein R' and R" are independently H or C1-C6 alkyl;

[0079] R 20 and R 21 are independently H, C1-C6 alkyl, or R 21 and R 20 Together with the nitrogen atom to which they are attached, they form a 6- or 5-membered ring optionally substituted with a polymerizable moiety;

[0080] R 23 and R 24are independently H, C1-C6 alkyl, or R 23 and R 24 Together with the nitrogen atom to which they are attached, they form a 6- or 5-membered ring optionally substituted with a polymerizable moiety;

[0081] R 22 and R 25 are independently H, C1-C6 alkyl, or R 21 and R 22 Together with the atoms to which they are attached, they form a 6- or 5-membered ring, or R 24 and R 25 Together with the atoms to which they are attached, they form a 6- or 5-membered ring; and

[0082] R 26 and R 27 are independently H, C1-C6 alkyl, or R 26 and R 20 Together with the atoms to which they are attached, they form a 6- or 5-membered ring, or R 27 and R 23 Together with the atoms to which they are attached, they form a 6- or 5-membered ring.

[0083] In certain embodiments, Y 1 It's SiMe2.

[0084] In some embodiments of the compounds disclosed herein, Z is optionally substituted phenylene or anthracene.

[0085] Another aspect relates to a polymer comprising as a monomeric repeating unit a residue of a compound of Formula I-IIIH, AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, AIIIE, IV-I, IV-IA, IV-IB, IV, IVA or IVB. The polymers provided herein can be luminescent biocompatible hydrogels.

[0086] Another aspect relates to various luminescent sensors comprising the polymers provided herein for detecting an analyte, such as glucose, in vivo or in vitro. The sensor can be in the form of a powder, fabric (eg, a bandage), needle, rod, disc, or any other suitable form.

[0087] In some embodiments, the luminescent sensors provided herein are tissue-integrated, or include a tissue-integrated scaffold, and generate a detectable signal in the presence of an analyte, e.g., when placed (e.g., implanted) into a subject's tissue, the sensor provides for detection of the analyte. Tissue-integrated sensors as described herein can provide for long-term detection of one or more analytes.

[0088] In some embodiments, the compound of Formula I-IIIH, AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, AIIIE, IV-I, IV-IA, IV-IB, IV, IVA, or IVB has excitation and emission spectra in the NIR optical window of mammalian skin. In some embodiments, the compound of Formula I-IIIH, AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, AIIIE, IV-I, IV-IA, IV-IB, IV, IVA, or IVB has excitation and emission wavelengths in the NIR optical window of mammalian skin.

[0089] In some embodiments of a compound of Formula I-IIIH, AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, AIIIE, IV-I, IV-IA, IV-IB, IV, IVA, or IVB, the compound has an absorption maximum between about 500 nm and about 900 nm and an emission maximum between about 600 nm or about 1000 nm.

[0090] In one aspect, the present disclosure relates to a sensor for detecting an analyte comprising a polymer, wherein the polymer comprises one or more residues of a compound of Formula I-IIIH, AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, AIIIE, IV-I, IV-IA, IV-IB, IV, IVA, or IVB. In one embodiment, the residue of the compound is present at a concentration of about 0.01 mM to about 20 mM, about 0.1 mM to about 20 mM, about 0.5 mM to about 10 mM, about 1 mM to about 20 mM, about 5 mM to about 20 mM, or about 5 mM to about 10 mM. In other embodiments, the residue of the compound is present at a concentration of about 1 mM, about 5 mM, about 10 mM, or about 20 mM.

[0091] In one embodiment of the sensor disclosed herein, the polymer is a hydrogel. In some embodiments, the polymer further comprises residues of hydroxyethyl methacrylate (HEMA), N,N-dimethylacrylamide, or polyethylene glycol diacrylamide. In other embodiments, the polymer further comprises residues of [2-(acryloyloxy)ethyl]trimethylammonium chloride, 2-carboxyethyl acrylate, or polyethylene glycol diacrylamide. In one embodiment, the polymer further comprises residues of N,N-dimethylacrylamide, acrylamide, or polyethylene glycol diacrylamide.

[0092] In one embodiment of the sensor as disclosed herein, the analyte is glucose. In some embodiments, the sensor generates a detectable luminescent signal when placed under the skin of a mammalian subject. In other embodiments, the sensor generates a detectable luminescent signal when placed under the skin of a mammalian subject to a depth of up to about 5 mm. In some embodiments, the sensor generates a detectable luminescent signal when placed under the skin of a mammalian subject to a depth of greater than 1 mm.

[0093] In one embodiment of the sensor as disclosed herein, the mammalian subject is a human.

[0094] In one embodiment of a sensor as disclosed herein, the sensor is stable in mammalian tissue for longer than 1 week, longer than 2 weeks, longer than one month, longer than 2 months, longer than 3 months, or longer than 1 year.

[0095] In one embodiment of the sensor as disclosed herein, the sensor is tissue integrated. In some embodiments, the sensor further comprises catalase. BRIEF DESCRIPTION OF THE DRAWINGS

[0096] Figure 1 Depicted are the performance of a glucose sensor prepared by copolymerization of an exemplary compound (Compound 21) implanted in the subcutaneous tissue of pigs.

[0097] Figures 2A to 2D Depicted are the long-term stability and performance of two glucose sensors prepared by copolymerization of an exemplary compound (Compound 21) implanted in the subcutaneous tissue of pigs. Figure 2A Stability at day 28 is depicted. Figure 2B Stability at day 50 is depicted. Figure 2C Stability at day 57 is depicted. Figure 2D Stability at day 109 is depicted. DETAILED DESCRIPTION

[0098] Described herein are polymerizable luminescent dyes useful for incorporation into polymers and polymers comprising residues of the dyes covalently linked, for example, as monomeric units. The dyes and polymers can be used in sensing and imaging applications, for example, to provide accurate and optionally long-term measurements of glucose in vivo.

[0099] In addition, described herein are sensors comprising the polymers described herein. The sensors can be implanted into a subject's tissue and used to continuously and semi-continuously collect data on various biochemical analytes over the long or short term, optionally without the use of any type of implantable hardware and / or enzymatic and electrochemical detection methods. In one aspect, the sensor is tissue-integrated, for example, allowing capillaries to grow in close proximity to all areas of the sensor (e.g., on the surface and internally), resulting in accurate analyte measurements, including long-term accurate analyte measurements.

[0100] Advantages of the dyes and light-emitting polymers provided herein include, but are not limited to: (1) excitation and emission wavelengths within the optical window of the skin (approximately 550 nm to 1100 nm), thereby allowing detection of analytes deep within tissues or organs; (2) high signal-to-noise ratios; (3) large Stokes shift and emission; and (4) photostability, e.g., the dyes and / or polymers do not undergo rapid photobleaching.

[0101] Advantages of the sensors described herein include, but are not limited to: (1) providing a device that produces a stable signal over an extended period of time (e.g., greater than 1 week, greater than 10 days, greater than 15 days, greater than 20 days, greater than 1 month, greater than 2 months, greater than 3 months, or greater than 6 months), (2) providing a device that is placed or implanted and integrated into the tissue of a subject (e.g., through tissue and / or capillary ingrowth); (3) providing a device that can be implanted by syringe injection or trocar injection, meaning that no surgery is required to place the sensing medium at the appropriate location in the body; (4) providing a device that does not include sensor electronics in the body; (5) providing a device that accurately assesses the concentration of an analyte (e.g., glucose) over an extended period of time (e.g., greater than 1 week, weeks, months, or years), and / or (6) providing a device of small size that will result in increased patient comfort and better body acceptance.

[0102] It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a sensor comprising "a sensing moiety" includes devices comprising two or more sensing moieties. Similarly, reference to "an analyte" refers to two or more analytes.

[0103] definition

[0104] The term "tissue integration" refers to a material (eg, a scaffold) that, when integrated into living tissue, remains in close proximity to the blood vessels (eg, capillaries) of the tissue.

[0105] By "long-term," it is meant that the implant continues to sense the analyte for greater than about 7 days, greater than about four weeks, greater than about one or more weeks, greater than about six weeks, greater than about one or more months, greater than about 100 days, or greater than about one or more years.

[0106] By "biodegradable" or "bioresorbable" is meant that the material is capable of being broken down by the body of a subject over a period of time ranging from days to weeks to months or years.

[0107] By "hydrogel" is meant a material that absorbs a solvent (eg, water), undergoes rapid swelling without discernible dissolution, and maintains a three-dimensional network structure capable of reversible deformation.

[0108] The term "stimuli-responsive" refers to substances, such as polymers, that change their physical state, e.g., undergo a phase transition, when exposed to an external stimulus or depending on the environment they are in. Non-limiting examples of such polymers are "smart polymers" (Kumar A. et al., Smart polymers: Physical forms and bioengineering applications. Prog. Polym. Sci. 32 (2007) 1205-1237).

[0109] As used herein, an electron withdrawing group or EWG is a moiety, such as an atom or group, that pulls electron density from adjacent atoms toward itself, typically through resonance or inductive effects. An electron donating group or EDG is a moiety, such as an atom or group, that releases electron density from itself to adjacent atoms, typically through resonance or inductive effects. Non-limiting examples of EWGs are halogens, C(O)R', COOR', C(O)NH2, NHC(O)R', C(O)NR'R", CF3, CN, SO3H, SO2CF3, SO2R', SO2NR'R", alkylammonium, and NO2, wherein R' and R" are independently H or C1-C6 alkyl. Non-limiting examples of EDGs are NR N1 R N2 , OR', NHC(O)R', OC(O)R', phenyl and vinyl, where R N1 、R N2 and R' are independently H or C1-C6 alkyl.

[0110] As used herein, a "linker group" or "linker" is an n-valent moiety that connects n other moieties within a molecule. Typically, a linker group is a divalent moiety that connects two other moieties within a molecule.

[0111] As used herein, the term "acyl" refers to a group of the form -C(O)R, where R is H or an optionally substituted group selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl.

[0112] As used herein, the terms "alkyl," "alkenyl," and "alkynyl" include straight, branched, and cyclic monovalent hydrocarbon radicals containing only C and H when they are unsubstituted, as well as combinations of these hydrocarbon radicals. Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylethyl, 2-propenyl, 3-butynyl, and the like. The total number of carbon atoms in each such radical is sometimes described herein; for example, when a radical may contain up to ten carbon atoms, it may be represented as 1-10C, C1-C 10 , C1-C10 or C1-10. As used herein, the terms "heteroalkyl," "heteroalkenyl," and "heteroalkynyl" refer to the corresponding hydrocarbon in which one or more chain carbon atoms have been replaced by a heteroatom. Exemplary heteroatoms include N, O, S, and P. When a heteroatom replaces a carbon atom, such as in a heteroalkyl group, the number of groups described, while still written as, for example, C1-C10, represents the sum of the number of carbon atoms in the ring or chain plus the number of such heteroatoms included in the ring or chain as a replacement for a carbon atom.

[0113] Alkyl, alkenyl, and alkynyl substituents may contain 1-10 carbon atoms (alkyl) or 2-10 carbon atoms (alkenyl or alkynyl). In one embodiment, they contain 1-8 carbon atoms (alkyl) or 2-8 carbon atoms (alkenyl or alkynyl). Sometimes, they contain 1-6 carbon atoms (alkyl) or 2-6 carbon atoms (alkenyl or alkynyl). Sometimes, they contain 1-4 carbon atoms (alkyl) or 2-4 carbon atoms (alkenyl or alkynyl). A single group may include more than one type of multiple bond or more than one multiple bond; such groups are included within the definition of the term "alkenyl" when they contain at least one carbon-carbon double bond, and are included within the term "alkynyl" when they contain at least one carbon-carbon triple bond.

[0114] Alkyl, alkenyl, and alkynyl groups may be optionally substituted to the extent that such substitution makes chemical sense. Substituents include, but are not limited to, halogen (F, Cl, Br, I), =O, =N--CN, =N--OR, =NR, OR, NR2, SR, S02R, S02NR2, NRS02R, NRCONR2, NRC(O)OR, NRC(O)R, CN, C(O)OR, C(O)NR2, OC(O)R, C(O)R, and NO2, wherein each R is independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C1-C8 acyl, C2-C8 heteroacyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C6-C10 aryl, or 5 to 6 alkyl radicals. 10-membered heteroaryl, and each R is optionally substituted by halogen (F, Cl, Br, I), =O, =N--CN, =N--OR', =NR', OR', NR'2, SR', S02R', S02NR'2, NR'S02R', NR'CONR'2, NR'C(O)OR', NR'C(O)R', CN, C(O)OR', C(O)NR'2, OC(O)R', C(O)R' and NO2, wherein each R' is independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl or 5- to 10-membered heteroaryl. The alkyl, alkenyl, and alkynyl groups may also be substituted with C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, each of which may be substituted with a substituent suitable for the particular group.

[0115] Although "alkyl" as used herein includes cycloalkyl and cycloalkylalkyl, the term "cycloalkyl" is used herein to describe a carbocyclic non-aromatic group attached through a ring carbon atom, and "cycloalkylalkyl" is used to describe a carbocyclic non-aromatic group attached to a molecule through an alkyl linker. Similarly, "heterocyclyl" is used to identify a non-aromatic cyclic group containing at least one heteroatom as a ring member and attached to a molecule through a ring atom that can be C or N; and "heterocyclylalkyl" can be used to describe such a group attached to another molecule through an alkylene linker. As used herein, these terms also include rings containing one double bond or two double bonds, as long as the ring is not aromatic.

[0116] As used herein, "perfluoroalkyl" includes alkyl groups in which all hydrogens are replaced by fluorine. Non-limiting examples include -CF3, -CF2CF3, -CF2CF2CF3, and -CF2CF2CF2CF3.

[0117] Although it can be understood from the various formulae described herein, some groups are divalent, such as L 1 , L 2 and L 3Those skilled in the art will appreciate that in such embodiments, groups such as "alkyl" will be divalent and attached to the rest of the molecule through two points of attachment. As used herein, terms such as "alkylene," "alkenylene," and "alkynylene" are intended to refer to divalent alkyl, alkenyl, and alkynyl groups, respectively.

[0118] An "aromatic" or "aryl" substituent or moiety refers to a monocyclic, fused bicyclic, fused tricyclic, or fused tetracyclic moiety having the well-known characteristics of aromaticity; examples include phenyl, naphthyl, and anthracenyl. Similarly, "heteroaromatic" and "heteroaryl" refer to such aromatic ring systems containing one or more heteroatoms as ring members. Suitable heteroatoms include N, O, and S, the inclusion of which allows for aromaticity in 5-membered as well as 6-membered rings. Heteroaromatic systems include monocyclic 5 to 6 membered heteroaryls such as pyridyl, pyrimidinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl and imidazolyl, and fused bicyclic moieties such as indolyl, benzimidazolyl, indazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, pyrazolopyridinyl, quinazolinyl, quinoxalinyl, cinnolinyl, etc. Any monocyclic or fused bicyclic ring system having aromatic characteristics in terms of electron distribution throughout the ring system is included in this definition. It also includes bicyclic groups in which at least the ring directly attached to the rest of the molecule has aromatic characteristics. Typically, monocyclic heteroaryls contain 5-6 ring members, and bicyclic heteroaryls contain 8-10 ring members.

[0119] The aryl and heteroaryl moieties may be substituted with a variety of substituents including C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C12 aryl, C1-C8 acyl, and heteroatom-containing versions of these substituents, each of which may itself be further substituted; other substituents for the aryl and heteroaryl moieties include halogen (F, Cl, Br, I), OR, NR2, SR, SO2R, SO2NR2, NRSO2R, NRCONR2, NRC(O)O R, NRC(O)R, CN, C(O)OR, C(O)NR2, OC(O)R, C(O)R and NO2, wherein each R is independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C7-C12 arylalkyl or (5- to 10-membered heteroaryl)(C1-C3 alkyl)-, and each R is optionally substituted as described above for alkyl. The substituent groups on the aryl or heteroaryl groups may, of course, be further substituted with groups as described herein for each type of such substituent or for each component of the substituent. Thus, for example, an arylalkyl substituent may be substituted on the aryl portion with substituents as described herein as typical for aryl groups, and it may be further substituted on the alkyl portion with substituents as described herein as typical for or suitable for alkyl groups.

[0120] As used herein, "optionally substituted" indicates that one or more hydrogen substituents of the particular group being described may be replaced by non-hydrogen substituents. In some optionally substituted groups or moieties, all hydrogen substituents are replaced by non-hydrogen substituents. If not otherwise specified, the total number of such substituents that may be present is equal to the number of H atoms present in the unsubstituted form of the described group. When an optional substituent is attached by a double bond, such as a carbonyl oxygen or an oxo group (=O), the group takes up two available valences, so the total number of substituents that may be included is reduced according to the number of available valences.

[0121] A. Emissive Compounds Comprising a NIR Dye Moiety and One or More Polymerizable Groups

[0122] One aspect relates to a compound of formula I:

[0123]

[0124] or an isomer, tautomer or salt thereof,

[0125] where dotted lines indicate bonds or the absence of bonds;

[0126] When connecting R 1 When the dotted line with O is a bond, R 1 It's CX 1 X 2 , and R15 does not exist; and when connecting R 1 The dotted line between R and O is when there is no bond. 15 is independently H or C1-C6 alkyl at each occurrence, and R 1 Each occurrence is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 10 a heteroalkyl group, a polymerizable moiety, a NIR dye moiety, an electron withdrawing group, or an electron donating group;

[0127] X 1 and X 2 are independently H or C1-C6 alkyl;

[0128] R 2 is H or C1-C6 alkyl;

[0129] Z is optionally replaced by R 11 、R 12 、R 14 or L 2 R 13 Substituted C6-C 14 arylene;

[0130] R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 11 、R 12 、R 13 and R 14 are independently H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C 10 a heteroalkyl group, a polymerizable moiety, a NIR dye moiety, an electron withdrawing group, or an electron donating group;

[0131] R 9 and R 10 is independently H, a C1-C6 alkyl, a polymerizable moiety, or a NIR dye moiety;

[0132] L 1 , L 2 and L 3 are independently a bond or a linker group; and

[0133] The compounds comprise one or more NIR dye moieties and one or more polymerizable moieties.

[0134] In certain embodiments of Formula I, the compound has the structure of Formula IA, IB, or IC:

[0135]

[0136] or an isomer, tautomer or salt thereof, wherein all substituents are as defined above for Formula I.

[0137] In other embodiments of Formula I, IA, IB or IC, the compound includes one NIR dye moiety. Exemplary NIR dye moieties of the compounds disclosed herein are selected from cyanine, hemicyanine, fluorone, oxazine, phenanthidine, rhodamine, rosamine, indolium, quinolinium, benzophenoxazine, benzopyrylium, bisindolylmaleimide, boron-dipyrromethene, boron-aza-dipyrromethene, carbopyronine, perylene, porphyrin, ruthenium complex, lanthanide complex, benzoxanthenium, xanthene, fluorescein, squarylium, coumarin, anthracene, tetracene, pentacene and pyrene dyes.

[0138] In some cases, the NIR dye moiety has a structure selected from the group consisting of:

[0139]

[0140] where R N1 and R N2 is independently a C1-C ... 10 Alkyl, and the wavy line indicates L 2 connection point.

[0141] In other embodiments, the NIR dye moiety has the structure:

[0142]

[0143] wherein R' at each occurrence is independently H, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl or optionally substituted C2-C 20 Heteroalkyl.

[0144] In other embodiments, the NIR dye moiety has the structure:

[0145]

[0146] where Y 1 is selected from O, P(O)R', SiR'R", and NR', wherein R' and R" are independently H or C1-C6 alkyl;

[0147] R 20 and R 21are independently H, C1-C6 alkyl, or R 21 and R 20 Together with the nitrogen atom to which they are attached, they form a 6- or 5-membered ring optionally substituted with a polymerizable moiety;

[0148] R 23 and R 24 are independently H, C1-C6 alkyl, or R 23 and R 24 Together with the nitrogen atom to which they are attached, they form a 6- or 5-membered ring optionally substituted with a polymerizable moiety;

[0149] R 22 and R 25 are independently H, C1-C6 alkyl, or R 21 and R 22 Together with the atoms to which they are attached, they form a 6- or 5-membered ring, or R 24 and R 25 Together with the atoms to which they are attached, they form a 6- or 5-membered ring; and

[0150] R 26 and R 27 are independently H, C1-C6 alkyl, or R 26 and R 20 Together with the atoms to which they are attached, they form a 6- or 5-membered ring, or R 27 and R 23 Together with the atoms to which they are attached, they form a 6- or 5-membered ring.

[0151] In certain embodiments, Y 1 It's SiMe2.

[0152] In some embodiments of the compounds disclosed herein, Z is optionally substituted phenylene or anthracene.

[0153] In other embodiments of Formula I, IA, IB or IC, the compound includes one polymerizable moiety. In other embodiments of Formula I, IA, IB or IC, the compound includes two polymerizable moieties. In certain embodiments of Formula I, IA, IB or IC, the polymerizable moieties have the same structure. In other embodiments of Formula I, IA, IB or IC, the polymerizable moieties have different structures.

[0154] In some embodiments of Formula I, IA, IB or IC, the electron withdrawing group is selected from the group consisting of halogen, C(O)R', COOR', C(O)NH2, C(O)NR'R", CF3, CN, SO3H, SO2CF3, SO2R', SO2NR'R", ammonium, alkylammonium and NO2, and wherein R' and R" are independently H or C1-C6 alkyl.

[0155] In other embodiments of Formula I, IA, IB or IC, the electron donating group is selected from the group consisting of: NR N1 R N2 , OR', NHC(O)R', OC(O)R', phenyl and vinyl, where R N1 、R N2 and R' are independently H or C1-C6 alkyl.

[0156] In other embodiments of Formula I, IA, IB or IC, L 1 is a bond or a linker group selected from the group consisting of optionally substituted amino, optionally substituted amide, -O-, optionally substituted -CH2C6H4O-, C2-C 20 PEG linker, optionally substituted C6-C 10 arylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted -C1-C6 alkylene-Ar-, optionally substituted -C2-C6 alkenylene-Ar-, optionally substituted -C2-C6 alkynylene-Ar-, optionally substituted -C(O)NH-C1-C6 alkylene-Ar-, optionally substituted -C1-C6 alkylene-C(O)NH-C1-C6 alkylene-, optionally substituted -C1-C6 alkylene-C(O)NH-C1-C6 alkylene-Ar-, optionally substituted -(CH2CH2O) n CH2-, optionally substituted -CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n CH2CH2-, optionally substituted-CH2CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n -, optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene and optionally substituted C2-C 20 heteroalkylene, wherein n is an integer between 1 and 10, and Ar is C6-C 10 arylene or 5- to 10-membered heteroarylene.

[0157] In other embodiments of Formula I, IA, IB or IC, L 2 is a bond or a linker group selected from the group consisting of optionally substituted amino, optionally substituted amide, -O-, optionally substituted -(CH2) m C6H4O-、C2-C 20 PEG linker, optionally substituted C6-C 10arylene, optionally substituted 5- to 10-membered heteroarylene, -[optionally substituted 5- to 10-membered heteroarylene]-[optionally substituted C6-C 10 Arylene]-, -[optionally substituted C6-C 10 arylene]-[optionally substituted 5- to 10-membered heteroarylene]-, -Ar-Ar-, optionally substituted -C1-C6 alkylene-Ar-, optionally substituted C2-C6 alkenylene-Ar-, optionally substituted C2-C6 alkynylene-Ar-, optionally substituted –C(O)NH-C1-C6 alkylene-Ar-, optionally substituted -C1-C6 alkylene-C(O)NH-C1-C6 alkylene-, optionally substituted –C1-C6 alkylene-C(O)NH-C1-C6 alkylene-Ar-, optionally substituted –(CH2CH2O) n CH2-, optionally substituted -CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n CH2CH2-, optionally substituted-CH2CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n -, optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene and optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20 heteroalkylene, wherein n is an integer between 1 and 10, m is an integer 0, 1 or 2, and Ar is C6-C 10 arylene or 5- to 10-membered heteroarylene, and combinations thereof.

[0158] In certain embodiments of Formula I, IA, IB or IC, L 3 is a bond or a linker group selected from the group consisting of optionally substituted amino, optionally substituted amide, -O-, optionally substituted -CH2C6H4O-, C2-C 20 PEG linker, optionally substituted C6-C 10 arylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted -C1-C6 alkylene-Ar-, optionally substituted C2-C6 alkenylene-Ar-, optionally substituted C2-C6 alkynylene-Ar-, optionally substituted -C(O)NH-C1-C6 alkylene-Ar-, optionally substituted -C1-C6 alkylene-C(O)NH-C1-C6 alkylene-, optionally substituted -C1-C6 alkylene-C(O)NH-C1-C6 alkylene-Ar-, optionally substituted -(CH2CH2O) n CH2-, optionally substituted -CH2(CH2CH2O) n-, optionally substituted -(CH2CH2O) n CH2CH2-, optionally substituted-CH2CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n -, optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene and optionally substituted C2-C 20 heteroalkylene, wherein n is an integer between 1 and 10, and Ar is C6-C 10 arylene or 5- to 10-membered heteroarylene, and combinations thereof.

[0159] In other embodiments of Formula I, IA, IB or IC, L 1 , L 2 and L 3 Independently optionally substituted with one or more groups selected from carboxyl groups, sulfonic acid groups, ammonium groups, amino groups, and combinations thereof.

[0160] In other embodiments of Formula I, IA, IB or IC, L 1 , L 2 and L 3 Independently include one or more substituents selected from carboxyl groups, sulfonic acid groups, ammonium and amino groups.

[0161] In some embodiments of Formula I, IA, IB, or IC, L 1 , L 2 and L 3 are independently optionally substituted -C1-C6 alkylene-Ar-, optionally substituted C2-C6 alkenylene-Ar-, optionally substituted C2-C6 alkynylene-Ar-, optionally substituted -C(O)NH-C1-C6 alkylene-Ar-, optionally substituted -C1-C6 alkylene-C(O)NH-C1-C6 alkylene-, optionally substituted -C1-C6 alkylene-C(O)NH-C1-C6 alkylene-Ar-, -(CH2CH2O) n -, wherein n is an integer between 1 and 10, and Ar is an optionally substituted phenylene or an optionally substituted 5-membered heteroarylene. In some of the above embodiments, one or more linker groups are optionally substituted with one or more groups selected from carboxyl groups, sulfonic acid groups, ammonium groups, amino groups, and combinations thereof.

[0162] In specific embodiments of Formula I, IA, IB or IC, the one or more polymerizable moieties include a group selected from: -NH(CO)C(R)CH2, -O(CO)C(R)CH2, and -CHCH2, wherein R is H or C1-C3 alkyl. In certain embodiments of Formula I, IA, IB or IC, the one or more polymerizable moieties are selected from: -NH(CO)C(R)CH2, -O(CO)C(R)CH2, and -CHCH2, wherein R is H or C1-C3 alkyl.

[0163] In some embodiments of Formula I, IA, IB, or IC, R 13 is H, a C1-C6 alkyl group, a polymerizable moiety, or a NIR dye moiety.

[0164] In other embodiments of Formula I, IA, IB or IC, R 13 is the NIR dye portion.

[0165] In some embodiments of Formula I, IA, IB, or IC, one or more NIR dye moieties are cyanine, hemicyanine, fluorone, oxazine, phenanthidine, rhodamine, rosamine, indolium, quinolinium, benzophenoxazine, benzopyrylium, bisindolylmaleimide, boron-dipyrromethene, boron-aza-dipyrromethene, carbopyronine, perylene, porphyrin, ruthenium complex, lanthanide complex, benzoxanthenium, xanthene, fluorescein, squarylium, coumarin, anthracene, tetracene, pentacene, or pyrene dye residues.

[0166] In certain embodiments of Formula I, IA, IB or IC, NIR dye has excitation and emission wavelength in the optical window of skin.In other embodiments of Formula I, IA, IB or IC, NIR dye has the maximum absorption between about 500nm and about 900nm, between about 600nm and about 1000nm and between about 500nm and about 1000nm.In other embodiments of Formula I, IA, IB or IC, NIR dye has the maximum absorption between about 550nm and about 900nm, between about 600nm and about 1000nm and between about 550nm and about 1100nm.In certain embodiments of Formula I, IA, IB or IC, compound itself is NIR dye, and has the maximum absorption between about 550nm and about 1000nm and the maximum emission between about 600nm and about 1100nm.Greater than 500nm, greater than 550nm, greater than 600nm, greater than 650nm, greater than the maximum absorption of 700nm. In certain embodiments of Formula I, IA, IB or IC, the compound itself is a NIR dye and has an absorption maximum of greater than 500 nm, greater than 550 nm, greater than 600 nm, greater than 650 nm, greater than 700 nm. In other embodiments of Formula I, IA, IB or IC, the compound itself is a NIR dye and has an emission maximum of greater than 550 nm, greater than 600 nm, greater than 650 nm, greater than 700 nm, greater than 800 nm, greater than 900 nm, greater than 1000 nm, greater than 1100 nm.

[0167] In certain embodiments of formula I, IA, IB or IC, Z is optionally substituted phenylene.

[0168] In other embodiments of Formula I, IA, IB, or IC, the compound has the structure of Formula II:

[0169]

[0170] or an isomer, tautomer or salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 , L 1 , L 2 and L3 As defined for the compound of Formula I, IA, IB or IC, and wherein the compound comprises one or more NIR dye moieties and one or more polymerizable moieties.

[0171] In other embodiments of Formula II, R 3 、R 5 、R 6 and R 8 It’s H.

[0172] In some embodiments of Formula II, the compound has the structure of Formula IIA:

[0173]

[0174] In certain embodiments of Formula II or IIA, L 2 does not exist, and R 13 is H. In other embodiments of Formula II or IIA, R 4 、R 7 、R 11 、R 12 and R 14 is H. In other embodiments of Formula II or IIA, L 3 is an optionally substituted C1-C6 alkylene. In a specific embodiment of Formula II or IIA, R 9 It is –NHC(O)CCH3CH2.

[0175] In certain embodiments of Formula II or IIA, R 1 The dotted line between R and O indicates that there is no bond. 15 does not exist, and R 1 and R 2 It’s H.

[0176] In some embodiments of Formula II or IIA, R 13 is H, a C1-C6 alkyl group, a polymerizable moiety, or a NIR dye moiety.

[0177] In other embodiments of Formula II or IIA, R 13 is the NIR dye portion.

[0178] In certain embodiments of Formula II or IIA, the compound has the structure of Formula IIB:

[0179]

[0180] In some embodiments of Formula II, IIA, or IIB, the compound is selected from Compound 1, 2, 3, 4, 5, 6, or 7 of Table 1.

[0181] In certain embodiments of Formula I, IA, IB, or IC, the compound has the structure of Formula III:

[0182]

[0183] or an isomer, tautomer or salt thereof,

[0184] where dotted lines indicate bonds or the absence of bonds;

[0185] When connecting R 1 When the dotted line with O is a bond, R 1 It's CX 1 X 2 , and R 15 does not exist; and when connecting R 1 The dotted line between R and O is when there is no bond. 15 is independently H or C1-C6 alkyl at each occurrence, and R 1 Each occurrence is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 10 a heteroalkyl group, a polymerizable moiety, a NIR dye moiety, an electron withdrawing group, or an electron donating group;

[0186] X 1 and X 2 are independently H or C1-C6 alkyl;

[0187] R 2 is H or C1-C6 alkyl;

[0188] R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 11 、R 12 and R 14 are independently H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C 10 a heteroalkyl group, a polymerizable moiety, a NIR dye moiety, an electron withdrawing group, or an electron donating group;

[0189] R 9 、R 10 and R 13 are independently H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C 10 heteroalkyl groups, polymerizable moieties, or NIR dyes;

[0190] L 1 , L 2 and L 3 are independently a linker group or a bond; and

[0191] wherein the compound comprises one or more NIR dye moieties and one or more polymerizable moieties.

[0192] In certain embodiments of Formula III, the electron withdrawing group is selected from the group consisting of halogen, C(O)R', COOR', C(O)NH2, C(O)NR'R", CF3, CN, SO3H, SO2CF3, SO2R', ammonium, alkylammonium and NO2, and wherein R' and R" are independently H or C1-C6 alkyl. In other embodiments of Formula III, the electron donating group is selected from the group consisting of NR N1 R N2 , OR', NHC(O)R', OC(O)R', phenyl and vinyl, where R N1 、R N2 and R' are independently H or C1-C6 alkyl.

[0193] In other embodiments of Formula III, L 1 is a bond or a linker group selected from the group consisting of optionally substituted amino, optionally substituted amide, -O-, optionally substituted -CH2C6H4O-, C2-C 20 PEG linker, optionally substituted C6-C 10 arylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted -C1-C6 alkylene-Ar-, optionally substituted C2-C6 alkenylene-Ar-, optionally substituted C2-C6 alkynylene-Ar-, optionally substituted -C(O)NH-C1-C6 alkylene-Ar-, optionally substituted -C1-C6 alkylene-C(O)NH-C1-C6 alkylene-, optionally substituted -C1-C6 alkylene-C(O)NH-C1-C6 alkylene-Ar-, optionally substituted -(CH2CH2O) n CH2-, optionally substituted -CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n CH2CH2-, optionally substituted-CH2CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n -, optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20heteroalkylene, wherein n is an integer between 1 and 10, and Ar is C6-C 10 arylene or 5- to 10-membered heteroarylene, and combinations thereof.

[0194] In certain embodiments of Formula III, wherein L 2 is a bond or a linker group selected from the group consisting of optionally substituted amino, optionally substituted amide, -O-, optionally substituted -(CH2) m C6H4O-、C2-C 20 PEG linker, optionally substituted C6-C 10 arylene, optionally substituted 5- to 10-membered heteroarylene, -[optionally substituted 5- to 10-membered heteroarylene]-[optionally substituted C6-C 10 Arylene]-, -[optionally substituted C6-C 10 arylene]-[optionally substituted 5- to 10-membered heteroarylene]-, -Ar-Ar-, optionally substituted -C1-C6 alkylene-Ar-, optionally substituted C2-C6 alkenylene-Ar-, optionally substituted C2-C6 alkynylene-Ar-, optionally substituted –C(O)NH-C1-C6 alkylene-Ar-, optionally substituted -C1-C6 alkylene-C(O)NH-C1-C6 alkylene-, optionally substituted –C1-C6 alkylene-C(O)NH-C1-C6 alkylene-Ar-, optionally substituted –(CH2CH2O) n CH2-, optionally substituted -CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n CH2CH2-, optionally substituted-CH2CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n -, optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20 heteroalkylene, wherein n is an integer between 1 and 10, m is 0, 1 or 2, and Ar is C6-C 10 arylene or 5- to 10-membered heteroarylene, and combinations thereof.

[0195] In some embodiments of Formula III, L 3 is a bond or a linker group selected from the group consisting of optionally substituted amino, optionally substituted amide, -O-, optionally substituted -CH2C6H4O-, C2-C 20 PEG linker, optionally substituted C6-C 10arylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted -C1-C6 alkylene-Ar-, optionally substituted C2-C6 alkenylene-Ar-, optionally substituted C2-C6 alkynylene-Ar-, optionally substituted -C(O)NH-C1-C6 alkylene-Ar-, optionally substituted -C1-C6 alkylene-C(O)NH-C1-C6 alkylene-, optionally substituted -C1-C6 alkylene-C(O)NH-C1-C6 alkylene-Ar-, optionally substituted -(CH2CH2O) n CH2-, optionally substituted -CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n CH2CH2-, optionally substituted-CH2CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n -, optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20 heteroalkylene, wherein n is an integer between 1 and 10, and Ar is C6-C 10 arylene or 5- to 10-membered heteroarylene, and combinations thereof.

[0196] In certain embodiments of Formula III, the linker group includes a substituent selected from the group consisting of a carboxyl group, a sulfonic acid group, an ammonium group, and an amino group. In certain embodiments of Formula III, the polymerizable moiety is selected from the group consisting of -NH(CO)C(R)CH2, -O(CO)C(R)CH2, and -CHCH2, wherein R is H or a C1-C3 alkyl group.

[0197] In some embodiments of Formula III, the NIR dye moiety is a cyanine, hemicyanine, fluorone, oxazine, phenanthidine, rhodamine, rosamine, indolium, quinolinium, benzophenoxazine, benzopyrylium, bisindolylmaleimide, boron-dipyrromethene, boron-aza-dipyrromethene, carbopyronine, perylene, porphyrin, ruthenium complex, lanthanide complex, benzoxanthenium, xanthene, fluorescein, squarylium, coumarin, anthracene, tetracene, pentacene, or pyrene dye residue.

[0198] In some embodiments of Formula III, R 13 is H, a C1-C6 alkyl group, a polymerizable moiety, or a NIR dye moiety.

[0199] In other embodiments of Formula III, R 13 is the NIR dye portion.

[0200] In other embodiments of formula III, the NIR dye moiety has excitation and emission wavelength in the optical window of skin.In the specific embodiment of formula III, the NIR dye moiety has an absorption maximum between about 500nm and about 900nm, between about 600nm and about 1000nm and between about 500nm and about 1000nm. In other embodiments of formula III, the NIR dye moiety has an absorption maximum between about 550nm and about 900nm, between about 600nm and about 1000nm and between about 550nm and about 1100nm. In certain embodiments of formula III, the compound itself is a NIR luminescent dye, and has an absorption maximum between about 550nm and about 1000nm and an emission maximum between about 600nm and about 1100nm. Greater than 500nm, greater than 550nm, greater than 600nm, greater than 650nm, greater than the absorption maximum of 700nm. In other embodiments of Formula III, the compound has an absorption maximum of greater than 500 nm, greater than 550 nm, greater than 600 nm, greater than 650 nm, greater than 700 nm. In other embodiments of Formula III, the compound has an emission maximum of greater than 550 nm, greater than 600 nm, greater than 650 nm, greater than 700 nm, greater than 800 nm, greater than 900 nm, greater than 1000 nm, greater than 1100 nm.

[0201] In certain embodiments of Formula III, R 3 、R 5 、R 6 and R 8 It’s H.

[0202] In certain embodiments of Formula III, the compound has the structure of Formula IIIA:

[0203]

[0204] or an isomer, tautomer or salt thereof.

[0205] In certain embodiments of Formula III or IIIA, L 2 does not exist, and R 13 is H. In other embodiments of Formula III or IIIA, R 4 、R 7 、R 11 、R 12 and R 14 Is H. In some embodiments of Formula III or IIIA, L 3 is an optionally substituted C1-C6 alkylene. In other embodiments of Formula III or IIIA, R 9is -NHC(O)C(CH3)CH2. In certain embodiments of Formula III or IIIA, the linker R 1 and O dotted line indicates the absence of a bond, and R 1 and R 2 It’s H.

[0206] In some embodiments of Formula IIIA, R 13 is H, a C1-C6 alkyl group, a polymerizable moiety, or a NIR dye moiety.

[0207] In other embodiments of Formula IIIA, R 13 is the NIR dye portion.

[0208] In certain embodiments of Formula III or IIIA, the compound has the structure of Formula IIIB:

[0209]

[0210] or an isomer, tautomer or salt thereof.

[0211] In certain embodiments of Formula IIIB, the compound is selected from Compound 8, 9, 10, 11, 12, or 13 of Table 1.

[0212] In certain embodiments of Formula III, the compound has the structure of Formula IIIC:

[0213]

[0214] or an isomer, tautomer or salt thereof.

[0215] In some embodiments of Formula IIIC, R 13 is H, a C1-C6 alkyl group, a polymerizable moiety, or a NIR dye moiety.

[0216] In other embodiments of Formula IIIC, R 13 is the NIR dye portion.

[0217] In some embodiments of Formula III or IIIC, L 2 is –CHCH-, and R 13 is a NIR dye moiety. In other embodiments of Formula III or IIIC, R 4 and R 7 It’s H.

[0218] In some embodiments of Formula IIIC, the compound is compound 14, 15, 16, 17, or 18 of Table 1.

[0219] In certain embodiments of Formula III, the compound has the structure of Formula IIID:

[0220]

[0221] or an isomer, tautomer or salt thereof, wherein

[0222] Connect R 1 The dotted line with O is a bond or there is no bond;

[0223] R 1 Is H or CX 1 X 2 ;

[0224] R 15 It is H or does not exist;

[0225] X 1 and X 2 are independently H or C1-C6 alkyl;

[0226] L 1 , L 2 and L 3 is a linker moiety independently selected from the group consisting of a bond, an optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20 Heteroalkylene; -CH2C6H4O-, C2-C 20 PEG linkers, amide, amino, and phenylene groups;

[0227] R 3 、R 4 and R 7 are independently H, C1-C6 alkyl, electron-withdrawing group or electron-donating group;

[0228] R 13 is a NIR dye moiety; and

[0229] R 10 and R 9 is H or a polymerizable moiety.

[0230] In some embodiments of Formula III or HID, L 1 and L 2 In other embodiments of Formula III or IIID, R 10 and R 9 is NHC(O)C(CH3)CH2. In other embodiments of Formula III or IIID, R 3 、R 4 and R 14is H. In certain embodiments of Formula III or HID, the compound is compound 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 of Table 1.

[0231] In certain embodiments of Formula III, the compound has the structure of Formula IIIE:

[0232]

[0233] or an isomer, tautomer or salt thereof,

[0234] wherein the dotted line represents a bond or the absence of a bond independently at each occurrence; and when connecting R 1 When the dotted line with O is a bond, R 1 It's CX 1 X 2 , and R 15 does not exist; and when connecting R 1 The dotted line between R and O is when there is no bond. 15 is H or C1-C6 alkyl;

[0235] L 1 , L 2 and L 3 is a linker moiety independently selected from the group consisting of a bond, an optionally substituted C1-C6 alkylene, an optionally substituted C2-C6 alkenylene, an optionally substituted C2-C6 alkynylene, -O-, an optionally substituted -(CH2CH2O) n -, optionally substituted -(CH2CH2O) n CH2-, optionally substituted -CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n CH2CH2-, optionally substituted-CH2CH2(CH2CH2O) n -, optionally substituted C2-C 20 PEG linker, optionally substituted amide, optionally substituted amino and optionally substituted C6-C 10 Arylene, wherein n is an integer between 1 and 10;

[0236] R 3 、R 4 and R 7 Independently selected from H, C1-C6 alkyl, electron withdrawing group and electron donating group;

[0237] R 13 is a NIR dye moiety; and

[0238] R 10 and R9 is H or a polymerizable moiety.

[0239] In certain embodiments of Formula IIIE, R 10 and R 9 It is NHC(O)C(CH3)CH2.

[0240] In specific embodiments of Formula IIIE, the compound is compound 36, 37, 38, 39, 40, or 41 of Table 1.

[0241] In certain embodiments of Formula III, the compound has the structure of Formula IIIF:

[0242]

[0243] or an isomer, tautomer or salt thereof,

[0244] wherein the dotted line represents a bond or the absence of a bond independently at each occurrence; and when connecting R 1 When the dotted line with O is a bond, R 1 It's CX 1 X 2 , and R 15 does not exist; and when connecting R 1 The dotted line between R and O is when there is no bond. 15 is H or C1-C6 alkyl, and R 1 Each occurrence is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 10 a heteroalkyl group, a polymerizable moiety, a NIR dye moiety, an electron withdrawing group, or an electron donating group;

[0245] X 1 and X 2 are independently H or C1-C6 alkyl;

[0246] R 2 is H or C1-C6 alkyl;

[0247] R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 11 、R 12 and R 14 are independently H, C1-C6 alkyl, a polymerizable moiety, an electron withdrawing group, or an electron donating group;

[0248] R 9 and R 10is independently H, a C1-C6 alkyl, a polymerizable moiety, or a NIR dye moiety;

[0249] L 1 and L 3 is independently a bond or a linker group selected from the group consisting of: optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20 heteroalkylene, optionally substituted -(CH2CH2O) n CH2-, optionally substituted -CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n CH2CH2-, optionally substituted-CH2CH2(CH2CH2O) n -, optionally substituted (CH2CH2O) n -, where n is an integer between 1 and 10;

[0250] L 2 is a bond, an optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20 Heteroalkylene; -O-, optionally substituted –(CH2) m C6H4O-, amide, amino, optionally substituted C6-C 10 arylene, optionally substituted 5- to 10-membered heteroarylene, -[optionally substituted 5- to 10-membered heteroarylene]-[optionally substituted C6-C 10 Arylene]-or-[optionally substituted C6-C 10 arylene]-[optionally substituted 5- to 10-membered heteroarylene]-; wherein m is 0, 1 or 2;

[0251] Y 1 Selected from -O-, -P(O)(R')-, -Si(R')(R")-, or -NR'-, wherein R' and R" are independently H or C1-C6 alkyl;

[0252] R 20 and R 21 are independently H or C1-C6 alkyl; or R 21 and R 20 Together with the nitrogen atom to which they are attached, they form a 6- or 5-membered ring optionally substituted with a polymerizable moiety;

[0253] R 23 and R24 are independently H or C1-C6 alkyl; or R 23 and R 24 Together with the nitrogen atom to which they are attached, they form a 6- or 5-membered ring optionally substituted with a polymerizable moiety;

[0254] R 22 and R 25 are independently H or C1-C6 alkyl; or R 21 and R 22 Together with the atoms to which they are attached, they form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring, or R 24 and R 25 Together with the atoms to which they are attached, they form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring;

[0255] R 26 and R 27 are independently H or C1-C6 alkyl; or R 26 and R 20 Together with the atoms to which they are attached, they form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring, or R 27 and R 23 Together with the atoms to which they are attached, they form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring; and

[0256] The compound comprises one or more polymerizable moieties.

[0257] In some embodiments of Formula IIIF, the compound is compound 42-77, 81, 82, 83, 84, 85, 86, 87, or 88 of Table 1.

[0258] In some embodiments of Formula IIIF, L 2 is a bond or an optionally substituted group selected from: phenylene, Or –C6H4-O-.

[0259] In some embodiments of Formula IIIF, Y 1 is -Si(Me)2-. In some embodiments of Formula IIIF, R 10 is -NHC(O)C(CH3)CH2. In some embodiments of Formula IIIF, R 9 It is -NHC(O)C(CH3)CH2.

[0260] In some embodiments of Formula IIIF, L 1 is an optionally substituted C1-C 10 Alkylene or optionally substituted C2-C 20 In some embodiments of Formula IIIF, L3 is an optionally substituted C1-C 10 Alkylene or optionally substituted C2-C 20 Heteroalkylene.

[0261] In some embodiments of Formula IIIF, R 11 、R 14 and R 12 is H. In some embodiments of Formula IIIF, R 22 、R 25 、R 26 and R 27 It’s H.

[0262] In some embodiments of Formula IIIF, each R 15 is H, and R 1 is independently selected at each occurrence from the group consisting of: H; an electron withdrawing group selected from the group consisting of halogen, -C(O)R', -COOR', -C(O)NH2, -C(O)NR'R", -CF3, -CN, -SO3H, -SO2CF3, -SO2R', -SO2NR'R", ammonium, alkylammonium and NO2, wherein R' and R" are independently H or C1-C6 alkyl; and an electron donating group selected from the group consisting of -NR N1 R N2 , -OR', -NHC(O)R', -OC(O)R', phenyl and vinyl, where R N1 、R N2 and R' is independently H or C1-C6 alkyl

[0263] In certain embodiments of Formula III, the compound has the structure of Formula IIIG:

[0264]

[0265] or an isomer, tautomer or salt thereof,

[0266] where dotted lines independently represent a bond or the absence of a bond; and when connecting R 1 When the dotted line with O is a bond, R 1 It's CX 1 X 2 , and R 15 does not exist; and when connecting R 1 The dotted line between R and O is when there is no bond. 15 is H or C1-C6 alkyl;

[0267] X 1 and X 2 are independently H or C1-C6 alkyl;

[0268] R2 is H or C1-C6 alkyl;

[0269] R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 11 、R 12 and R 14 are independently H, C1-C6 alkyl, a polymerizable moiety, an electron withdrawing group, or an electron donating group;

[0270] R 9 and R 10 is independently H, a C1-C6 alkyl group, a polymerizable moiety, or a NIR dye;

[0271] L 1 and L 3 is independently a bond or a linker group selected from the group consisting of: optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20 heteroalkylene;

[0272] L 2 is a bond, an optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20 Heteroalkylene; -O-, optionally substituted -CH2C6H4O-, C2-C 20 PEG linker, amide, amino, optionally substituted C6-C 10 arylene or optionally substituted 5- to 10-membered heteroarylene;

[0273] R' is independently at each occurrence H, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl or optionally substituted C2-C 20 heteroalkyl; and

[0274] wherein the compound comprises one or more polymerizable moieties.

[0275] In certain embodiments of Formula III, the compound has the structure of Formula IIIH:

[0276]

[0277] or an isomer, tautomer or salt thereof,

[0278] where dotted lines independently represent a bond or the absence of a bond; and when connecting R 1 When the dotted line with O is a bond, R 1 It's CX 1 X 2 , and R 15 does not exist; and when connecting R 1 The dotted line between R and O is when there is no bond. 15 is H or C1-C6 alkyl;

[0279] X 1 and X 2 are independently H or C1-C6 alkyl;

[0280] R 2 is H or C1-C6 alkyl;

[0281] R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 11 、R 12 and R 14 are independently H, C1-C6 alkyl, a polymerizable moiety, an electron withdrawing group, or an electron donating group;

[0282] R 9 and R 10 is independently H, a C1-C6 alkyl group, a polymerizable moiety, or a NIR dye;

[0283] L 1 and L 3 is independently a bond or a linker group selected from the group consisting of: optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20 heteroalkylene;

[0284] L 2 is a bond, an optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20 Heteroalkylene; -O-, optionally substituted -CH2C6H4O-, C2-C 20 PEG linker, amide, amino, optionally substituted C6-C10 arylene or optionally substituted 5- to 10-membered heteroarylene;

[0285] R 13 is an optionally substituted dye moiety selected from:

[0286]

[0287] where R N1 and R N2 is independently H or C1-C1 optionally substituted with one or more sulfonyl or carboxylic acid groups 10 Alkyl, and the wavy line indicates L 2 connection point.

[0288] In some embodiments of Formula IIIF-IIIH, L 2 is a bond or an optionally substituted group selected from: phenylene, Or –C6H4-O-.

[0289] In some embodiments of the compound of Formula IIIF-IIIH, R 10 It is NHC(O)C(CH3)CH2.

[0290] In certain embodiments of the compound of Formula IIIF-IIIH, R 9 It is NHC(O)C(CH3)CH2.

[0291] In some embodiments of the compound of formula IIIF-IIIH, the NIR dye moiety is a siloxamine dye moiety. In certain embodiments of the compound of formula IIIF-IIIH, Y 1 It's SiMe2.

[0292] In certain embodiments of the compound of Formula IIIF-IIIH, L 1 is an optionally substituted C1-C 10 Alkylene or optionally substituted C2-C 20 In certain embodiments, L 3 is an optionally substituted C1-C 10 Alkylene or optionally substituted C2-C 20 Heteroalkylene.

[0293] In some embodiments of the compound of Formula IIIF-IIIH, R 11 、R 14 and R 12 Is H. In certain embodiments of the compound of Formula IIIF, R 22 、R 25 、R 26 and R 27 It’s H.

[0294] In some embodiments, wherein two R 15 Both are H, and R 1 is independently selected at each occurrence from the group consisting of: H; an electron withdrawing group selected from the group consisting of halogen, C(O)R′, COOR′, C(O)NH2, C(O)NR′R″, CF3, CN, SO3H, SO2CF3, SO2R′, SO2NR′R″, ammonium, alkylammonium, and NO2, wherein R′ and R″ are independently H or C1-C6 alkyl; and an electron donating group selected from the group consisting of NR N1 R N2 , OR', NHC(O)R', OC(O)R', phenyl and vinyl groups, wherein R N1 、R N2 and R' are independently H or C1-C6 alkyl.

[0295] In other embodiments of Formula III, IIIA, IIIB, IIIC, IIID, IIIE, IIIF, IIIG or IIIH, the NIR dye portion has excitation and emission wavelengths in the optical window of the skin. In specific embodiments of Formula III, IIIA, IIIB, IIIC, IIID, IIIE, IIIF, IIIG or IIIH, the NIR dye portion has an absorption maximum between about 500 nm and about 900 nm, between about 600 nm and about 1000 nm, and between about 500 nm and about 1000 nm. In other embodiments of Formula III, IIIA, IIIB, IIIC, IIID, IIIE, IIIF, IIIG or IIIH, the NIR dye portion has an emission maximum between about 550 nm and about 900 nm, between about 600 nm and about 1000 nm, and between about 550 nm and about 1100 nm. In certain embodiments of formula III, IIIA, IIIB, IIIC, IIID, IIIE, IIIF, IIIG or IIIH, the compound itself is a NIR luminescent dye and has an absorption maximum between about 550 nm and about 1000 nm and an emission maximum between about 600 nm and about 1100 nm. An absorption maximum of greater than 500 nm, greater than 550 nm, greater than 600 nm, greater than 650 nm, greater than 700 nm. In other embodiments of formula III, IIIA, IIIB, IIIC, IIID, IIIE, IIIF, IIIG or IIIH, the compound has an absorption maximum of greater than 500 nm, greater than 550 nm, greater than 600 nm, greater than 650 nm, greater than 700 nm. In other embodiments of formula III, the compound has an emission maximum of greater than 550 nm, greater than 600 nm, greater than 650 nm, greater than 700 nm, greater than 800 nm, greater than 900 nm, greater than 1000 nm, greater than 1100 nm.

[0296] In some embodiments of any of the formulae disclosed herein (e.g., Formulae I-IIIF), one or more NIR dye moieties have a structure selected from: or an isomer, tautomer or salt thereof, wherein R N1 and R N2 are independently optionally selected from one or more of -SO3H, -SO3 – , –CO2H or –CO2 – C1-C 10 alkyl, and Indicates that L 2 connection point.

[0297] In some embodiments of Formula I, IA, IB, or IC, one or more NIR dye moieties have the following structure:

[0298]

[0299] where Y 1 is -O-, -P(O)(R')-, -Si(R')(R")-, or -NR'-, wherein R' and R" are independently H or C1-C6 alkyl;

[0300] R 20 and R 21 are independently H or C1-C6 alkyl; or R 21 and R 20 Together with the nitrogen atom to which they are attached, they form a 6- or 5-membered ring optionally substituted with a polymerizable moiety;

[0301] R 23 and R 24 are independently H or C1-C6 alkyl; or R 23 and R 24 Together with the nitrogen atom to which they are attached, they form a 6- or 5-membered ring optionally substituted with a polymerizable moiety;

[0302] R 22 and R 25 are independently H or C1-C6 alkyl; or R 21 and R 22 Together with the atoms to which they are attached, they form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring, or R 24 and R 25 Together with the atoms to which they are attached, they form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring; and

[0303] R 26 and R 27 are independently H or C1-C6 alkyl; or R 26 and R 20 Together with the atoms to which they are attached, they form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring, or R 27 and R 23 Together with the atoms to which they are attached, they form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring.

[0304] In some embodiments, Y 1 It is -Si(Me)2-.

[0305] In one embodiment, the compound of formula I-IIIH is a near infrared emitting dye. In one embodiment, the compound of formula I-IIIH has an absorption maximum between about 500nm and about 1000nm, between about 550nm and about 700nm, between about 550nm and about 800nm, between about 550nm and about 900nm, between about 600nm and about 800nm, between about 600nm and about 900nm, or between about 600nm and about 1000nm. In some embodiments, the compound of formula I-IIIH has an emission maximum between 550 and 1100nm, between about 600nm and about 1100nm, between about 700nm and about 1100nm, between about 600nm and about 900nm, between about 600nm and about 800nm, or between about 600nm and about 1000nm. In one embodiment, the compound of Formula I-IIIH is photostable and has excitation and emission spectra in the NIR optical window of the skin. In one embodiment, the compound of Formula I-IIIH is photostable and has excitation and emission wavelengths in the NIR optical window of the skin.

[0306] In certain embodiments, the compound of Formula I-IIIH has an absorption maximum of greater than 500 nm, greater than 550 nm, greater than 600 nm, greater than 650 nm, greater than 700 nm. In other embodiments, the compound of Formula I-IIIH has an emission maximum of greater than 550 nm, greater than 600 nm, greater than 650 nm, greater than 700 nm, greater than 800 nm, greater than 900 nm, greater than 1000 nm, greater than 1100 nm.

[0307] In some embodiments, the dye is encapsulated into oxygen-impermeable solid nanospheres. The nanospheres can be used for luminescent non-oxygen sensitive applications.

[0308] In one aspect, the present disclosure relates to a compound of formula AI:

[0309]

[0310] or an isomer, tautomer or salt thereof,

[0311] where dotted lines indicate bonds or the absence of bonds;

[0312] When connecting R 1 When the dotted line with O is a bond, R 1 It's CX 1 X 2 , and R 15 does not exist; and when connecting R 1 The dotted line between R and O is when there is no bond. 15is independently H or C1-C6 alkyl at each occurrence, and R 1 Each occurrence is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 10 a heteroalkyl group, a polymerizable moiety, a NIR dye moiety, an electron withdrawing group, or an electron donating group;

[0313] X 1 and X 2 are independently H or C1-C6 alkyl;

[0314] R 2 is H or C1-C6 alkyl;

[0315] Z is optionally replaced by R 11 、R 12 、R 14 or L 2 R 13 Substituted C6-C 14 arylene;

[0316] R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 11 、R 12 、R 13 and R 14 are independently H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C 10 a heteroalkyl group, a polymerizable moiety, a NIR dye moiety, an electron withdrawing group, or an electron donating group;

[0317] R 9 and R 10 is independently H, a C1-C6 alkyl, a polymerizable moiety, or a NIR dye moiety;

[0318] L 1 , L 2 and L 3 are independently a bond or a linker group; and

[0319] The compounds comprise one or more NIR dye moieties and one or more polymerizable moieties.

[0320] In some embodiments of the compound of Formula AI, the compound has the structure of Formula AIA, AIB, or AIC:

[0321]

[0322] or an isomer, tautomer or salt thereof.

[0323] In some embodiments of the compound of Formula AI, the compound has the structure of Formula AII:

[0324]

[0325] or an isomer, tautomer or salt thereof,

[0326] where R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 , L 1 , L 2 and L 3 As defined for the compound of formula AI, and wherein the compound comprises one or more NIR dye moieties and one or more polymerizable moieties.

[0327] In some embodiments of the compound of Formula AI, AIA, AIB, AIC, or AII, R 3 、R 5 、R 6 and R 8 It’s H.

[0328] In some embodiments of the compound of Formula AII, the compound has the structure of Formula AIIA:

[0329]

[0330] or an isomer, tautomer or salt thereof.

[0331] In some embodiments of the compound of Formula AI, AIA, AIB, AIC, AII or AIIA, L 2 is a key, and R 13 is H. In some embodiments, R 4 、R 7 、R 11 、R 12 and R 14 is H. In other embodiments, L 3 is an optionally substituted C1-C6 alkylene. 9It is –NHC(O)C(CH3)CH2.

[0332] In some embodiments of the compound of Formula AIIA, R 1 The two dotted lines between R and O are both non-bonded. 15 do not exist, and R 1 and R 2 Each of is H.

[0333] In some embodiments of the compound of Formula AII, the compound has the structure of Formula AIIB:

[0334]

[0335] or an isomer, tautomer or salt thereof.

[0336] In some embodiments of a compound of Formula AI, AIA, AIB, AIC, AII, AIIA, or AIIB, the compound is selected from Compounds 1, 2, 3, 4, 5, 6, or 7 of Table 1. In some embodiments of a compound of Formula AI, AIA, AIB, AIC, AII, AIIA, or AIIB, the compound is selected from Table 1 or Table 2. In some embodiments of a compound of Formula AI, AIA, AIB, AIC, AII, AIIA, or AIIB, the compound is selected from Table 1, Table 2, and / or Table 3.

[0337] In some embodiments of the compound of Formula AI, the compound has the structure of Formula AIII:

[0338]

[0339] or an isomer, tautomer or salt thereof,

[0340] where dotted lines indicate bonds or the absence of bonds;

[0341] When connecting R 1 When the dotted line with O is a bond, R 1 It's CX 1 X 2 , and R 15 does not exist; and when connecting R 1 The dotted line between R and O is when there is no bond. 15 is independently H or C1-C6 alkyl at each occurrence, and R 1 Each occurrence is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 10 a heteroalkyl group, a polymerizable moiety, a NIR dye moiety, an electron withdrawing group, or an electron donating group;

[0342] X1 and X 2 are independently H or C1-C6 alkyl;

[0343] R 2 is H or C1-C6 alkyl;

[0344] R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 11 、R 12 and R 14 are independently H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C 10 a heteroalkyl group, a polymerizable moiety, a NIR dye moiety, an electron withdrawing group, or an electron donating group;

[0345] R 9 、R 10 and R 13 are independently H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C 10 heteroalkyl groups, polymerizable moieties, or NIR dyes;

[0346] L 1 , L 2 and L 3 are independently a linker group or a bond; and

[0347] wherein the compound comprises one or more NIR dye moieties and one or more polymerizable moieties.

[0348] In some embodiments of the compound of Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB or AIII, the electron withdrawing group is selected from the group consisting of halogen, -C(O)R', -COOR', -C(O)NH2, -C(O)NR'R", -CF3, -CH2F, -CHF2, C1-C6 perfluoroalkyl, -OCF3, -SCF3, -N(CF3)2, -CN, -SO3H, -SO2CF3, -SO2R', -SO2NR'R", -P(O)R a R b R c , ammonium, alkylammonium and -NO2, wherein R' and R" are independently H or C1-C6 alkyl; or R' and R" together with the nitrogen atom form a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclic ring optionally containing one additional heteroatom selected from S, O or N; and wherein R a、R b and R c are independently C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy or C6-C 10 Aryloxy.

[0349] In some embodiments of the compound of Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB, or AIII, the electron donating group is selected from the group consisting of: -NR N1 R N2 , -OR', -NHC(O)R', -OC(O)R', phenyl and vinyl, where R N1 、R N2 and R' are independently H or C1-C6 alkyl.

[0350] In some embodiments of the compound of Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB or AIII, L 1 is a bond or a linker group selected from the group consisting of optionally substituted amino, optionally substituted amide, -O-, optionally substituted -CH2C6H4O-, C2-C 20 PEG linker, optionally substituted C6-C 10 arylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted -C1-C6 alkylene-Ar-, optionally substituted -C2-C6 alkenylene-Ar-, optionally substituted -C2-C6 alkynylene-Ar-, optionally substituted -C(O)NH-C1-C6 alkylene-Ar-, optionally substituted -C1-C6 alkylene-C(O)NH-C1-C6 alkylene-, optionally substituted -C1-C6 alkylene-C(O)NH-C1-C6 alkylene-Ar-, optionally substituted -(CH2CH2O) n CH2-, optionally substituted -CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n CH2CH2-, optionally substituted-CH2CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n -, optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene and optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20 heteroalkylene, wherein n is an integer between 1 and 10, and Ar is C6-C 10 In some embodiments, L 1Contains one or more substituents selected from the group consisting of carboxyl groups, sulfonic acid groups, ammonium groups and amino groups.

[0351] In some embodiments of the compound of Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB or AIII, L 2 is a bond or a linker group selected from the group consisting of optionally substituted amino, optionally substituted amide, -O-, optionally substituted –(CH2) m C6H4O-、C2-C 20 PEG linker, optionally substituted C6-C 10 arylene, optionally substituted 5- to 10-membered heteroarylene, -[optionally substituted 5- to 10-membered heteroarylene]-[optionally substituted C6-C 10 Arylene]-, -[optionally substituted C6-C 10 arylene]-[optionally substituted 5- to 10-membered heteroarylene]-, -Ar-Ar-, optionally substituted -C1-C6 alkylene-Ar-, optionally substituted C2-C6 alkenylene-Ar-, optionally substituted C2-C6 alkynylene-Ar-, optionally substituted –C(O)NH-C1-C6 alkylene-Ar-, optionally substituted -C1-C6 alkylene-C(O)NH-C1-C6 alkylene-, optionally substituted –C1-C6 alkylene-C(O)NH-C1-C6 alkylene-Ar-, optionally substituted –(CH2CH2O) n CH2-, optionally substituted -CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n CH2CH2-, optionally substituted-CH2CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n -, optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene and optionally substituted C2-C 20 heteroalkylene, wherein n is an integer between 1 and 10, m is an integer 0, 1 or 2, and Ar is C6-C 10 In some embodiments, L 2 Contains one or more substituents selected from the group consisting of carboxyl groups, sulfonic acid groups, ammonium groups and amino groups.

[0352] In some embodiments of the compound of Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB or AIII, L 2is a bond or a linker group selected from the group consisting of optionally substituted amino, optionally substituted amide, -O-, optionally substituted -CH2C6H4O-, C2-C 20 PEG linker, optionally substituted C6-C 10 arylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted -C1-C6 alkylene-Ar-, optionally substituted C2-C6 alkenylene-Ar-, optionally substituted C2-C6 alkynylene-Ar-, optionally substituted -C(O)NH-C1-C6 alkylene-Ar-, optionally substituted -C1-C6 alkylene-C(O)NH-C1-C6 alkylene-, optionally substituted -C1-C6 alkylene-C(O)NH-C1-C6 alkylene-Ar-, optionally substituted -(CH2CH2O) n CH2-, optionally substituted -CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n CH2CH2-, optionally substituted-CH2CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n -, optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene and optionally substituted C2-C 20 heteroalkylene, wherein n is an integer between 1 and 10, and Ar is C6-C 10 In some embodiments, L 3 Contains one or more substituents selected from the group consisting of carboxyl groups, sulfonic acid groups, ammonium groups and amino groups.

[0353] In some embodiments of compounds of Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB, or AIII, the polymerizable moiety is selected from -NH(C=O)C(R)=CH2, -O(C=O)C(R)=CH2, and -CH=CH2, wherein R is H or C1-C3 alkyl.

[0354] In some embodiments of compounds of Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB, or AIII, the NIR dye moiety is a cyanine, hemicyanine, fluorone, oxazine, phenanthidine, rhodamine, rosamine, indolium, quinolinium, benzophenoxazine, benzopyrylium, bisindolylmaleimide, boron-dipyrromethene, boron-aza-dipyrromethene, carbopyronine, perylene, porphyrin, ruthenium complex, lanthanide complex, benzoxanthenium, xanthene, fluorescein, squarylium, coumarin, anthracene, tetracene, pentacene, or pyrene dye residue.

[0355] In some embodiments of any of Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB, or AIII, one or more NIR dye moieties have a structure selected from: or an isomer, tautomer or salt thereof, wherein R N1 and R N2 are independently optionally selected from one or more of -SO3H, -SO3 – , –CO2H or –CO2 – C1-C 10 alkyl, and Indicates that L 2 connection point.

[0356] In some embodiments of any of Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB, or AIII, one or more NIR dye moieties have a structure selected from:

[0357]

[0358] or an isomer, tautomer or salt thereof, wherein Indicates that L 2 connection point.

[0359] In some embodiments of any of Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB, or AIII, one or more NIR dye moieties have the following structure:

[0360]

[0361] wherein R' at each occurrence is independently H, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl or optionally substituted C2-C 20 Heteroalkyl.

[0362] In some embodiments of any of Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB, or AIII, the NIR dye moiety has the following structure:

[0363]

[0364] where Y 1 Yes-Ge(R d )(R e )-、-O-、-P(O)(Rd )-、-Si(R d )(R e )-or–NR d -, where R d and R e are independently H, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy or C6-C 10 aryloxy;

[0365] R 20 and R 21 are independently H, C1-C6 alkyl or optionally substituted -C1-C6 alkylene-aryl; or R 21 and R 20 Together with the nitrogen atom to which they are attached, they form a 6-, 5-, or 4-membered ring optionally substituted with a polymerizable moiety;

[0366] R 23 and R 24 are independently H, C1-C6 alkyl or optionally substituted -C1-C6 alkylene-aryl; or R 23 and R 24 Together with the nitrogen atom to which they are attached, they form a 6-, 5-, or 4-membered ring optionally substituted with a polymerizable moiety;

[0367] R 22 and R 25 are independently H or C1-C6 alkyl; or R 21 and R 22 Together with the atoms to which they are attached, they form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring, or R 24 and R 25 Together with the atoms to which they are attached, they form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring; and

[0368] R 26 and R 27 are independently H or C1-C6 alkyl; or R 26 and R 20 Together with the atoms to which they are attached, they form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring, or R 27 and R 23 Together with the atoms to which they are attached, they form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring.

[0369] In some embodiments of the compound of Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB or AIII, Y 1 Is –Si(Me)2- or –Ge(Me)2–.

[0370] In some embodiments of a compound of Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB, or AIII, Z is optionally substituted phenylene or anthracene.

[0371] In some embodiments of the compound of Formula AI, the compound has the structure of Formula AIIIF:

[0372]

[0373] or an isomer, tautomer or salt thereof,

[0374] wherein the dotted line represents a bond or the absence of a bond independently at each occurrence; and when connecting R 1 When the dotted line with O is a bond, R 1 It's CX 1 X 2 , and R 15 does not exist; and when connecting R 1 The dotted line between R and O is when there is no bond. 15 is H or C1-C6 alkyl, and R 1 Each occurrence is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 10 a heteroalkyl group, a polymerizable moiety, a NIR dye moiety, an electron withdrawing group, or an electron donating group;

[0375] X 1 and X 2 are independently H or C1-C6 alkyl;

[0376] R 2 is H or C1-C6 alkyl;

[0377] R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 11 、R 12 and R 14 are independently H, C1-C6 alkyl, a polymerizable moiety, an electron withdrawing group, or an electron donating group;

[0378] R 9 and R 10 is independently H, a C1-C6 alkyl, a polymerizable moiety, or a NIR dye moiety;

[0379] L 1 and L 3 is independently a bond or a linker group selected from the group consisting of: optionally substituted C1-C10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20 heteroalkylene, optionally substituted -(CH2CH2O) n CH2-, optionally substituted -CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n CH2CH2-, optionally substituted-CH2CH2(CH2CH2O) n -, optionally substituted (CH2CH2O) n -, where n is an integer between 1 and 10;

[0380] L 2 is a bond, an optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20 Heteroalkylene; -O-, optionally substituted –(CH2) m C6H4O-, amide, amino, optionally substituted C6-C 10 arylene, optionally substituted 5- to 10-membered heteroarylene, -[optionally substituted 5- to 10-membered heteroarylene]-[optionally substituted C6-C 10 Arylene]-, -[optionally substituted C6-C 10 arylene]-[optionally substituted 5- to 10-membered heteroarylene]-, wherein m is 0, 1 or 2;

[0381] Y 1 Yes-Ge(R d )(R e )-、-O-、-P(O)(R d )-、-Si(R d )(R e )-or-NR d -, where R d and R e are independently H, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy or C6-C 10 aryloxy;

[0382] R 20 and R 21 are independently H, C1-C6 alkyl or optionally substituted -C1-C6 alkylene-aryl; or R 21 and R 20Together with the nitrogen atom to which they are attached, they form a 6-, 5-, or 4-membered ring optionally substituted with a polymerizable moiety;

[0383] R 23 and R 24 are independently H, C1-C6 alkyl or optionally substituted -C1-C6 alkylene-aryl; or R 23 and R 24 Together with the nitrogen atom to which they are attached, they form a 6-, 5-, or 4-membered ring optionally substituted with a polymerizable moiety;

[0384] R 22 and R 25 are independently H or C1-C6 alkyl; or R 21 and R 22 Together with the atoms to which they are attached, they form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring, or R 24 and R 25 Together with the atoms to which they are attached, they form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring;

[0385] R 26 and R 27 are independently H or C1-C6 alkyl; or R 26 and R 20 Together with the atoms to which they are attached, they form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring, or R 27 and R 23 Together with the atoms to which they are attached, they form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring; and

[0386] Compounds containing one or more polymerizable moieties

[0387] In some embodiments of the compound of Formula AIIIF, L 2 is a bond or an optionally substituted group selected from: phenylene, Or –C6H4-O-.

[0388] In some embodiments of the compound of Formula AIIIF, Y 1 is -Si(Me)2- or -Ge(Me)2-. In some embodiments of the compound of formula AIIIF, R 10 is -NHC(O)C(CH3)CH2. In some embodiments of the compound of formula AIIIF, R 9 It is -NHC(O)C(CH3)CH2.

[0389] In some embodiments of the compound of Formula AIIIF, L 1is an optionally substituted C1-C 10 Alkylene or optionally substituted C2-C 20 In some embodiments of the compound of formula AIIIF, L 3 is an optionally substituted C1-C 10 Alkylene or optionally substituted C2-C 20 Heteroalkylene.

[0390] In some embodiments of the compound of Formula AIIIF, R 11 、R 14 and R 12 is H. In some embodiments of the compound of Formula AIIIF, R 22 、R 25 、R 26 and R 27 is H. In some embodiments of the compound of Formula AIIIF, R 15 Each is H, and R 1 is independently selected at each occurrence from H; an electron withdrawing group selected from halogen, -C(O)R', -COOR', -C(O)NH2, -C(O)NR'R", -CF3, -CH2F, -CHF2, C1-C6 perfluoroalkyl, -OCF3, -SCF3, -N(CF3)2, -CN, -SO3H, -SO2CF3, -SO2R', -SO2NR'R", -P(O)R a R b R c , ammonium, alkylammonium and -NO2, wherein R' and R" are independently H or C1-C6 alkyl; or R' and R" together with the nitrogen atom form a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclic ring optionally containing one additional heteroatom selected from S, O or N; and wherein R a 、R b and R c are independently C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy or C6-C 10 Aryloxy; or an electron-donating group selected from -NR N1 R N2 , -OR', -NHC(O)R', -OC(O)R', phenyl and vinyl groups, wherein R N1 、R N2 and R' are independently H or C1-C6 alkyl.

[0391] In some embodiments of the compound of Formula AI, the compound has the structure of Formula AIIIE:

[0392]

[0393] or an isomer, tautomer or salt thereof,

[0394] in:

[0395] The dotted line represents a bond or the absence of a bond independently at each occurrence; and when connecting R 1 When the dotted line with O is a bond, R 1 It's CX 1 X 2 , and R 15 does not exist; and when connecting R 1 The dotted line between R and O is when there is no bond. 15 is H or C1-C6 alkyl;

[0396] L 1 , L 2 and L 3 is a linker moiety independently selected from the group consisting of a bond, an optionally substituted C1-C6 alkylene, an optionally substituted C2-C6 alkenylene, an optionally substituted C2-C6 alkynylene, -O-, an optionally substituted -(CH2CH2O) n CH2-, optionally substituted -CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n CH2CH2-, optionally substituted-CH2CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n -, optionally substituted C2-C 20 PEG linker, optionally substituted amide, optionally substituted amino and optionally substituted C6-C 10 Arylene, wherein n is an integer between 1 and 10;

[0397] R 3 、R 4 and R 7 Independently selected from H, C1-C6 alkyl, electron withdrawing group and electron donating group;

[0398] R 13 is a NIR dye moiety; and

[0399] R 10 and R 9 is H or a polymerizable moiety.

[0400] In some embodiments of the compound of Formula AIIIE, R 9 and R 10 It is -NHC(O)C(CH3)CH2.

[0401] In one embodiment of the compound of Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF or AIIIE, the compound is selected from Table 1. In one embodiment of the compound of Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF or AIIIE, the compound is selected from Table 2. In one embodiment of the compound of Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF or AIIIE, the compound is selected from Table 3.

[0402] In one embodiment, the compound of formula AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF or AIIIE is a near-infrared emitting dye. In one embodiment, the compound of formula I-IIIH has an absorption maximum between about 500 nm and about 1000 nm, between about 550 nm and about 700 nm, between about 550 nm and about 800 nm, between about 550 nm and about 900 nm, between about 600 nm and about 800 nm, between about 600 nm and about 900 nm, or between about 600 nm and about 1000 nm. In some embodiments, the compound of formula AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF or AIIIE has an emission maximum between 550 and 1100 nm, between about 600 nm and about 1100 nm, between about 700 nm and about 1100 nm, between about 600 nm and about 900 nm, between about 600 nm and about 800 nm, or between about 600 nm and about 1000 nm. In one embodiment, the compound of formula AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF or AIIIE is photostable and has an excitation and emission spectrum in the NIR optical window of skin. In one embodiment, the compound of formula AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF or AIIIE is photostable and has an excitation and emission wavelength in the NIR optical window of skin.

[0403] In certain embodiments, the compound of Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, or AIIIE has an absorption maximum of greater than 500 nm, greater than 550 nm, greater than 600 nm, greater than 650 nm, or greater than 700 nm. In other embodiments, the compound of Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, or AIIIE has an emission maximum of greater than 550 nm, greater than 600 nm, greater than 650 nm, greater than 700 nm, greater than 800 nm, greater than 900 nm, greater than 1000 nm, or greater than 1100 nm.

[0404] In some embodiments, the dye is encapsulated into oxygen-impermeable solid nanospheres. The nanospheres can be used for luminescent non-oxygen sensitive applications.

[0405] In one aspect, the present disclosure relates to a compound of formula IV-I:

[0406]

[0407] or an isomer, tautomer, solvate or salt thereof, wherein:

[0408] R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 11 、R 12 and R 14 Each is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C 10 Heteroalkyl, halogen, -C(O)R', -COOR', -C(O)NH2, -C(O)NR'R", -CF3, -CN, -SO3H, -SO2CF3, -SO2R', -SO2NR'R", -N(R')2, -N(R')3 + , -NO2, -OR', -NHC(O)R', -OC(O)R' or phenyl, wherein R' and R" are each independently H or C1-C6 alkyl; or R' and R" together with the nitrogen atom form a 5- or 6-membered heterocyclic ring optionally containing one additional heteroatom selected from S, O or N;

[0409] R 2 and R 15 Each independently is H or C1-C6 alkyl;

[0410] R 9 and R 10are independently H, C1-C6 alkyl or -NHC(O)C(CH3)CH2;

[0411] L 1 and L 3 is independently a bond or a linker group selected from the group consisting of: optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20 heteroalkylene, optionally substituted -(CH2CH2O) n CH2-, optionally substituted -CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O)nCH2CH2-, optionally substituted -CH2CH2(CH2CH2O) n -, optionally substituted (CH2CH2O) n -, where n is an integer between 1 and 10;

[0412] L 2 is a bond, optionally substituted phenylene, optionally substituted -alkylene-phenylene-, optionally substituted -phenylene-alkylene-, or optionally substituted 5- or 6-membered heteroarylene;

[0413] Y 1 Selected from -P(O)(R d )-、-Ge(R d )(R e )-or-Si(R d )(R e )-, where R d and R e Each is H, -OH, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy or C6-C 10 aryloxy;

[0414] R 20 、R 21 、R 23 and R 24 are each independently H; optionally replaced by -NH2 or -NH3 + Substituted C1-C6 alkyl; C2-C6 alkenyl; or optionally substituted by -B(OR 2 )2 substituted benzyl;

[0415] R 22 、R 25 、R 26 and R 27 Each independently is H or C1-C6 alkyl;

[0416] Alternatively, (R 21 and R 20 ) and / or (R 23 and R 24 ) together with the nitrogen atom to which they are attached, form a 6-, 5- or 4-membered saturated or partially saturated ring;

[0417] Alternatively, (R 21 and R 22 )、(R 24 and R 25 )、(R 23 and R 27 ) and / or (R 26 and R 20 ) together with the atoms to which they are attached form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring.

[0418] In one embodiment of the compound of formula (IV-I), Y 1 Yes-P(O)(R d )-. In one embodiment, Y 1 Yes-P(O)(R d )-, and R d is C1-C6 alkoxy. In one embodiment, Y 1 Yes-P(O)(R d )-, and R d is –OH, methoxy, or ethoxy.

[0419] In one embodiment of the compound of formula (IV-I), Y 1 Yes-Ge(R d )(R e )-or-Si(R d )(R e )-, where R d and R e Each is H, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy or C6-C 10 Aryloxy.

[0420] In some embodiments of the compound of Formula (IV-I), the compound has the structure of Formula (IV-IA):

[0421]

[0422] or an isomer, tautomer, solvate or salt thereof, wherein:

[0423] R 1 、R 3 、R 4 、R 5 、R6 、R 7 、R 8 、R 11 、R 12 and R 14 Each is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C 10 Heteroalkyl, halogen, -C(O)R', -COOR', -C(O)NH2, -C(O)NR'R", -CF3, -CN, -SO3H, -SO2CF3, -SO2R', -SO2NR'R", -N(R')2, -N(R')3 + , -NO2, -OR', -NHC(O)R', -OC(O)R' or phenyl;

[0424] R' and R" are each independently H or C1-C6 alkyl; or R' and R" together with the nitrogen atom to which they are attached may form a 5- or 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains one additional heteroatom selected from S, O or N;

[0425] R d and R e Each is H, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy or C6-C 10 aryloxy;

[0426] R 2 and R 15 Each independently is H or C1-C6 alkyl;

[0427] R 9 and R 10 are independently H, C1-C6 alkyl or -NHC(O)C(CH3)CH2;

[0428] L 1 and L 3 is independently a bond or a linker group selected from the group consisting of: optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20 heteroalkylene, optionally substituted -(CH2CH2O) n CH2-, optionally substituted -CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O)nCH2CH2-, optionally substituted -CH2CH2(CH2CH2O) n -, optionally substituted (CH2CH2O) n-, where n is an integer between 1 and 5;

[0429] L 2 is a bond, optionally substituted phenylene, optionally substituted -alkylene-phenylene-, optionally substituted -phenylene-alkylene-, or optionally substituted 5- or 6-membered heteroarylene;

[0430] R 20 、R 21 、R 23 and R 24 are each independently H; optionally replaced by -NH2 or -NH3 + Substituted C1-C6 alkyl; C2-C6 alkenyl; or optionally substituted by -B(OR 2 )2 substituted benzyl;

[0431] R 22 、R 25 、R 26 and R 27 Each independently is H or C1-C6 alkyl;

[0432] Alternatively, (R 21 and R 20 ) and / or (R 23 and R 24 ) together with the nitrogen atom to which they are attached, form a 6-, 5- or 4-membered saturated or partially saturated ring;

[0433] Alternatively, (R 21 and R 22 )、(R 24 and R 25 )、(R 23 and R 27 ) and / or (R 26 and R 20 ) together with the atoms to which they are attached form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring.

[0434] In some embodiments of the compound of formula (IV-I), the compound has the structure of formula (IV-IB):

[0435]

[0436] or an isomer, tautomer, solvate or salt thereof, wherein:

[0437] R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 11 、R12 and R 14 Each is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C 10 Heteroalkyl, halogen, -C(O)R', -COOR', -C(O)NH2, -C(O)NR'R", -CF3, -CN, -SO3H, -SO2CF3, -SO2R', -SO2NR'R", -N(R')2, -N(R')3 + , -NO2, -OR', -NHC(O)R', -OC(O)R' or phenyl;

[0438] R' and R" are each independently H or C1-C6 alkyl; or optionally, R' and R" in -SO2NR'R" may form together with the nitrogen atom to which they are attached a 5- or 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains one additional heteroatom selected from S, O or N;

[0439] R d and R e Each is H, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy or C6-C 10 aryloxy;

[0440] R 2 and R 15 Each independently is H or C1-C6 alkyl;

[0441] R 9 and R 10 are independently H, C1-C6 alkyl or -NHC(O)C(CH3)CH2;

[0442] L 1 and L 3 is independently a bond or a linker group selected from the group consisting of: optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20 heteroalkylene, optionally substituted -(CH2CH2O) n CH2-, optionally substituted -CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O)nCH2CH2-, optionally substituted -CH2CH2(CH2CH2O) n -, optionally substituted (CH2CH2O) n -, where n is an integer between 1 and 5;

[0443] L 2is a bond; phenylene optionally substituted by at least one substituent selected from C1-C3 alkyl, C1-C3 alkoxy or halogen; optionally substituted -C1-C3 alkylene-phenylene-; optionally substituted -phenylene-C1-C3 alkylene-;

[0444] R 20 、R 21 、R 23 and R 24 are each independently H; optionally replaced by -NH2 or -NH3 + Substituted C1-C6 alkyl; C2-C6 alkenyl; or optionally substituted by -B(OR 2 )2 substituted benzyl;

[0445] R 22 、R 25 、R 26 and R 27 Each independently is H or C1-C6 alkyl;

[0446] Alternatively, (R 21 and R 20 ) and / or (R 23 and R 24 ) together with the nitrogen atom to which they are attached, form a 6-, 5- or 4-membered saturated or partially saturated ring;

[0447] Alternatively, (R 21 and R 22 )、(R 24 and R 25 )、(R 23 and R 27 ) and / or (R 26 and R 20 ) together with the atoms to which they are attached form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring; and

[0448] When L 2 When it is a key, R 20 、R 21 、R 23 and R 24 At least one of is optionally replaced by -B(OR 2 )2 substituted benzyl;

[0449] Provided that the compound is not compounds 27, 54, 63, 64, 65, 66, 67, 69, 73, 74, 75, 76, 77, 81, 82 and 83.

[0450] In one embodiment of the compounds of formula (IV-I), (IV-IA) and / or (IV-IB), R 20 、R21 、R 23 and R 24 are each independently H; optionally replaced by -NH2 or -NH3 + substituted C1-C4 alkyl; C2-C4 alkenyl; or optionally substituted by -B(OR 2 )2 substituted benzyl; or alternatively, (R 21 and R 22 )、(R 24 and R 25 )、(R 23 and R 27 ) and / or (R 26 and R 20 ) together with the atoms to which they are attached form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring. In one embodiment, R 20 、R 21 、R 23 and R 24 are each independently H; optionally replaced by -NH2 or -NH3 + substituted C1-C3 alkyl; or C2-C3 alkenyl; or alternatively, (R 21 and R 22 )、(R 24 and R 25 )、(R 23 and R 27 ) and / or (R 26 and R 20 ) together with the atoms to which they are attached form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring. In one embodiment, R 20 、R 21 、R 23 and R 24 are each independently H, methyl, ethyl or -CH2CH=CH2, or alternatively, (R 21 and R 22 )、(R 24 and R 25 )、(R 23 and R 27 ) and / or (R 26 and R 20 ) together with the atoms to which they are attached form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring. In one embodiment, R 20 、R 21 、R 23 and R 24 Each is independently H, methyl, ethyl or -CH2CH=CH2.

[0451] In one embodiment of the compounds of Formula (IV-I), (IV-IA), (IV-IB), (IV), (IVA) and / or (IVB), R 20 、R 21 、R 23 and R 24 are each independently H, C1-C6 alkyl or optionally substituted by -B(OR 2 )2-substituted benzyl.

[0452] In one embodiment of the compounds of formula (IV-I), (IV-IA) and / or (IV-IB), L 2 is a bond, optionally substituted phenylene, optionally substituted -alkylene-phenylene-, optionally substituted -phenylene-alkylene-, or optionally substituted 5- or 6-membered heteroarylene; wherein the optional substituent is halogen, C1-C3 alkyl, or C1-C3 alkoxy. In one embodiment, L 2 is a bond, optionally substituted phenylene, optionally substituted -alkylene-phenylene-, optionally substituted -phenylene-alkylene- or optionally substituted 5- or 6-membered heteroarylene; wherein the optional substituent is halogen, C1-C3 alkyl or C1-C3 alkoxy.

[0453] In one embodiment of the compounds of formula (IV-I), (IV-IA) and / or (IV-IB), L 2 is optionally substituted -C1-C3 alkylene-phenylene- or optionally substituted -phenylene-C1-C3 alkylene-.

[0454] In one embodiment, L 2 yes Each is optionally substituted.

[0455] In one embodiment of the compound of Formula (IV-I), (IV-IA), (IV-IB), (IV), (IVA) and / or (IVB), L 2 is a bond, optionally substituted phenylene or optionally substituted 5- or 6-membered heteroarylene.

[0456] In one embodiment of the compounds of formula (IV-I), (IV-IA), (IV) and / or (IVA), L 2 is a bond, optionally substituted phenylene or optionally substituted 5- or 6-membered heteroarylene.

[0457] In one embodiment of the compounds of formula (IV-I), (IV-IB), (IV) and / or (IVB), L 2 is a bond; phenylene optionally substituted by at least one substituent selected from C1-C3 alkyl, C1-C3 alkoxy or halogen;

[0458] In one aspect, the present disclosure relates to a compound of formula IV:

[0459]

[0460] or an isomer, tautomer, solvate or salt thereof, wherein:

[0461] R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 11 、R 12 and R 14 Each is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C 10 Heteroalkyl, halogen, -C(O)R', -COOR', -C(O)NH2, -C(O)NR'R", -CF3, -CN, -SO3H, -SO2CF3, -SO2R', -SO2NR'R", -N(R')2, -N(R')3 + , -NO2, -OR', -NHC(O)R', -OC(O)R' or phenyl, wherein R' and R" are each independently H or C1-C6 alkyl; or R' and R" together with the nitrogen atom form a 5- or 6-membered heterocyclic ring optionally containing one additional heteroatom selected from S, O or N;

[0462] R 2 and R 15 Each independently is H or C1-C6 alkyl;

[0463] R 9 and R 10 are independently H, C1-C6 alkyl or -NHC(O)C(CH3)CH2;

[0464] L 1 and L 3 is independently a bond or a linker group selected from the group consisting of: optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20 heteroalkylene, optionally substituted -(CH2CH2O) n CH2-, optionally substituted -CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O)n CH2CH2-, optionally substituted-CH2CH2(CH2CH2O) n -, optionally substituted (CH2CH2O) n -, where n is an integer between 1 and 10;

[0465] L 2 is a bond, optionally substituted phenylene or optionally substituted 5- or 6-membered heteroarylene;

[0466] Y 1 Selected from -Ge(R d )(R e )-or-Si(R d )(R e )-, where R d and R e Each is H, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy or C6-C 10 aryloxy;

[0467] R 20 、R 21 、R 23 and R 24 are each independently H, C1-C6 alkyl, optionally substituted by -B(OR 2 )2 substituted benzyl;

[0468] R 22 、R 25 、R 26 and R 27 Each independently is H or C1-C6 alkyl;

[0469] Alternatively, (R 21 and R 20 ) and / or (R 23 and R 24 ) together with the nitrogen atom to which they are attached, form a 6-, 5- or 4-membered saturated or partially saturated ring;

[0470] Alternatively, (R 21 and R 22 )、(R 24 and R 25 )、(R 23 and R 27 ) and / or (R 26 and R 20 ) together with the atoms to which they are attached form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring.

[0471] In some embodiments of the compound of Formula (IV) and / or (IV-I), the compound is not compounds 27, 54, 63, 64, 65, 66, 67, 69, 73, 74, 75, 76, 77, 81, 82, and 83 of Table 1.

[0472] In some embodiments of the compound of formula (IV), the compound has the structure of formula (IVA):

[0473]

[0474] or an isomer, tautomer, solvate or salt thereof, wherein:

[0475] R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 11 、R 12 and R 14 Each is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C 10 Heteroalkyl, halogen, -C(O)R', -COOR', -C(O)NH2, -C(O)NR'R", -CF3, -CN, -SO3H, -SO2CF3, -SO2R', -SO2NR'R", -N(R')2, -N(R')3 + , -NO2, -OR', -NHC(O)R', -OC(O)R' or phenyl;

[0476] R' and R" are each independently H or C1-C6 alkyl; or R' and R" together with the nitrogen atom to which they are attached may form a 5- or 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains one additional heteroatom selected from S, O or N;

[0477] R d and R e Each is H, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy or C6-C 10 aryloxy;

[0478] R 2 and R 15 Each independently is H or C1-C6 alkyl;

[0479] R 9 and R 10 are independently H, C1-C6 alkyl or -NHC(O)C(CH3)CH2;

[0480] L 1 and L 3 is independently a bond or a linker group selected from the group consisting of: optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20 heteroalkylene, optionally substituted -(CH2CH2O) n CH2-, optionally substituted -CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n CH2CH2-, optionally substituted-CH2CH2(CH2CH2O) n -, optionally substituted (CH2CH2O) n -, where n is an integer between 1 and 5;

[0481] L 2 is a bond, optionally substituted phenylene or optionally substituted 5- or 6-membered heteroarylene;

[0482] R 20 、R 21 、R 23 and R 24 are each independently H, C1-C6 alkyl, optionally substituted by -B(OR 2 )2 substituted benzyl;

[0483] R 22 、R 25 、R 26 and R 27 Each independently is H or C1-C6 alkyl;

[0484] Alternatively, (R 21 and R 20 ) and / or (R 23 and R 24 ) together with the nitrogen atom to which they are attached, form a 6-, 5- or 4-membered saturated or partially saturated ring;

[0485] Alternatively, (R 21 and R 22 )、(R 24 and R 25 )、(R 23 and R 27 ) and / or (R 26 and R 20 ) together with the atoms to which they are attached form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring.

[0486] In some embodiments of the compound of formula (IV), the compound has the structure of formula (IVB):

[0487]

[0488] or an isomer, tautomer, solvate or salt thereof, wherein:

[0489] R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 11 、R 12 and R 14 Each is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C 10 Heteroalkyl, halogen, -C(O)R', -COOR', -C(O)NH2, -C(O)NR'R", -CF3, -CN, -SO3H, -SO2CF3, -SO2R', -SO2NR'R", -N(R')2, -N(R')3 + , -NO2, -OR', -NHC(O)R', -OC(O)R' or phenyl;

[0490] R' and R" are each independently H or C1-C6 alkyl; or optionally, R' and R" in -SO2NR'R" may form together with the nitrogen atom to which they are attached a 5- or 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains one additional heteroatom selected from S, O or N;

[0491] R d and R e Each is H, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy or C6-C 10 aryloxy;

[0492] R 2 and R 15 Each independently is H or C1-C6 alkyl;

[0493] R 9 and R 10 are independently H, C1-C6 alkyl or -NHC(O)C(CH3)CH2;

[0494] L 1 and L 3 is independently a bond or a linker group selected from the group consisting of: optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10Alkenylene, optionally substituted C2-C 10 Alkynylidene, optionally substituted C2-C 20 heteroalkylene, optionally substituted -(CH2CH2O) n CH2-, optionally substituted -CH2(CH2CH2O) n -, optionally substituted -(CH2CH2O) n CH2CH2-, optionally substituted-CH2CH2(CH2CH2O) n -, optionally substituted (CH2CH2O) n -, where n is an integer between 1 and 5;

[0495] L 2 is a bond; phenylene optionally substituted by at least one substituent selected from C1-C3 alkyl, C1-C3 alkoxy or halogen;

[0496] R 20 、R 21 、R 23 and R 24 are each independently H, C1-C6 alkyl, optionally substituted by -B(OR 2 )2 substituted benzyl;

[0497] R 22 、R 25 、R 26 and R 27 Each independently is H or C1-C6 alkyl;

[0498] Alternatively, (R 21 and R 20 ) and / or (R 23 and R 24 ) together with the nitrogen atom to which they are attached, form a 6-, 5- or 4-membered saturated or partially saturated ring;

[0499] Alternatively, (R 21 and R 22 )、(R 24 and R 25 )、(R 23 and R 27 ) and / or (R 26 and R 20 ) together with the atoms to which they are attached form an optionally substituted 6- or 5-membered saturated, unsaturated or partially saturated ring; and

[0500] When L 2 When it is a key, R 20 、R 21 、R 23 and R 24At least one of is optionally replaced by -B(OR 2 )2 substituted benzyl;

[0501] Provided that the compound is not compounds 27, 54, 63, 64, 65, 66, 67, 69, 73, 74, 75, 76, 77, 81, 82 and 83.

[0502] In one aspect of the compounds of Formula (IV-I), (IV-IA), (IV-IB), (IV), (IVA) and / or (IVB), L 2 Select from key,

[0503] In one aspect of the compounds of Formula (IV-I), (IV-IA), (IV-IB), (IV), (IVA) and / or (IVB), L 2 is phenylene substituted by 0, 1 or 2 substituents selected from halogen, methyl or methoxy.

[0504] In some embodiments of the compound of Formula (IV-I), (IV-IA), (IV-IB), (IV), (IVA), and / or (IVB), L 2 Select from key,

[0505] In some embodiments of compounds of Formula (IV-I), (IV-IA), (IV-IB), (IV), (IVA), and / or (IVB), R d and R e Each is a methyl group.

[0506] In some embodiments of compounds of Formula (IV-I), (IV-IA), (IV-IB), (IV), (IVA), and / or (IVB), R 10 is -NHC(O)C(CH3)CH2. In some embodiments of compounds of Formula (IV-I), (IV-IA), (IV-IB), (IV), (IVA) and / or (IVB), R 9 It is -NHC(O)C(CH3)CH2.

[0507] In some embodiments of the compound of Formula (IV-I), (IV-IA), (IV-IB), (IV), (IVA), and / or (IVB), L 1 It is C1-C 10 Alkylene, C2-C 20 Heteroalkylene, -(CH2CH2O) nCH2-, -(CH2CH2O) n CH2CH2- or -(CH2CH2O) n In some embodiments of the compound of Formula (IV-I), (IV-IA), (IV-IB), (IV), (IVA) and / or (IVB), L 3 It is C1-C 10 Alkylene, C2-C 20 Heteroalkylene, -CH2(CH2CH2O) n -、-CH2CH2-(CH2CH2O) n 、-(CH2CH2O) n CH2-, -(CH2CH2O) n CH2CH2- or -(CH2CH2O) n In some embodiments of the compound of Formula (IV-I), (IV-IA), (IV-IB), (IV), (IVA) and / or (IVB), L 1 and L 3 It is –CH2-CH2-CH2- or -(CH2CH2O)4CH2CH2-.

[0508] In some embodiments of compounds of Formula (IV-I), (IV-IA), (IV-IB), (IV), (IVA), and / or (IVB), R 11 、R 14 and R 12 is H. In some embodiments of compounds of Formula (IV-I), (IV-IA), (IV-IB), (IV), (IVA), and / or (IVB), R 22 、R 25 、R 26 and R 27 It’s H.

[0509] In some embodiments of compounds of Formula (IV-I), (IV-IA), (IV-IB), (IV), (IVA), and / or (IVB), R 3 、R 4 、R 7 and R 8 is selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, -SO2NR'R", -CN and -NO2. In some embodiments of the compounds of Formula (IV-I), (IV-IA), (IV-IB), (IV), (IVA) and / or (IVB), R 3 、R 4 、R 7 and R 8At least one of the following is selected from methyl, -CF3, methoxy, halogen, -SO2N(Me)2, -SO2NHMe, -CN, -NO2 and In some embodiments of compounds of Formula (IV-I), (IV-IA), (IV-IB), (IV), (IVA), and / or (IVB), R 2 and R 15 Each is H.

[0510] In some embodiments of the compound of Formula (IV-IA) and / or (IVA), the compound is selected from:

[0511]

[0512] or an isomer, tautomer, solvate or salt thereof.

[0513] In some embodiments of the compound of Formula (IV-IA) and / or (IVA), the compound is selected from:

[0514]

[0515] In some embodiments of the compound of Formula (IV-IA) and / or (IVA), the compound is selected from:

[0516]

[0517] or an isomer, tautomer, solvate or salt thereof.

[0518] In some embodiments of the compound of Formula (IV-IA) and / or (IVA), the compound is selected from:

[0519]

[0520] In some embodiments of the compound of Formula (IV-IB) and / or (IVB), the compound is selected from:

[0521]

[0522]

[0523] or an isomer, tautomer, solvate or salt thereof.

[0524] In some embodiments of the compound of Formula (IV-IB) and / or (IVB), the compound is selected from:

[0525]

[0526]

[0527]

[0528]

[0529] In one aspect of the compounds of formula (IV-IB) and / or (IVB), the compound is selected from:

[0530]

[0531]

[0532] or an isomer, tautomer, solvate or salt thereof.

[0533] In one aspect of the compounds of formula (IV-IB) and / or (IVB), the compound is selected from:

[0534]

[0535]

[0536]

[0537] In one aspect of the compounds of formula (IV-IB) and / or (IVB), the compound is selected from:

[0538] or an isomer, tautomer, solvate or salt thereof.

[0539] In one aspect of the compounds of formula (IV-IB) and / or (IVB), the compound is selected from:

[0540]

[0541] In one aspect of the compound of Formula (IV-I), (IV-IA), (IV-IB), (IV), (IVA) and / or (IVB), the compound is selected from Table 1, Table 2 and / or Table 3, or an isomer, tautomer, solvate or salt thereof. In one aspect of the compound of Formula (IV-I), (IV-IA), (IV-IB), (IV), (IVA) and / or (IVB), the compound is selected from Table 1, Table 2 and / or Table 3.

[0542] In one aspect, the disclosure relates to a composition comprising a compound of Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, AIIIE, IV-I, IV-IA, IV-IB, IV, IVA and / or IVB.

[0543] In some embodiments, the various embodiments described for Formula I-IIIH can be applied to Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, AIIIE, IV-I, IV-IA, IV-IB, IV, IVA, and / or IVB. In some embodiments, the various embodiments described for Formula AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, or AIIIE can be applied to Formula IV-I, IV-IA, IV-IB, IV, IVA, and / or IVB.

[0544] The compounds can be synthesized using techniques known in the art. The syntheses of non-limiting examples of the compounds are described in detail below.

[0545] B. Polymer

[0546] Fluorescent dye comprises polymerizable moieties, for example the residue of acrylic acid or methacrylic acid, and can be copolymerized with other monomers to provide the polymer comprising near-infrared luminescent group.When compound has 2 or more polymerizable moieties, the polymer obtained by copolymerization with them and other monomers can be crosslinked.Or, another crosslinking monomer can be added in the polymerization mixture to realize the higher crosslinking degree of the obtained polymer.

[0547] Polymers as described herein can be prepared in any suitable manner. For example, but not limited to, suitable synthetic methods for producing polymers provided herein include cationic, anionic and free radical polymerization. In certain embodiments, polymer synthesis is carried out simply or in any suitable solvent. Suitable solvents include but are not limited to pentane, hexane, dichloromethane, chloroform, water, ethylene glycol, propylene glycol, DMSO or dimethylformamide (DMF). In certain embodiments, polymer synthesis is carried out at any suitable reaction temperature including, for example, about -50°C to about 100°C or about 0°C to about 70°C.

[0548] In one embodiment, the polymer is prepared by means of free radical polymerization. When using a free radical polymerization process, (i) monomers, (ii) optional one or more comonomers, and (iii) optional free radical sources are provided to trigger the free radical polymerization process. In some embodiments, the source of free radicals is optional because some monomers can self-initiate after heating at high temperatures. In some cases, after forming a polymer mixture, the mixture is subjected to polymerization conditions. Such conditions are optionally changed to reach any suitable level, and for example, include temperature, pressure, light, atmosphere, the ratio of the starting components used in the polymer mixture and the reaction time. Polymerization is carried out in any suitable manner, including, for example, in the form of a solution, dispersion, suspension, emulsion or bulk.

[0549] In some embodiments, an initiator is present in the reaction mixture. If it can be used in the polymerization process described herein, any suitable initiator is optionally utilized. For example, but not limited to, such initiators include one or more of the following: alkyl peroxides, substituted alkyl peroxides, aryl peroxides, substituted aryl peroxides, acyl peroxides, alkyl hydroperoxides, substituted alkyl hydroperoxides, aryl hydroperoxides, substituted aryl hydroperoxides, heteroalkyl peroxides, substituted heteroalkyl peroxides, heteroalkyl hydroperoxides, substituted heteroalkyl hydroperoxides, heteroaryl peroxides, substituted heteroaryl peroxides, heteroaryl hydroperoxides, substituted heteroaryl hydroperoxides, alkyl peresters, substituted alkyl peresters, aryl peresters, substituted aryl peresters, or azo compounds. In specific embodiments, benzoyl peroxide (BPO) and / or AIBN are used as initiators.

[0550] In some embodiments, the polymerization process is carried out in a controlled (living) mode. Non-limiting examples of controlled (living) polymerization processes include reversible addition-fragmentation chain transfer (RAFT) polymerization processes and atom transfer radical polymerization (ATRP).

[0551] In certain embodiments, the polymer may be a hydrogel. For example, a hydrogel can be prepared by reacting hydroxyethyl methacrylate (HEMA) to form poly(hydroxyethyl methacrylate) pHEMA. In addition, various comonomers can be used in combination to change the hydrophilicity, mechanical and swelling properties of the hydrogel (e.g., PEG, NVP, MAA). Non-limiting examples of polymers include 2-hydroxyethyl methacrylate, polyacrylamide, N-vinyl pyrrolidone, N,N-dimethylacrylamide, poly(ethylene glycol) monomethacrylate (with different molecular weights), diethylene glycol methacrylate, N-(2-hydroxypropyl) methacrylamide, glycerol monomethacrylate, 2,3-dihydroxypropyl methacrylate, and combinations thereof. Non-limiting examples of cross-linking agents include tetraethylene glycol dimethacrylate, poly(ethylene glycol) (n) diacrylate (with different molecular weights), ethoxylated trimethylolpropane triacrylate, bisacrylamide, and combinations thereof. Non-limiting examples of initiators include Ingacure series (UV), azobisisobutyronitrile (AIBN) (thermal), ammonium persulfate (APS) (thermal).

[0552] In one embodiment, the polymer is a light-emitting hydrogel prepared by copolymerization of HEMA and a compound of Formula I-IIIH, AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, AIIIE, IV-I, IV-IA, IV-IB, IV, IVA and / or IVB.

[0553] In an exemplary embodiment, the polymer is prepared by copolymerization of DMA (N,N-dimethylacrylamide), AAm (acrylamide), PEGDAAm (polyethylene glycol diacrylamide) and a compound of Formula I-IIIH, AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, AIIIE, IV-I, IV-IA, IV-IB, IV, IVA or IVB in the presence of 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride in a suitable solvent, such as a mixture of DMSO and water.

[0554] In another exemplary embodiment, the polymer is prepared by copolymerization of AETACI ([2-(acryloyloxy)ethyl]trimethylammonium chloride), PEGDAAm (polyethylene glycol diacrylamide), a compound of Formula I-IIIH, AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, AIIIE, IV-I, IV-IA, IV-IB, IV, IVA or IVB in the presence of 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride in a suitable solvent, such as a mixture of DMSO and water.

[0555] In other exemplary embodiments, the polymer is prepared by copolymerization of HEMA (2-hydroxyethyl methacrylate) (44.1 uL), DMA (N,N-dimethylacrylamide) (29.4 uL), PEGDAAm (polyethylene glycol diacrylamide), a compound of Formula I-IIIH, AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, AIIIE, IV-I, IV-IA, IV-IB, IV, IVA or IVB in the presence of 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride in a suitable solvent, such as a mixture of DMSO and water.

[0556] The polymer may be degradable by the body (biodegradable) or degradable by application of an external trigger to initiate or accelerate the degradation process (e.g., ultraviolet light, ultrasound, radiofrequency, temperature, or other external source to initiate degradation). For example, the polymer may be biodegradable or bioabsorbable, or may include any biodegradable or bioabsorbable segment, including but not limited to degradable forms of alginate, poly(lactic acid), poly(vinyl alcohol), polyanhydrides, poly(glycolic acid), microporous polyesters, microporous polyethers, and cross-linked collagen. A specific example is the UV polymerization of poly(ethylene glycol)-diacrylate with an acrylated protease-degradable peptide and VEGF, as described by Phelps et al. (2010) Proc. Nat'l. Acad. Sci. USA 107(8):3323-3328.

[0557] In one embodiment, the polymer provided herein is biocompatible. On the other hand, the polymer is biodegradable. Degradable hydrogels can be synthesized by copolymerization of HEMA with polymerizable luminescent dyes described herein using atom transfer radical polymerization (ATRP). Porous sensor skeletons based on non-degradable and degradable glucose sensing hydrogels can be produced by using sphere template manufacturing technology. Degradable and non-degradable HEMA reagents and polymerizable dyes will be polymerized on template microspheres, which are then dissolved and removed with a solvent to produce the desired non-degradable and degradable skeletons. In brief, using controlled ATRP, HEMA will be polymerized in the presence of a bifunctional, degradable, PCL-based ATRP initiator and cross-linker. In this synthesis process, pHEMA chains grow from both sides of the degradable initiator at the same rate, thereby producing degradation products with a molecular weight (MW) that is half that of the parent polymer. By controlling the MW of the parent polymer and the PEG and PCL units in the initiator and / or cross-linker, the degradation rate of the polymer can be changed. Limiting the MW of the matrix polymer to 10 kDa results in degradation products that can be cleared by the body and an increased degradation rate, while still maintaining the mechanical strength of the hydrogel.

[0558] In certain embodiments, provided herein are polymers that are stimulus-responsive, such as temperature or pH-sensitive polymers. A non-limiting example of such stimulus-responsive polymers is a temperature-sensitive polymer obtained by copolymerization of NIPAM. Such polymers can be used to implant a sensor comprising the polymer in a desired location within a tissue in the following manner: first, the polymer is dissolved in a medium suitable for injection below body temperature, and then the resulting solution is injected into the tissue of the body and / or injected at the desired location of the body. When the polymer is subjected to a higher (e.g., body) temperature, it precipitates in or near the injection site where the analyte needs to be monitored.

[0559] C.Sensor

[0560] In some embodiments, polymers can be incorporated into sensors that can be used to detect analytes. Detection of analytes can be in vitro or in vivo. Polymers can have molecules of Formula I-IIIH, AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, AIIIE, IV-I, IV-IA, IV-IB, IV, IVA, or IVB covalently bound to the polymer backbone and optional other polymerizable monomers. Formula I-IIIH, AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, AIIIE, IV-I, IV-IA, IV-IB, IV, IVA, or IVB molecules can be attached to nanoparticle carriers or microparticle carriers or other carriers that are connected to the polymer or contained in the polymer, for example, by covalent bonds or other means, or be contained in the nanoparticle carriers or microparticle carriers or other carriers. Such carriers can be covalently bound to the polymer backbone. In some embodiments, the term "polymer" can be used interchangeably with the term "sensor."

[0561] In one embodiment, the sensor may include catalase. As described in US 6,858,403 (which is hereby incorporated by reference herein in its entirety), catalase can be used to remove hydrogen peroxide from hydrogel-based sensors.

[0562] In one embodiment, the sensor can be a solid material that can be in the form of a plate, disk, rod, cylinder, particle, or powder. In a specific embodiment, the sensor is in the form of a rod. In another embodiment, the sensor is in the form of a cylinder. In other embodiments, the sensor is in the form of a disk.

[0563] In another embodiment, the polymer can be a tissue integration skeleton, or can be incorporated into a tissue integration skeleton to provide a tissue integration sensor (as described in U.S. Patent Application 2012 / 0265034, incorporated herein by reference). In one embodiment, the tissue integration skeleton can be constructed with materials and / or microstructures that allow the skeleton to promote tissue integration and / or vascularization. For example, a porous skeleton provides tissue biomaterial anchoring and promotes ingrowth throughout the hole. The resulting "aisle" or "channel" tissue growth pattern persists over time and promotes healthy gap-filling clumps of host cell integration. Most or all of the pores of the biomaterials described herein may be interconnected (co-continuous). The co-continuous pore structure of the biomaterial promotes gap-filling ingrowth of cells in the implant, which in turn limits allogeneic responses and causes the implant to persist in its ability to act as a sensor for a long time (greater than one week, and up to several years). Alternative structures for providing tissue-integrating scaffolds include fibers (e.g., 1 to 10 or more micrometers in diameter, such as 5, 6, 7, 8, 9, 10 or more micrometers) that can be arranged in a non-random or random configuration. Tissue-integrating scaffolds (in any configuration) can also be formed by multiphoton polymerization techniques. Kaehr et al. (2008) Proc. Nat'l. Acad. Sci. USA 105(26):8850-8854; Nielson et al. (2009) Small 1:120-125; Kasprzak, Doctoral Dissertation, Georgia Institute of Technology, May 2009.

[0564] The polymer that can be in the form of a tissue integration skeleton can include any material in combination with a compound of formula I-IIIH, AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, AIIIE, IV-I, IV-IA, IV-IB, IV, IVA or IVB, including but not limited to synthetic polymers, naturally occurring substances or mixtures thereof. Exemplary synthetic polymers include but are not limited to polyethylene glycol (PEG), 2-hydroxyethyl methacrylate (HEMA), silicone rubber, poly([ε]-caprolactone) dimethacrylate, polysulfone, poly(methyl methacrylate) (PMMA), soluble Teflon-AF (Teflon-AF), polyethylene terephthalate (PET, Dacron), nylon, polyvinyl alcohol, polyacrylamide, polyurethane and mixtures thereof. Exemplary naturally occurring materials include but are not limited to fibrous or globular proteins, complex carbohydrates, glycosaminoglycans, extracellular matrix or mixtures thereof. Thus, the polymer backbone may include all types of collagen, elastin, hyaluronic acid, alginic acid, desmin, versican, matricellular proteins such as SPARC (osteonectin), osteopontin, thrombospondin 1 and 2, fibrin, fibronectin, vitronectin, albumin, chitosan, etc. Natural polymers may be used as backbones or additives.

[0565] In certain embodiments, the polymer comprises a hydrogel. For example, the polymer can comprise a hydrogel, for example, by reacting hydroxyethyl methacrylate (HEMA) and a compound of Formula I-IIIH, AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, AIIIE, IV-I, IV-IA, IV-IB, IV, IVA, or IVB with one or more comonomers to form a poly(hydroxyethyl methacrylate) pHEMA-copolymer. Various comonomers can be used in combination to modify the hydrophilicity, mechanical, and swelling properties of the hydrogel (e.g., PEG, NVP, MAA). Non-limiting examples of polymers include 2-hydroxyethyl methacrylate, polyacrylamide, N-vinyl pyrrolidone, N,N-dimethylacrylamide, poly(ethylene glycol) monomethacrylate (having different molecular weights), diethylene glycol methacrylate, N-(2-hydroxypropyl) methacrylamide, glycerol monomethacrylate, 2,3-dihydroxypropyl methacrylate, and combinations thereof. Non-limiting examples of crosslinking agents include tetraethylene glycol dimethacrylate, poly(ethylene glycol)(n) diacrylate (with different molecular weights), ethoxylated trimethylolpropane triacrylate, bisacrylamide, and combinations thereof. Non-limiting examples of initiators include irgacure series (UV), azobisisobutyronitrile (AIBN) (thermal), ammonium persulfate (APS) (thermal).

[0566] The polymer may be a sphere-templated hydrogel, such as an inverse colloidal crystal, for example as described in US Patent Publication No. 2008 / 0075752 to Ratner et al., incorporated herein by reference; or other tissue-integrating materials.

[0567] The polymer may be degradable by the body (biodegradable) or degradable by application of an external trigger to initiate or accelerate the degradation process (e.g., ultraviolet light, ultrasound, radiofrequency, or other external source to initiate degradation). For example, the polymer may include any biodegradable or bioabsorbable polymer, including but not limited to degradable forms of alginate, poly(lactic acid), poly(vinyl alcohol), polyanhydrides, poly(glycolic acid), microporous polyesters, microporous polyethers, and cross-linked collagen. A specific example is the UV polymerization of poly(ethylene glycol)-diacrylate with an acrylated protease-degradable peptide and VEGF, as described by Phelps et al. (2010) Proc. Nat'l. Acad. Sci. USA 107(8):3323-3328.

[0568] Other specific examples are polymers whose degradation is controlled by exposure to exogenous forms of energy as described by Kloxin et al. (2009) Science 324:59-63 and U.S. Patent No. 6,013,122, as well as by Alexeev et al. (2003) Anal. Chem. 75:2316–2323; Badylak et al. (2008) Seminars in Immunology 20:109–116; Bridges et al. (2010) 94(1):252-258; Isenhath et al. (2007) Research 83A:915-922; Marshall et al. (2004) Polymer Preprints, American Chemical Society, Division of Polymer Chemistry 45:100-101; Phelps et al. (2010) Proc Nat'l Acad Sci US A.107(8):3323-8; Ostendorf and Chichkov (2006) Two Photon Polymerization: A New Approach to MicroMachining, Photonics Spectra; Ozdemir et al. (2005) Experimental and Clinical Research, Plast. Reconstr. Surg.115:183; U.S. Patent Publication No. 20080075752; Sanders et al. (2003) Journal of Biomedical Materials Research Part A 67A(4):1181-1187; Sanders et al. (2002) Journal of Biomedical Materials Research 62(2):222-227; Sanders et al. (2003) Journal of Biomedical Materials Research 65(4):462-467; Sanders et al. (2005) Biomaterials 26:813-818; Sanders et al. (2005) Journal of Biomedical Materials Research Part A 72(3):335-342; Sanders (2003) Journal of Biomedical Materials Research 67(4):1412-1416; Sanders et al. (2000) Journal of Biomedical Materials Research 52(1):231-237; and polymers described by Young Min Ju et al. (2008) J Biomed Mater Res 87A:136–146.

[0569] In addition, polymers can be constructed so that they have conduits, holes, or pockets that are hollow or filled with degradable substances, angiogenic substances, or other substances (e.g., stem cells). As indicated above, once in the body, the biodegradation of the material filling the conduits, holes, or pockets creates gaps for the integration of tissue and material, including capillaries. The degradable material initially filling the conduits, holes, or pockets can enhance vascular growth or tissue growth within the framework. This structure promotes new blood vessel formation and maintains healthy living tissue inside and around the implant.

[0570] The polymer can be constructed so that it is permeable to the target analyte (eg, glucose can diffuse into the hydrogel backbone and reach the sensing moiety embedded within the hydrogel matrix).

[0571] The polymer can have any suitable form, including but not limited to blocks (or any thickness), cubes, disks, cylinders, ovoids, circles, random or non-random configurations of fibers, etc. In certain embodiments, the sensor includes one or more fibers that can be organized in a non-random manner (e.g., a grid, a layered grid, etc.) or in a random manner.

[0572] The polymers described herein can be combined with (or consist of) a sensing moiety that detects one or more analytes. In one embodiment, the sensing moiety is a residue of a compound of Formula I-IIIH, AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, AIIIE, IV-I, IV-IA, IV-IB, IV, IVA, and / or IVB incorporated into a hydrogel backbone.

[0573] In another embodiment, the polymer that can be in the form of a tissue-integrating scaffold comprises a second sensing moiety in addition to the first compound of Formula I-IIIH, AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, AIIIE, IV-I, IV-IA, IV-IB, IV, IVA or IVB. In one embodiment, the second sensing moiety is a second compound of Formula I-IIIH, AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, AIIIE, IV-I, IV-IA, IV-IB, IV, IVA and / or IVB.

[0574] In another embodiment, a polymer, for example in the form of a tissue-integrating scaffold, can be a multi-analyte sensor in which glucose is one of two or more analytes detected and reported. In this embodiment, the polymer comprises a residue of a compound of Formula I-IIIH, AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, AIIIE, IV-I, IV-IA, IV-IB, IV, IVA, or IVB for detecting glucose, and a second sensing moiety for detecting another substance. Non-limiting examples of analytes that can be detected by the sensing moiety include oxygen, reactive oxygen species, glucose, lactate, pyruvate, cortisol, creatinine, urea, sodium, magnesium, calcium, potassium, vasopressin, hormones (e.g., luteinizing hormone), pH, cytokines, chemokines, eicosanoids, insulin, leptin, small molecule drugs, ethanol, myoglobin, nucleic acids (RNA, DNA), fragments, polypeptides, single amino acids, and the like.

[0575] In some embodiments, the sensing moiety, such as a polymer, can include a residue of a compound of Formula I-IIIH, AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, AIIIE, IV-I, IV-IA, IV-IB, IV, IVA, or IVB that is a reversibly luminescent binding molecule. To measure an analyte such as glucose in tissue, over the long life of the implant, the polymer is illuminated from a patch reader at desired intervals (e.g., every 5-60 minutes over a period of 90 days or longer) with light having a wavelength that can penetrate the skin, such as 650 nm light. The amount of luminescent signal detected (e.g., from the luminescent molecule) is proportional to the concentration of the analyte (e.g., glucose) in the tissue.

[0576] In another embodiment, an internal reference control material can be used to help correct for tissue optical deviations. The implanted biosensor can reside 1-6mm, 2-6mm, 3-6mm, 3-4mm, or 3-5mm below the surface of the skin. It is well known that skin excitation light and emitted fluorescence in the near-infrared range are highly scattered when light passes through the tissue between the reader patch and the implant. The degree of absorption and scattering is affected by physical properties such as temperature or by changes in tissue composition, including but not limited to changes in blood perfusion, hydration, and melanin concentration. Skin variations can exist between users or between different time points in the case of a single patient, and these variations can affect the fluorescence excitation and emission signals, resulting in inaccurate signals used to obtain analyte-specific signals. Therefore, a separate luminescent molecule whose emission spectrum can be distinguished from the analyte-specific luminescence can be fixed to the skeleton. The luminescence from the molecule can be measured separately from the analyte-specific luminescence to measure the signal that tells about changes in tissue composition. The second dye selected for this purpose can have a response to tissue changes similar to that of the analyte-specific dye.

[0577] In some embodiments, the sensor can be a tissue-integrated sensor comprising one or more cylindrical elements (e.g., fibers) that eliminates or greatly reduces foreign body responses compared to currently available implants. Furthermore, unlike other known sensors, the average diffusion distance from the capillary supply to all parts of the sensing medium is similar to that of native tissue.

[0578] The overall size of the sensing medium (implantable sensor) varies depending on the subject and / or one or more analytes to be measured. The implant is between about 0.001 mm and about 2 mm in thickness (or any value therebetween), and between about 1 mm and about 1 cm in diameter (or equal cross-sectional area for a non-circular shape, such as length / width), and 15 mm or less in length, such as a disc-shaped sensor with a thickness of 2 mm or less and a diameter of 10 mm or less. In certain embodiments, the approximate sensor size is about 100-1000 microns in diameter and has a length between 0.25 mm and 10 mm. The size of the tissue-integrated sensing medium in the form of a disc can be 2 mm in thickness and 10 mm or less in diameter.

[0579] Another aspect is a tissue-integrated biosensor system for semi-continuous, continuous, and / or chronic use within a mammalian body.

[0580] One advantageous property of the polymers and sensors described herein is their stability. In one aspect, the sensors are stable in mammalian tissue for extended periods of time, e.g., longer than 1 week, longer than 1 month, longer than 2 months, longer than 6 months.

[0581] Example

[0582] NMR spectral data were recorded at room temperature on a 400 MHz instrument. NMR spectra were corrected for the solvent signal of deuterated DMSO-d6, MeOH-d4, or CDCl3. The following abbreviations are used to indicate signal multiplicity: s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), br (broad), m (multiplet). Analytical HPLC-MS data were recorded on an HPLC system using a C18 reverse-phase silica column coupled to an electrospray ionization (ESI) mass spectrometer. The listed UV / Vis absorption maxima were recorded by HPLC DAD in an eluent system (acetonitrile / water + 0.1% HCOOH). Commercially available monomers and chemical building blocks were purchased from Polysciences, Sigma-Aldrich, VWR, Combi-Blocks, Acros Organics, Oakwood Chemical, AK Scientific, and Strem Chemicals. Some advanced intermediates were synthesized by BioDuro.

[0583] Exemplary formulas I-IIIH, AI, AIA, AIB, AIC, AII, AIIA, AIIB, AIII, AIIIF, AIIIE, IV-I, IV- Synthesis of Compounds IA, IV-IB, IV, IVA, or IVB

[0584] Synthesis of compound 1

[0585]

[0586] Scheme 5. Synthesis of Compound 1

[0587] General Procedures I. Preparation of N-[2-bromo-3-(phenylamino)-2-propenylidene]-phenylammonium bromide 1-1

[0588] A solution of aniline (17.7 mL, 194 mmol) in anhydrous EtOH (25 mL) was added dropwise to a pre-cooled (0 ° C) solution of mucobromic acid (25 g, 97 mmol) in anhydrous EtOH (75 mL). The reaction mixture was stirred for 1 hour and then concentrated to 50 mL in vacuo. After storage at 4 ° C for 3 days, the product crystallized from the concentrated solution. The crystals were collected by filtration and rinsed with acetone and cold EtOH to produce the title compound 1-1 (24.2 g, 83%) as an orange / yellow solid.

[0589] General Procedure II. Preparation of pentamethine cyanine fluorophore (Cy5). Preparation of 2-[3-bromo-5-(1,3-dihydro-1,3,3-trimethyl-2H-indol-2-ylidene)-1,3-pentadien-1-yl]-1,3,3-trimethyl-3H-indolium iodide 1-2

[0590] A solution of compound 1-1 (1.01 g, 2.65 mmol), 1,2,3,3-tetramethyl-3H-indolium iodide (4.0 g, 13.3 mmol) and sodium acetate (2.16 g, 26.5 mmol) in acetic anhydride (40 mL) was heated at 80 ° C for 20 minutes. The reaction was then diluted with DCM and washed with water and brine. The DCM layer was then dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, eluted with DCM and MeOH) to provide the title product 1-2 (758 mg, 48%).

[0591] General Procedures III. Suzuki-Miyaura cross coupling with pinacol boronate. Preparation of 2-[3-(4-aminomethylphenyl)-5-(1,3-dihydro-1,3,3-trimethyl-2H-indol-2-ylidene)-1,3-pentadien-1-yl]-1,3,3-trimethyl-3H-indolium iodide 1-3

[0592] In a flame-dried flask, intermediate 1-2 (758 mg, 1.28 mmol), 4-aminomethylphenylboronic acid pinacol ester hydrochloride (600 mg, 2.57 mmol) and cesium carbonate (1.25 g, 3.85 mmol) were mixed with EtOH (50 mL) and water (25 mL). The mixture was degassed by bubbling dry argon at 60 ° C for 1 hour. Palladium (II) acetate (60 mg, 0.128 mmol) and triphenylphosphine (200 mg, 0.514 mmol) were then added, and the reaction mixture was stirred at 60 ° C under argon for 16 hours. Additional 4-aminomethylphenylboronic acid pinacol ester hydrochloride (90 mg, 0.386 mmol), palladium (II) acetate (60 mg, 0.128 mmol) and triphenylphosphine (200 mg, 0.514 mmol) were then added, and the reaction was stirred at 60 ° C under Ar for 16 hours. The reaction mixture was then concentrated in vacuo, diluted with DCM, and The mixture was filtered. The filtrate was washed with water and brine, then dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, eluted with 0.09% HCl in MeOH and DCM). The pure product was dissolved in DCM and washed 3 times with saturated NaHCO3. The DCM portion was then dried over MgSO4 and concentrated in vacuo to produce product 1-3 (258 mg, 41%).

[0593] Preparation of N-{3-[(4-formylphenyl)methylamino]propyl}methacrylamide 1-4

[0594] A mixture of N-(3-aminopropyl) methacrylamide hydrochloride (APMA HCl; 4.47 g, 25.1 mmol) and K2CO3 (13.8 g, 100.5 mmol) in anhydrous MeOH (10 mL) was stirred for 15 minutes and then diluted with anhydrous DCM (100 mL). 4-bromomethyl-benzaldehyde (2 g, 10.0 mmol) and triethylamine (5 mL, 35.8 mmol) were added, and the reaction mixture was stirred for 16 hours. The mixture was then filtered, a small amount of 4-methoxyphenol (MEHQ, polymerization inhibitor) was added to the filtrate, and it was concentrated in vacuo. Drying under high vacuum provided the title compound 1-4 (3.25 g, 124%) as a white solid.

[0595] General Procedure IV. Reductive amination. Preparation of Compounds 1-6

[0596] A solution of amine 1-3 (258 mg, 0.419 mmol), glacial acetic acid (0.15 mL, 2.50 mmol) and aldehyde 1-4 (319 mg, 1.20 mmol) in anhydrous MeOH (15 mL) and anhydrous DCE (5 mL) was prepared over molecular sieves ( The product was stirred for 15 minutes on 4% paraformaldehyde (200mg, 400mg, 1.88mmol). Then sodium triacetoxyborohydride (400mg, 1.88mmol) was added in three portions at 10 minute intervals. After the reaction was complete, the slurry was filtered and the filtrate was concentrated to about 5mL in a vacuum. The concentrate was diluted with DCM, washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated in a vacuum. The residue was purified by flash chromatography (SiO2, eluted with DCM and 0.05% HCl in MeOH). The purified product was dissolved in DCM, washed 3 times with saturated NaHCO3, dried over MgSO4, and concentrated in a vacuum to produce the title product 1-6 (198mg, 55%).

[0597] General Procedures V. Alkylation with free 2-bromomethylphenylboronic acid or the corresponding neopentyl glycol ester. Preparation of compound 1

[0598] To a solution of diamine 1-6 (198 mg, 0.23 mmol) in anhydrous DCM (15 mL) and anhydrous DMF (2 mL) was added KCO (257 mg, 1.86 mmol), 2-bromomethylphenylboronic acid (300 mg, 1.4 mmol) and DIPEA (0.4 mL, 2.3 mmol). The reaction mixture was stirred for 1 hour, and 2-bromomethylphenylboronic acid (150 mg, 0.697 mmol) and DIPEA (0.081 mL, 0.465 mmol) were added repeatedly. After 1 hour, a fresh portion of 2-bromomethylphenylboronic acid (450 mg, 2.8 mmol) was added, and the mixture was stirred for 16 hours. The crude product was precipitated by hexane, collected by centrifugation, and purified by flash chromatography (SiO , eluted with DCM and 0.05% HCl in MeOH). The pure product was dissolved in DCM, washed three times with saturated NaHCO 3 , dried over MgSO 4 , and concentrated in vacuo to give the title product Compound 1 (78 mg, 30% yield). HPLC-MS: m / z 1000.7 (for M + Calculated value: 1000.6); λ max =650nm.

[0599] Preparation of compound 2

[0600]

[0601] General Procedure VI. Alkylation of 2,3,3-trimethyl-3H-indole with sultones. Preparation of compound 2-1.

[0602] A mixture of 2,3,3-trimethyl-3H-indole (9.90 g, 62.3 mmol) and 1,3-propane sultone (11.4 g, 93.4 mmol) in anhydrous MeCN (150 mL) was heated overnight at 90° C. in a sealed container. The mixture was then poured into diethyl ether (500 mL) with vigorous stirring and filtered. The solid product was dried under high vacuum to provide intermediate 2-1 (15 g, 86% yield) as a pink solid.

[0603] Compound 2 was prepared from intermediate 2-1 following general procedures II, III, IV, and V as outlined in the above scheme. HPLC-MS: m / z = 1217.1 (for M + Calculated value: 1216.5); λ max =650nm.

[0604] Preparation of compound 3

[0605]

[0606] Preparation of compound 3-1

[0607] At room temperature and under a nitrogen atmosphere, p-(chloromethyl)benzoyl chloride (5.67g, 30mmol) was added dropwise to a stirred solution of 2,4-dimethylpyrrole (5.7g, 60mmol) in DCM (120mL). The mixture was stirred for 12 hours. Triethylamine (20mL) was added, the reaction mixture was stirred for another hour at room temperature, and then boron trifluoride ether (20mL) was added. The reaction mixture was stirred for 2 hours and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, eluted with hexane / EtOAc=8:1) to produce intermediate 3-1 (3.0g, 27% yield) as an orange solid.

[0608] Preparation of compound 3-2

[0609] To a mixture of compound 3-1 (3.75 g, 10.0 mmol) in DMF (60 mL) was added sodium azide (0.98 g, 15.0 mmol) at room temperature. The resulting mixture was stirred overnight at 40 ° C., then diluted with water (500 mL) and extracted with EtOAc (3 × 200 mL). The organic layers were combined, washed with brine (3 × 100 mL), dried over sodium sulfate, filtered, and concentrated to produce compound 3-2 (2.6 g, 75% yield) as a brown solid, which was used directly in the next step without further purification.

[0610] Preparation of compound 3-3

[0611] To a solution of compound 3-2 (2.05 g, 5.78 mmol, 1.0 equivalent) in THF (100 mL) was added triphenylphosphine (2.07 g, 7.09 mmol) and water (10 mL) at room temperature. The resulting mixture was stirred overnight at 50 ° C under a nitrogen atmosphere. The mixture was then concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, eluted with DCM / EtOAc=1:1 and DCM / MeOH=10:1) to provide compound 3-4 (1.5 g, 81% yield) as a brown solid.

[0612] Compound 3 was prepared from intermediate 3-3 following general procedures IV and V. HPLC-MS: m / z 867.2 (for M+H + Calculated value: 866.5); λ max =502nm.

[0613] Preparation of compound 4

[0614]

[0615] General Procedure VII. Preparation of BODIPY Fluorophores from Aldehydes and Pyrroles. Preparation of Compound 4-1.

[0616] A mixture of 4-nitrobenzaldehyde (1.20 g, 7.9 mmol), 2,4-dimethylpyrrole (1.6 mL, 15.9 mmol) and TFA (0.12 mL, 1.6 mmol) in anhydrous DCM (300 mL) was stirred for 3 hours at room temperature. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.80 g, 7.9 mmol) was then added, and the darkened reaction mixture was stirred for 1 hour. Triethylamine (11 mL, 79 mmol) and boron trifluoride etherate (12.7 mL, 103 mmol) were subsequently added, and the mixture was stirred for 1 hour. The reaction mixture was then washed with water (2 × 500 mL) and brine (250 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, eluted with a gradient of 0% to 30% EtOAc in hexane). Yield: 0.60 g (21%).

[0617] Preparation of compound 4-2.

[0618] The mixture of intermediate 4-1 (1.23 g, 3.3 mmol) and iron powder (3.53 g, 63.3 mmol) in THF (75 mL), 0.5 M HCl methanol solution (20 mL) and water (5 mL) was refluxed for 2 hours. The reaction mixture was then concentrated in vacuo, the residue was redissolved in DCM (100 mL), filtered, and concentrated again. The residue was purified by flash chromatography (SiO , eluted with a gradient of 0% to 30% EtOAc in hexane) to produce the title compound 4-2 (0.85 g, 76% yield) as a reddish-orange solid.

[0619] Compound 4 was prepared from intermediates 4-2 and 1-4 following general procedures IV and V. HPLC-MS: m / z 852.5 (for M+H + Calculated value: 852.4); λ max =500nm. 1 H NMR(400MHz,MeOH-d4+NaOD)δppm 7.61(d,J=7.6Hz,2H),7.23-7.33(m,4H),6.96-7.13(m,4H),6.91-6.96(m,2H),6.88(d, J=8.7Hz,2H),6.78(d,J=8.7Hz,2H),6.00(s,2H),5.49(s,1H),5.25(q,J=1.1Hz,1H),5. 0.9 (br.s., 2H), 4.70 (br.s., 2H), 3.83 (br.s., 2H), 3.58 (br.s., 2H), 3.06 (t, J = 6.5 Hz, 2H), 2.41 (t, J = 7.0 Hz, 2H), 1.82 (q, J = 1.1 Hz, 3H), 1.73 (quin, J = 6.7 Hz, 2H), 1.50 (s, 6H). The six methyl protons from BODIPY overlap with the solvent peak.

[0620] Preparation of compound 6

[0621]

[0622] Scheme 4. Preparation of Compound 6

[0623] General Procedure VIII. Nucleophilic Substitution at the Cy7 Fluorophore. 2-(2-{2-chloro-3-[(1,3-dihydro-3, 3-dimethyl-1-propyl-2H-indol-2-ylidene)ethylidene]-2-(4-carbamic acid tert-butylaminomethylphenoxy)-1- Preparation of (cyclohexen-1-yl}vinyl)-3,3-dimethyl-1-propylindolium iodide 6-2

[0624] A mixture of tert-butyl (4-hydroxyphenylmethyl)carbamate (348 mg, 1.5 mmol), IR-780(6-1) (500 mg, 0.75 mmol) and cesium carbonate (487 mg, 1.5 mmol) in anhydrous DCM (50 mL) was stirred at 40° C. under argon. After 1 hour, the reaction mixture was Filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography (SiO 2 , eluted with DCM and MeOH) to give the title product 6-2 (1.3 g, quantitative).

[0625] General Procedure IX. Boc deprotection. 2-(2-{2-chloro-3-[(1,3-dihydro-3,3-dimethyl-1-propyl-2H- indol-2-ylidene)ethylidene]-2-(4-aminomethylphenoxy)-1-cyclohexen-1-yl}vinyl)-3,3-dimethyl-1- Preparation of Propyl Indolium Iodide 6-3

[0626] Intermediate 6-2 (625 mg, 0.73 mmol) was dissolved in pure TFA (10 mL) at 0 ° C. While stirring under argon, the reaction mixture was allowed to warm to room temperature over 5 minutes. The solution was then concentrated in vacuo. The crude product was purified by flash chromatography (SiO 2 , eluted with DCM and MeOH) to provide pure product 6-3 (466 mg, 88%).

[0627] Preparation of compound 6-4

[0628] To the molecular sieve ( To a solution of intermediate 6-3 (895 mg, 1.19 mmol) prepared from the above product (500 mg) in anhydrous MeOH (40 mL) was added glacial acetic acid (0.35 mL, 6.0 mmol) and intermediate 1-4 (752 mg, 1.49 mmol). The reaction mixture was stirred at room temperature for 15 minutes, followed by the addition of sodium triacetoxyborohydride (3 × 277 mg, 3.90 mmol) at 10 minute intervals. 15 minutes after the last addition, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was then diluted with DCM and washed with saturated NaHCO 3 and brine. The DCM layer was then dried over MgSO 4 and concentrated in vacuo. The crude product was purified by flash chromatography (SiO 2 , eluted with DCM and MeOH) to produce the title compound 6-4 (415 mg, 35%).

[0629] Preparation of compound 6

[0630] To a solution of intermediate 6-4 (400 mg, 0.40 mmol) in anhydrous DMF (4 mL) was added 2-bromomethylphenylboronic acid (600 mg, 2.8 mmol) and K2CO3 (1.35 g, 10.0 mmol) in three portions. The reaction mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was purified by flash chromatography (SiO2, eluted with 0.05% HCl in MeOH and DCM). The pure product was dissolved in DCM and washed three times with saturated NaHCO3. The DCM portion was then dried over MgSO4 and concentrated in vacuo to produce the title compound 6 (90 mg, 18%). HPLC-MS: m / z 1138.5 (for M + Calculated value: 1138.7); λ max =775nm. 1 H NMR(400MHz,MeOH-d4)δppm 7.96(d,J=14.3Hz,1H),7.63(d,J=7.3Hz,1H),7.36-7.44(m,6H),7.32(m,J=7.6,7.6Hz,3H),7.23-7.29(m,3H),7.15-7.22(m,7H ),7.12(m,J=7.3,7.3Hz,4H),6.14(d,J=14.2Hz,2H),5.52(s,1H),5.22(s,1H),4.13(br.s.,2H),4.04(t,J=7.4Hz,4H),4.03(s, 2H),3.65(br.s.,2H),3.52(s,2H),3.50(br.s,2H),3.35(s,1H),3.10(t,J=6.0Hz,2H),2.74(t,J=6.0Hz,4H),2.54-2.68(m,2H) ,2.04(quin,J=6.0Hz,2H),1.86-1.96(m,2H),1.80(m,J=7.7,7.7,7.7Hz,4H),1.76(s,3H),1.25(s,12H),0.99(t,J=7.4Hz,6H).

[0631] Preparation of compound 5

[0632]

[0633] 2-[2-(3-{2-[1,3-dihydro-3,3-dimethyl-1-(4-sulfobutyl)-2H-indol-2-ylidene]ethylidene}-2- (4-aminomethylphenoxy)-1-cyclohexen-1-yl)vinyl]-3,3-dimethyl-1-(4-sulfobutyl)-3H-indolium monohydrate Preparation of sodium salt (5-2)

[0634] A mixture of IR-783 (5-1) (4 g, 5.54 mmol), tert-butyl (4-hydroxyphenylmethyl)carbamate (2.47 g, 11.1 mmol) and cesium carbonate (3.6 g, 11.1 mmol) in anhydrous DCM (100 mL) was stirred at room temperature for 16 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The crude intermediate was dissolved in TFA (25 mL), the solution was stirred for 5 minutes, and then concentrated in vacuo. The residue was purified by reverse phase flash chromatography (C18 SiO2, eluted with a 0.09% HCl gradient in MeOH). The combined and concentrated fractions were basified with saturated NaHCO3 and then triple extracted with DCM to isolate the pure product. The combined DCM layers were then dried over MgSO4 and concentrated in vacuo to produce the title product 10-2 (5.4 g, quantitative). HPLC-MS: m / z 1326.0 (calculated value: 1326.6); λ max =775nm.

[0635] Preparation of compound 7

[0636]

[0637] Compound 7 was prepared from IR-780 and 4-N-Boc-aminophenol by analogy with compound 6, following general procedures VIII, IX, IV and V. HPLC-MS: m / z 1124.5 (calculated: 1124.7); max =775nm. 1 H NMR(400MHz,MeOH-d4)δppm 7.97(d,J=14.2Hz,2H),7.60(br.s.,1H),7.34-7.42(m,5H),7.20-7.33(m,11H),7.13-7.20(m,3 H),6.92(s,4H),6.11(d,J=14.2Hz,2H),5.59(s,1H),5.33(s,1H),4.58(s,2H),4.44(s,2H),4.1 6(br.s.,2H),4.05(t,J=7.4Hz,4H),4.00(br.s,2H),3.08(t,J=6.2Hz,2H),2.69(t,J=6.0Hz,4H ), 2.75 (br.s, 2H), 2.00 (m, J = 6.4Hz, 2H), 1.72-1.89 (m, 9H), 1.30 (s, 12H), 1.01 (t, J = 7.4Hz, 6H).

[0638] Preparation of compound 10

[0639]

[0640] Scheme 3. Preparation of Compound 10

[0641] Preparation of 10-[(3-methacrylamidopropan-1-yl)aminomethyl]-9-anthracenecarboxaldehyde 10-2

[0642] To a solution of N-(3-aminopropyl) methacrylamide hydrochloride (1.00 g, 5.78 mmol) in anhydrous MeOH (5 mL) was added anthracene-9,10-dicarbaldehyde (2.7 g, 11.56 mmol) in anhydrous DCM (10 mL). The resulting mixture was diluted with anhydrous THF (150 mL) and acetic acid (0.52 mL, 8.6 mmol), followed by the addition of sodium triacetoxyborohydride (2.45 g, 11.56 mmol). The mixture was stirred at room temperature. After 1 hour, a second portion of sodium triacetoxyborohydride (1.2 g, 5.75 mmol) was added, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was then diluted with DCM and washed with saturated NaHCO and brine. The DCM portion was then dried over MgSO and concentrated in vacuo. The crude product was purified by flash chromatography (SiO 2 , eluting with MeOH and DCM) to provide the title compound 10-2 (424 mg, 20%).

[0643] Preparation of compound 10-3

[0644] Intermediate 5-2 (294 mg, 0.351), molecular sieves A mixture of glacial acetic acid (200 μL, 1.4 mmol) and intermediate 10-2 (190 mg, 0.528 mmol) in anhydrous MeOH (10 mL) and DCE (5 mL) was stirred for 15 minutes. Sodium triacetoxyborohydride (112 mg, 0.528 mmol) was then added and the addition was repeated three times over 20 hours. The reaction was then concentrated to approximately 2 mL in vacuo and basified by saturated NaHCO 3 . The crude product was purified by three reverse phase flash chromatography steps (C 18 SiO 2 , gradient elution with water and MeOH with 0.1% TFA) to provide the pure title product 10-3 (105 mg, 21.7%).

[0645] Preparation of compound 10

[0646] A solution of intermediate 10-3 (90 mg, 0.065 mmol) and DIPEA (42.2 mg, 0.327 mmol) in anhydrous DCM (8 mL) was stirred for 10 minutes, followed by the addition of 2-bromomethylphenylboronic acid (58.5 mg, 0.327 mmol). After 90 minutes, the reaction mixture was diluted with hexane and centrifuged. The precipitate was purified by reverse phase flash chromatography (C18 SiO2, gradient elution with water and MeOH). Pure title compound 10 (61 mg, 64%) was obtained by precipitation from concentrated DCM solution with diethyl ether. HPLC-MS: m / z 1428.6 (for M+H + Calculated value: 1426.7); λ max =760nm. 1 H NMR(400MHz,MeOH-d4)δppm 8.42(d,J=8.2Hz,2H),8.31(d,J=8.8Hz,2H),7.94(d,J=14.2Hz,2H),7.34-7.59(m,9H),7.16-7.34(m,9H),7. 12(d,J=8.5Hz,2H),6.94-7.06(m,4H),6.15(d,J=14.2Hz,2H),5.37(s,1H),5.18(quin,J=1.3Hz,1H),4.41(b R.s., 2H), 4.13 (br.s., 2H), 4.06 (t, J = 6.5 Hz, 4H), 3.60 (br.s., 2H), 3.53 (s, 2H), 2.99 (t, J = 6.5 Hz, 2H), 2.86 (t, J = 6.8 Hz, 4H), 2.66-2.80 (m, 6H), 2.04 (quin, J = 6.5 Hz, 2H), 1.81-1.97 (m, 10H), 1.70 (s, 3H), 1.16 (s, 12H). A benzyl CH2 group overlapped with the solvent signal.

[0647] Preparation of compound 8

[0648]

[0649] Preparation of compound 8-1

[0650] By analogy with intermediate 10-3, anthracenecarboxaldehyde 10-2 (272 mg, 0.76 mmol) was coupled with Cy5-benzylamine 2-3 (500 mg, 0.69 mmol) in the presence of triacetoxyborohydride (726 mg, 3.4 mmol) and acetic acid (124 mg, 2.1 mmol). After purification by reverse phase flash chromatography (MeOH-water + 0.25% HCl), the desired product was isolated as a blue solid (13 mg, 2% yield).

[0651] Preparation of compound 8

[0652] By analogy with the synthetic procedure for compound 10, diamine 8-2 (13 mg, 0.012 mmol) was alkylated with 2-bromomethylphenylboronic acid (6.5 mg, 0.030 mmol) to provide the desired product as a dark blue solid (7 mg, 44% yield). HPLC-MS: m / z 1317.5 (for M+H + Calculated value: 1316.6); λ max =640nm.

[0653] Preparation of compound 9

[0654]

[0655] Intermediate 9-1 was prepared from 1,1,2-trimethyl-1H-benz[e]indole following General Procedures VI, II, and III (see Intermediate 2-3). Compound 9 was then synthesized from Intermediates 10-2 and 9-1 following General Procedures IV and V, following a similar approach to that described for Compound 8. HPLC-MS: 1417.5 m / z (for M+H + Calculated value: 1416.6); λ max =630,685nm.

[0656] Preparation of compound 11

[0657]

[0658] Preparation of compound 11-1

[0659] Formaldehyde (63.52g, 0.807mol, in the form of 38% aqueous solution), acetic acid (1500mL) and 3-bromo-N, N-dimethylaniline (323g, 1.615mol) are combined and stirred for 2 hours at 60°C under argon. The reaction mixture is then concentrated under reduced pressure. The residue is dissolved in DCM (100mL), washed with saturated NaHCO and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2, eluent: 1:5DCM / hexane). This provides the title intermediate 11-1 (216g, 65% yield) as a pink solid.

[0660] Preparation of compound 11-2

[0661] Under an argon atmosphere, sec-butyllithium (1.3M in cyclohexane, 168 mL, 218 mmol) was added dropwise to a solution of intermediate 11-1 (30 g, 73 mmol) in anhydrous THF (200 mL) cooled to -78 ° C over 30 minutes. The resulting mixture was stirred at 78 ° C for 2 hours, followed by the addition of dichlorodimethylsilane (16.9 g, 131.1 mmol). The mixture was allowed to warm to room temperature over 2 hours. The reaction was then quenched with 1M HCl, the pH was adjusted to 8 with NaOH, and the mixture was extracted with DCM (3×300 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to produce crude compound 11-2 (28 g) as a green solid. The crude product was used directly in the next step without further purification.

[0662] Preparation of compound 11-3.

[0663] The crude compound 11-2 (28 g, theoretical value: 73 mmol) was dissolved in acetone (300 mL) and cooled to -15 ° C. To this solution, KMnO4 (42.5 g, 271 mmol) was added portionwise over 30 minutes, and the reaction mixture was stirred at -15 ° C for 2 hours. The reaction was then allowed to warm to room temperature and The mixture was filtered and the filter cake was rinsed with acetone. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, eluent: DCM). This produced compound 11-3 (8 g, 26% yield) as a yellow-green solid.

[0664] Preparation of compound 11-4

[0665] A mixture of 4-bromobenzylamine (1.0 g, 5.4 mmol) and triethylamine (1.50 mL, 10.7 mmol) in anhydrous DCM (50 mL) was cooled to 0°C under an argon atmosphere. A solution of 1,2-bis(chlorodimethylsilyl)ethane (1.16 g, 5.4 mmol) in anhydrous DCM (20 mL) was added via cannula. The mixture was stirred at 0°C for 1 hour and then at room temperature for 1 hour. The solvent was removed in vacuo, and the residue was suspended in hexane and filtered. The filtrate was concentrated in vacuo and used in the next step without further purification.

[0666] General Procedure X. Preparation of Silosamin Fluorophores by Lithium-Halogen Exchange with sec-BuLi. Compound 11- 5. Preparation

[0667] Under an argon atmosphere, sec-butyllithium (c = 1.4 M, in cyclohexane, 5.76 mL, 8.1 mmol) was added dropwise to a solution of aryl bromide 11-4 (theoretical value: 5.4 mmol) in anhydrous THF (20 mL) cooled to -78 ° C. The mixture was stirred at -78 ° C for 1 hour. A solution of silanthone 11-3 (0.17 g, 0.5 mmol) in anhydrous THF (10 mL) was then added via a cannula, and the mixture was allowed to warm to room temperature overnight. The reaction was quenched with 1M HCl (10 mL) and stirred for 30 minutes to 3 hours (progress monitored by LCMS). The pH was adjusted to 8 with NaOH, and the mixture was extracted with DCM. The combined organic layers were dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (C18 SiO 2 , gradient elution with 0.25% HCl (aqueous solution) in MeOH). Yield: 250 mg (quantitative) as a dark blue solid.

[0668] Compound 11 was synthesized from intermediates 11-5 and 10-2 following general procedures IV and V. HPLC-MS: m / z 1027.1 (for M + Calculated value: 1026.5); λ max =650nm.

[0669] Preparation of compound 12

[0670]

[0671] Compound 12 was synthesized from intermediates 3-3 and 10-2 following general procedures IV and V. HPLC-MS: m / z 967.4 (for M+H + Calculated value: 966.5); λ max =500nm.

[0672] Preparation of compound 13

[0673]

[0674] Preparation of compound 13-1.

[0675] A mixture of amine 10-2 (0.61 g, 1.69 mmol), triethylamine (0.55 mL, 3.9 mmol) and di-tert-butyl dicarbonate (0.70 g, 3.2 mmol) in THF (20 mL) was stirred overnight at room temperature. The solvent was removed in vacuo, and the residue was purified by flash chromatography (SiO , gradient elution with 0 to 10% MeOH in DCM). Yield: 209 mg (27%) as a yellow foam.

[0676] Compound 13 was synthesized from intermediates 7-2 and 13-1 following general procedures IV, IX, and V. HPLC-MS: m / z 1225.3 (calculated: 1224.7); max =780nm.

[0677] Preparation of compound 14

[0678]

[0679] Scheme 6. Preparation of Compound 14

[0680] Preparation of 6-hydrazino-2-naphthalenesulfonic acid hydrochloride 14-1

[0681] To a cold (0 ° C) solution of 6-amino-2-naphthalenesulfonic acid monohydrate (15.2 g, 68.1 mmol) in an aqueous HCl solution (12 M, 100 mL) was added a solution of NaNO2 in water (25 mL) dropwise over 10 minutes, and the reaction mixture was stirred at 0 ° C for 45 minutes. Then, while keeping the temperature at 0 ° C, a solution of SnCl2 in HCl (12 M, 25 mL) was added dropwise over 1 hour. The reaction mixture was stirred at 0 ° C for 45 minutes, then at room temperature for 1.5 hours. The mixture was concentrated in vacuo, and the resulting solid was triturated with acetone. The precipitate was rinsed with acetone to produce the title compound 14-1 (17 g, 90%) as a pale pink solid.

[0682] Preparation of potassium 1,1,2-trimethyl-1H-benz[e]indole-7-sulfonate 14-2

[0683] A solution of intermediate 14-1 (12 g, 68.1 mmol), KOAc (6.39 g, 65.1 mmol) and isopropyl methyl ketone (8.41 g, 10.5 mmol) in AcOH (200 mL) was heated at 90 ° C for 16 hours and then allowed to cool to room temperature. The reaction mixture was then concentrated to dryness in vacuo, the residue was suspended in acetone, and filtered. The insoluble solid material was washed with EtOH. The combined filtrate was concentrated in vacuo. The residue was purified by reverse phase flash chromatography (C18 SiO2, acetonitrile gradient elution in water) to produce the title compound 14-2 (7.5 g, 34%).

[0684] Preparation of 1,1,2-trimethyl-3-(3-sulfopropyl)-1H-benz[e]indolium-7-sulfonate potassium 14-3

[0685] To a solution of intermediate 14-2 (5.7 g, 17.4 mmol) in anhydrous DMF (120 mL) was added 1,3-propane sultone (4.47 mL, 50.9 mmol), and the reaction mixture was stirred at 100° C. for 5 hours, then concentrated in vacuo. The crude product was purified by reverse phase flash chromatography (C18 SiO 2 , eluting with water) to give the title compound 14-3 (3.1 g, 40%) as an orange foam.

[0686] Preparation of 2-acetyl-9,10-dimethylanthracene 14-X

[0687] To a solution of 9,10-dimethylanthracene (10.0 g, 48.5 mmol) in carbon disulfide (300 mL) was added acetyl chloride (4.9 mL, 75.6 mmol) and aluminum chloride (9.3 g, 69.8 mmol) in sequence. The reddish-brown reaction mixture was stirred overnight at room temperature and then stirred at 45 ° C for 4 hours. The reaction was quenched by adding ice (50 g), concentrated HCl (1 mL) and stirred for 30 minutes. DCM (200 mL) was then added until all black solids dissolved. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with water and dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, eluted with DCM). 6.7 g of the title product (56%) was obtained as a yellow solid.

[0688] Preparation of 9,10-dimethyl-2-anthracenecarboxylic acid 14-4

[0689] A solution of 9,10-dimethyl-2-acetylanthracene (7.6 g, 30.6 mmol) in dioxane (150 mL) was heated at 80° C., added to a solution of NaOCl (14.5%, 80 mL) and NaOH (6.7%, 50 mL), and stirred at 80° C. for 16 hours. The reaction mixture was then diluted with water (100 mL) and acidified with HCl (1 M) until pH 1. The suspension was filtered, and the solid product was washed thoroughly with water to provide compound 14-4 (6.3 g, 84%) as a yellow solid.

[0690] Preparation of 9,10-dimethyl-2-anthracenecarboxylic acid methyl ester 14-5

[0691] A solution of compound 14-4 (6.3 g, 25.1 mmol) and p-toluenesulfonic acid (8.7 g, 50.3 mmol) in MeOH (100 mL) was refluxed for 22 hours. The reaction was then concentrated in vacuo, diluted with DCM, and washed with saturated NaHCO , 1M NaHCO , and brine. The organic layer was dried over anhydrous MgSO , filtered, and concentrated in vacuo to yield compound 14-5 (6.13 g, 92%) as a yellow solid.

[0692] Preparation of 9,10-dimethyl-2-hydroxymethylanthracene 14-6

[0693] A suspension of LiAlH4 (2.63 g, 69.4 mmol) in anhydrous THF (100 mL) was cooled to 0 ° C. A solution of compound 14-5 (6.12 g, 23.1 mmol) in anhydrous THF (100 mL) was added dropwise over 15 minutes. After stirring at 0 ° C for 45 minutes, the reaction was quenched with water (12 mL) and NaOH (15%, 3 mL) at 0 ° C. The reaction mixture was then diluted with ether (150 mL) and filtered. The solid was washed with ethyl acetate. The combined filtrate and washings were concentrated in vacuo, and the residue was then dissolved in ethyl acetate and washed with brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to produce compound 14-6 (4.6 g, 86%) as a yellow solid.

[0694] Preparation of 9,10-dimethyl-2-anthracenecarboxaldehyde 14-7

[0695] In a flame-dried 500mL 3-neck flask, under argon, potassium chlorochromate (5.48g, 25.4mmol) was suspended in anhydrous 1,2-dichloroethane (100mL). A solution of compound 14-6 (4.62mg, 19.5mmol) in anhydrous 1,2-dichloroethane (150mL) was added dropwise to the slurry over 20 minutes. After stirring at room temperature for 6 hours, the reaction mixture was filtered through Celite and the plugged column was rinsed with DCM. The filtrate was concentrated in vacuo to produce compound 14-7 (720mg, 15%) as a yellow solid.

[0696] Preparation of 9,10-bis(bromomethyl)-2-anthracenecarboxaldehyde 14-8

[0697] A mixture of compound 14-7 (720 mg, 3.1 mmol) and N-bromosuccinimide (1.20 g, 6.7 mmol) in anhydrous CCl4 (50 mL) was refluxed for 1 hour. The reaction mixture was then diluted with toluene (100 mL) and cooled to -20 ° C for 3 days. The resulting yellow crystals were separated by filtration and washed with MeOH to produce compound 14-8 (830 mg, 69%) as a yellow solid.

[0698] Preparation of compound 14-9

[0699] A mixture of N-(3-aminopropyl)methacrylamide hydrochloride (1.54 g, 8.6 mmol), triethylamine (1.25 mL, 8.67 mmol) and compound 14-8 in anhydrous DCM (75 mL) was refluxed under argon for 16 hours. The reaction mixture was then concentrated in vacuo, and the residue was purified by flash chromatography (SiO , eluting with a gradient of 0 to 10% MeOH in DCM). Product 14-9 was obtained as an amber oil (812 mg, 73%).

[0700] Preparation of compound 14-10

[0701] To a solution of compound 14-9 in anhydrous acetonitrile (25 mL) and anhydrous DMF (3 mL) was added K2CO3 (821 mg, 4.39 mmol) and 2-bromomethylphenylboronic acid (519 mg, 2.41 mmol). The reaction was stirred at room temperature for 4 days, filtered, and the filtrate was concentrated in vacuo. Toluene was then added to the residue and removed in vacuo to facilitate removal of DMF, and the dilution-evaporation was repeated twice. The residue was dried under high vacuum and then purified by reverse phase flash chromatography (C18 SiO2, eluted with 0.1% TFA in MeCN). The combined and concentrated fractions were basified with saturated NaHCO3 and then triple extracted with DCM to isolate the pure product. The DCM portion was then dried over MgSO4 and concentrated in vacuo to provide the title compound 14-10 (280 mg, 32%) as a yellow residue.

[0702] Preparation of compound 14

[0703] A solution of compound 14-10 (260 mg, 0.33 mmol) and 14-3 (448 mg, 0.99 mmol) in ethanol (50 mL) was refluxed for 2 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified twice by reverse phase flash chromatography (C18 SiO2, eluted with MeCN and water). After lyophilization, the pure product (125 mg, 28%) was obtained as a pink / red solid. HPLC-MS: m / z 1176.9 (for M+H + Calculated value: 1176.5); λ max =655,687nm.

[0704] Preparation of compound 15

[0705]

[0706] Scheme 9. Preparation of compound 15.

[0707] Preparation of 7-(diethylamino)-2-phenyl-4H-1-benzopyran-4-one (15-1)

[0708] At 180 DEG C under argon, a mixture of N, N-diethyl-3-aminophenol (4.0g, 24.2mmol) and ethyl benzoyl acetate (9.30g, 48.4mmol) was heated for 16 hours. Then, additional ethyl benzoyl acetate (2.0mL, 11mmol) was introduced into the reaction mixture, and it was stirred for 3 hours, then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (20mL), and hexane was subsequently added, which produced a precipitation. The suspension was centrifuged, and the supernatant was washed three times with 0.05M HCl. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, eluted with ethyl acetate and hexane) to provide compound 15-1 (773mg, 10%) as a light yellow solid.

[0709] Preparation of 7-(diethylamino)-4-methyl-2-phenyl-1-benzopyrylium tetrafluoroborate (15-2)

[0710] Under argon, a solution of compound 15-1 (773 mg, 2.6 mmol) in anhydrous THF (10 mL) was cooled to 0 ° C. Methylmagnesium bromide (1.2 mL, 3.6 mmol) was added dropwise over 15 minutes. The flask was warmed to room temperature and stirred for 24 hours. 48% tetrafluoroboric acid (1.4 mL, 10.7 mmol) was then added, and the mixture was stirred for 15 minutes. The solution was then diluted with DCM and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (C18 SiO2, eluted with water and MeOH). The fractions containing the pure product were combined and concentrated in vacuo to remove MeOH. The residual aqueous solution was then extracted three times with DCM. The combined DCM layer was dried over MgSO4, filtered, and concentrated in vacuo to produce compound 15-2 (625 mg, 60%) as a purple-red solid.

[0711] Preparation of compound 15

[0712] A mixture of compound 14-10 (100 mg, 0.12 mmol) and 15-2 (53.3 mg, 0.14 mmol) in ethyl acetate (5 mL) was heated at 75 ° C for 16 hours. The reaction mixture was concentrated in vacuo and adsorbed on silica. Impurities were removed by washing the solid with a mixture of MeOH in DCM. The product was then recovered by sonicating the silica in DMSO and then filtering. The filtrate was lyophilized to provide pure compound 15 (10 mg, 7%). HPLC-MS: m / z 1056 (for M + Calculated value: 1056.6); λ max=530nm (width).

[0713] Preparation of compound 17

[0714]

[0715] Scheme 7. Preparation of compound 17.

[0716] Preparation of (4-hydrazinophenyl)acetic acid hydrochloride (17-1)

[0717] A mixture of 4-aminophenylacetic acid (6.86 g, 45.3 mmol) and HCl (12 M, 100 mL) was refluxed for 15 minutes. After heating, the solution was cooled to -5 ° C., and NaNO aqueous solution (25 mL) was added dropwise at 0 ° C. over 10 minutes. After the reaction mixture was stirred for 20 minutes, SnCl was added dropwise over 10 minutes while keeping the temperature below 0 ° C. HCl solution (12 M, 50 mL) was added dropwise. The reaction mixture was then stirred for another 2 hours, then filtered, and the precipitate was washed with cold water (100 mL), cold ethanol (200 mL) and ether (50 mL). The solid was then dried under high vacuum to produce compound 17-1 (6.68 g, 73%) as a beige solid.

[0718] Preparation of 2,3,3-trimethyl-3H-indole-5-acetic acid (17-2)

[0719] A mixture of compound 17-1 (6.6 g, 32.5 mmol), acetic acid (80 mL), potassium acetate (6.39 g, 65.1 mmol) and isopropyl methyl ketone (8.41 g, 10.5 mmol) was refluxed for 3 hours and then cooled to room temperature. The solution was then concentrated in vacuo. The residue was dissolved in DCM and washed with brine, then dried over MgSO , filtered, and concentrated in vacuo. The resulting solid was purified by flash chromatography (SiO , gradient elution with 0 to 15% MeOH in DCM) to produce compound 17-2 (4.9 g, 59%) as a pale pink solid.

[0720] Preparation of compound 17-3

[0721] A mixture of compound 17-2 (2.0 g, 7.8 mmol), N-(3-aminopropyl)methacrylamide hydrochloride (1.67 g, 9.39 mmol), HOBt (1.26 g, 9.39 mmol), EDC (2.25 g, 11.7 mmol) and triethylamine (3.39 mL, 23.5 mmol) in DCM (30 mL) was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was purified by flash chromatography (SiO 2 , eluted with MeOH and DCM) to provide compound 17-3 (3.0 g, quantitative).

[0722] Preparation of compound 17-4

[0723] A solution of compound 17-3 (3.0 g, 8.7 mmol) and 1,3-propane sultone (7.7 mL, 87.8 mmol) in anhydrous acetonitrile (50 mL) was heated to 50 ° C for 4 days. The reaction mixture was then concentrated to 10 mL in vacuo. The concentrate was then diluted with ether / acetone (40 mL) to produce a large amount of precipitation. The slurry was centrifuged and the supernatant was discarded. The solid was washed with acetone and dried in vacuo to produce compound 17-4 (3.5 g, 85%) as a purple foam.

[0724] Preparation of compound 17-10

[0725] A mixture of aldehyde 14-8 (250 mg, 0.63 mmol), 2-[(methylamino)methyl]phenylboronic acid (420.8 mg, 2.5 mmol) and triethylamine (0.367 mL, 2.5 mmol) in DCM (40 mL) and DMF (8 mL) was heated to reflux for 3 days. The reaction mixture was washed three times with water. The DCM layer was loaded onto a silica column and eluted with a gradient of 0-15% MeOH in DCM. Product 17-10 was obtained as a crude yellow oil (320 mg, 89%).

[0726] Preparation of compound 17

[0727] A mixture of compound 17-10 (318 mg, 0.56 mmol) and 17-4 (637 mg, 1.4 mmol) in ethanol (50 mL) was refluxed for 16 hours. The reaction was then concentrated in vacuo, and the residue was purified by reverse phase flash chromatography (C18SiO2, gradient elution with 0.25% HCl (aqueous) in MeOH). The product was isolated by basifying the combined and concentrated pure fractions with saturated NaHCO3 and then performing triple extraction with DCM. The DCM portion was then dried over MgSO4 and concentrated in vacuo to provide the title compound 17 (150 mg, 26%) as a dark red solid after trituration with diethyl ether. HPLC-MS: m / z 1006.6 (for M+H + Calculated value: 1006.5); λ max =525nm (width).

[0728] Preparation of compound 18

[0729]

[0730] Scheme 8. Preparation of compound 18.

[0731] Preparation of 1-(5-carboxypentyl)-4-methylquinolinium bromide (18-1)

[0732] A mixture of 4-methylquinoline (lepidine) (2.0 mL, 14.7 mmol) and 6-bromohexanoic acid (4.33 g, 22.2 mmol) was heated at 120°C for 5 hours, followed by heating at 130°C for 16 hours. The reaction mixture was then cooled to room temperature and sonicated with acetone for 15 minutes. The supernatant was decanted, and the solid residue was washed twice more with fresh acetone under sonication to yield compound 18-1 (2.4 g, 76%) as a fine gray solid.

[0733] Preparation of compound 18-2

[0734] In a dry 100mL flask, compound 18-1 (1.0g, 2.9mmol) was dissolved in 3:1DCM / DMF (50mL), followed by the addition of N-(3-aminopropyl)methacrylamide hydrochloride (633mg, 3.5mmol), HOBt (598mg, 4.4mmol), EDC (849mg, 4.4mmol) and triethylamine (0.857mL, 5.9mmol). The reaction mixture was stirred at room temperature for 16 hours and then diluted with diethyl ether. The resulting suspension was centrifuged and the supernatant was discarded. The solid residue was purified by flash chromatography (SiO2, eluted with MeOH and DCM) to provide the target compound 18-2 (884mg, 65%) as a pink amorphous solid.

[0735] Preparation of compound 18

[0736] A mixture of compound 17-10 (100 mg, 0.17 mmol) and 18-2 (200 mg, 0.43 mmol) in ethanol (10 mL) was refluxed for 5 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (SiO 2 , eluted sequentially with a 0 to 30% gradient of MeOH in DCM and 100% of MeOH with 0.1% TFA). The resulting yellow oil was repurified in the same manner. The pure product was dissolved in DCM, and the solution was washed with saturated NaHCO 3 , dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo. Pure compound 18 was obtained as an orange amorphous solid (9 mg, 5%). HPLC-MS: m / z 924.8 (for M + Calculated value: 924.5); λ max =380nm (width).

[0737] Preparation of compound 35

[0738]

[0739] Scheme 1. Preparation of compound 35

[0740] Preparation of 2-bromo-9,10-dimethylanthracene (35-2)

[0741] In a 4-neck 10L flask, 2-bromoanthraquinone (compound 35-1,500 g, 1.74 mol) was dissolved in anhydrous THF (6.5 L). The solution was cooled to -78°C under a nitrogen atmosphere, and MeLi (2.39 L, 3.83 mol) was added dropwise over 2 hours. The darkening reaction mixture was stirred at -78°C for an additional hour, then allowed to reach room temperature overnight. The reaction was quenched with saturated NH4Cl (1.5 L). The organic layer was separated, washed with H2O, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting yellow solid was then dissolved in MTBE (3.4 L). A solution of SnCl2·2H2O (2.12 kg, 9.40 mol) in concentrated HCl (1.67 L) was added over 30 minutes while cooling in an ice bath. The reaction mixture was stirred at room temperature for 3 hours, then transferred to a separatory funnel, washed with H2O, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, eluent: 20:1 petroleum ether / DCM) to give the title compound 35-2 (220 g, 44%) as a yellow solid.

[0742] Preparation of 2-bromo-9,10-bis(bromomethyl)anthracene 35-3

[0743] A mixture of 2-bromo-9,10-dimethylanthracene 35-2 (6.89 g, 24.6 mmol) and N-bromosuccinimide (9.46 g, 53.15 mmol, 2.2 equiv) in 1,2-dichloroethane (100 mL) was refluxed for 2 h. The solvent was removed in vacuo, and the residue was triturated with methanol (100 mL), filtered, rinsed thoroughly with methanol, and dried to yield compound 35-3 (10.14 g, 95%) as a yellow-orange solid.

[0744] General Procedure XI. Hydrolysis of bis-(bromomethyl)anthracene. Preparation of 2-bromo-9,10-bis(hydroxymethyl)anthracene 35-4

[0745] A mixture of 2-bromo-9,10-bis(bromomethyl)anthracene 35-3 (22.9 g, 51.7 mmol) and anhydrous calcium carbonate (31.02 g, 310.2 mmol, 6 equivalents) in 2:1 1,4-dioxane / HO (250 mL) was stirred at reflux for 20 hours. The reaction was then concentrated to remove dioxane, acidified with 1M HCl (50 mL), and filtered. The collected solid was rinsed with water (3×50 mL) and dried under high vacuum to yield the product 35-4 (15.0 g, 92%) as an orange-yellow solid.

[0746] Preparation of 2-bromoanthracene-9,10-dicarbaldehyde 35-5

[0747] At 0 ° C under nitrogen, Dess-Martin periodinane (3.3 g, 7.88 mmol) was added to a solution of 35-4 (1 g, 3.15 mmol) in 1: 1 THF / DCM (250 mL). The solution was stirred at room temperature for 3 hours, then filtered and diluted with saturated NaHCO 3. The resulting mixture was transferred to a separatory funnel and extracted three times with DCM. The combined DCM layers were dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash chromatography (SiO 2, eluent: 100% DCM) to provide 35-5 (440 mg, 44%) as an orange solid.

[0748] Preparation of 2-bromo-9,10-bis[(3-methacrylamidopropyl)aminomethyl]anthracene 35-6

[0749] In a 1 L flame-dried flask, a mixture of APMA·HCl (5.75 g, 33.3 mmol) and DIPEA (5.8 mL, 33.3 mmol) in anhydrous THF (500 mL) was sonicated for 30 minutes. Anhydrous DMSO was then added until a clear solution (approximately 20 mL) was obtained. Glacial acetic acid (0.48 mL, 8.3 mmol) and dialdehyde 35-5 (1.3 g, 4.2 mmol) were added to the solution, which was then stirred at room temperature for 45 minutes. Sodium triacetoxyborohydride (9.3 g, 44.4 mmol) was added in four equal portions over 2 hours, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo, diluted with DCM and saturated NaHCO 3 , and transferred to a separatory funnel. The aqueous layer was extracted 5 times with DCM. The combined DCM layers were then dried over MgSO 4 and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (C18 SiO2, gradient elution with 0.25% HCl (aq) in MeOH). The pure product was obtained by lyophilization as a light yellow solid (0.29 g, 11%).

[0750] General Procedure XII. Pd-catalyzed borylation of aryl bromides. Preparation of {2-[9,10-bis(3-methacrylamidopropyl)aminomethyl]anthracene}boronic acid 35-7

[0751] A mixture of diamine 35-6 (2 g, 3.53 mmol), bis(pinacolato)diboron (1.8 g, 7.07 mmol), potassium acetate (2.1 g, 21.2 mmol) and Pd(dppf)Cl2 was purged with dry argon 5 times. Anhydrous DMSO (120 mL) was then added, and the reaction mixture was stirred at 50 ° C under argon for 16 hours. After the starting material was consumed, the reaction mixture was diluted with DCM (350 mL) and water (350 mL), stirred at room temperature for 20 minutes, and then transferred to a separatory funnel. The organic layer was discarded, and the aqueous layer was washed 4 times with DCM. The remaining aqueous layer was concentrated in vacuo and used for reverse phase flash chromatography (C18SiO2, eluted with a gradient of 0.09% HCl (aqueous solution) in MeOH). The pure product was collected by lyophilization to produce boronic acid 35-7 (558 mg, 30%) as a yellow-orange solid.

[0752] Preparation of 4-{[9,10-bis(3-methacrylamidopropyl)aminomethyl]anthracen-2-yl}-2,2'-bipyridine 35-8

[0753] In a flame-dried 50-mL 3-neck flask equipped with a condenser, a mixture of anthraceneboronic acid 35-7 (522 mg, 0.985 mmol), 4-bromo-2,2'-bipyridine (154 mg, 0.657 mmol) and cesium carbonate (640 mg, 1.97 mmol) in EtOH (15 mL) and water (2 mL) was degassed by refluxing for 75 minutes under an argon stream. Pd(OAc)2 (29.7 mg, 0.131 mmol) and PPh3 (138 mg, 0.526 mmol) were then added in one go. Reflux under argon was continued until the reaction was complete within 90 minutes. The reaction mixture was then cooled to room temperature and filtered; the solid residue was rinsed with DCM and MeOH. The filtrate was concentrated in vacuo, and the resulting residue was purified by reverse phase flash chromatography (C18 SiO2, eluted with a gradient of 0.09% HCl in MeOH). The pure product was isolated by basifying the combined and concentrated fractions with solid NaHCO 3 (200 mg) followed by extraction twice with DCM The combined DCM layers were then dried over MgSO 4 and concentrated in vacuo to give the product as a yellow solid (316 mg, 50%).

[0754] Preparation of Bis(2,2'-bipyridine)-4-{[9,10-bis(3-methacrylamidopropyl)aminomethyl]anthracen-2-yl}-2,2'-bipyridineruthenium bis(hexafluorophosphate) 35-9

[0755] To a degassed solution of diamine 35-8 (75 mg, 0.117 mmol) in EtOH (20 mL) was added Ru(bpy)2Cl2·2H2O (57 mg, 0.117 mmol) and the reaction was refluxed at 80°C under a stream of argon for 20 hours, at which point the reaction was complete. The solvent was removed in vacuo, and the residue was purified by reverse phase flash chromatography (C18 SiO2, eluting with a gradient of 0.09% HCl (aq) in acetonitrile). The combined fractions with the pure product were concentrated in vacuo to remove the acetonitrile. The product was then precipitated by the addition of saturated ammonium hexafluorophosphate solution (0.25 mL), collected by filtration, rinsed with water and diethyl ether, and dried in vacuo. Yield: 159 mg (quantitative).

[0756] Preparation of compound 35

[0757] A mixture of intermediate 35-9 (409 mg, 0.30 mmol) and K2CO3 (415 mg, 3 mmol) in anhydrous DMF (4 mL) was stirred at room temperature under argon for 16 hours. 2-Bromomethylphenylboronic acid (259 mg, 1.2 mmol) was then added, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was separated by reverse phase flash chromatography (C18 SiO2, eluted with a gradient of 0.09% HCl (aqueous solution) in acetonitrile). The combined fractions with pure product were concentrated in vacuo to remove acetonitrile. The product was then precipitated by adding saturated ammonium hexafluorophosphate solution (0.25 mL) to the aqueous solution and collected by centrifugation. The supernatant was discarded, and the precipitate was washed three times with diethyl ether to provide the title compound (123 mg, 65%) as an orange-red to dark red solid. HPLC-MS: m / z 661.7 (for M +2 Calculated value: 668.8); λ max =465nm (width).

[0758] Preparation of compound 19

[0759]

[0760] Intermediate 19-4 was synthesized following a published protocol (Cui, J.; Jin, J.; Hsieh, Y.-H.; Yang, H.; Ke, B.; Damera, K.; Tai, PC; Wang, B. ChemMedChem 2013, 8(8), 1384–1393).

[0761] General Procedure XIII. TBDMS Protection. Preparation of Compound 19-5.

[0762] Under argon, a solution of diol 35-4 (81g, 0.256mol), tert-butyldimethylchlorosilane (154g, 1.02mol) and imidazole (69.5g, 1.02mol) in anhydrous DCM (900mL) was stirred for 3 hours. The reaction mixture was then filtered, and the filtrate was concentrated to about 200mL under reduced pressure. The concentrate was passed through a silica plugging column (eluent: EtOAc / hexane=1:1). The fractions containing the main product (assessed by TLC) were collected and concentrated under reduced pressure. The residue was further purified by flash chromatography (SiO2, eluent: a gradient of 0 to 10% DCM in hexane) to provide intermediate 19-5 (60g, 43%) as a yellow solid.

[0763] Following General Procedure X, compound 19-6 was synthesized from intermediates 19-4 and 19-5.

[0764] General Procedure XIV. Double Amination of Anthracene Diol via Dibromide Formation. Preparation of Compound 19-7.

[0765] Phosphorus tribromide (0.27 mL, 2.8 mmol) was added to a solution of diol 19-6 (560 mg, 1.11 mmol) in anhydrous DCM (100 mL), and the mixture was stirred at room temperature for 15 minutes. The solvent was then removed under reduced pressure. The residue was resuspended in anhydrous MeCN (10 mL) and transferred to a slurry of APMA·HCl (597 mg, 3.3 mmol) and K2CO3 (1.32 g, 6.7 mmol) in a 1:1 mixture (30 mL) of anhydrous MeCN and DCM, which was pre-stirred at room temperature for at least 24 hours. The reaction mixture was stirred for 2–16 hours and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase flash chromatography (C18 SiO2, gradient elution with MeOH+0.25% HCl in water) to provide the title compound 19-7 (134 mg, 22% yield).

[0766] Compound 19 was synthesized from intermediate 19-7 following General Procedure V. HPLC-MS: m / z 1020.5 (for M + Calculated value: 1019.5); λ max =565nm. 1H NMR(400MHz,MeOH-d4)δppm 8.62(d,J=9.7Hz,1H),8.56(t,J=8.0Hz,1H),8.32(dd,J=7.1,2.9Hz,1H),7.63-7.72(m,2H),7.49-7.59(m,2H),7.23-7.33(m,8H),7.17-7 .23(m,2H),7.10(d,J=2.3Hz,2H),7.00(dd,J=9.6,2.2Hz,2H),5.37(s,1H),5.26(s,1H),5.20(quin,J=1.5Hz,1H),5.13(quin,J=1.5Hz,1H ),4.80(br.s.,2H),4.73(br.s.,2H),4.59(s,2H),4.00(s,2H),3.79(s,2H),3.36(s,12H),3.06(t,J=6.7Hz,2H),2.89(t,J=6.8Hz,2H),2 .70(t,J=7.6Hz,2H),2.55(t,J=7.4Hz,2H),1.92-1.97(m,2H),1.88-1.92(m,2H),1.73(dd,J=1.6,1.0Hz,3H),1.65(dd,J=1.6,1.0Hz,3H).

[0767] Preparation of compound 20

[0768]

[0769] Intermediate 20-2 was prepared by analogy from published procedures (Cui, J.; Jin, J.; Hsieh, Y.-H.; Yang, H.; Ke, B.; Damera, K.; Tai, PC; Wang, B. ChemMedChem 2013, 8(8), 1384–1393).

[0770] Compound 20 was synthesized from intermediates 20-2 and 19-5 following general procedures X, XIV, and V. HPLC-MS: m / z 1066.1 (for M + Calculated value: 1065.5); λ max =700nm.

[0771] Preparation of compound 21

[0772]

[0773] Intermediate 21-2 was synthesized from Intermediates 19-5 and 11-3 following General Procedures X and XIV.

[0774] General Procedure XV. Alkylation with MIDA boronate followed by deprotection. Preparation of Compound 21.

[0775] A solution of diamine 21-2 (1.5 g, 1.65 mmol), DIPEA (0.99 mL, 5.68 mmol) and 2-(bromomethyl)phenylboronic acid MIDA ester (1.7 g, 5.1 mmol) in a mixture of anhydrous DCM and acetonitrile (20 mL: 20 mL) was stirred for 1 hour at ambient temperature. The solvent was then removed under reduced pressure, the residue was dissolved in MeOH (25 mL), and treated with a 2M Na2CO3 aqueous solution (15 mL). The mixture was stirred vigorously for 2 hours. The suspension was then filtered and rinsed with MeOH (150 mL). The filtrate was concentrated under reduced pressure, and the residue was distributed between saturated NaHCO3 (100 mL) and DCM (50 mL). The layers were separated, and the aqueous layer was extracted with DCM (3 × 30 mL). The combined DCM layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (C18 SiO2, eluting with a gradient of 35% to 100% MeOH in water + 0.05% TFA). Yield: 747 mg (39% yield as a mono-TFA salt) as a dark blue solid. HPLC-MS: m / z 1062.4 (for M + Calculated value: 1061.6). UV / Vis: λ max =660nm. 1H NMR(400MHz,MeOH-d4)δppm0.67(s,3H)0.86(br.s.,3H)1.67(s,3H)1.69-1 .73(m,2H)1.74(s,3H)1.85-2.00(m,2H)2.61(t,J=7.18Hz,2H)2.70-2.78(m ,2H)2.93(t,J=7.10Hz,2H)3.08(t,J=6.51Hz,2H)3.37(s,12H)3.86(br.s. ,2H)4.06(br.s.,2H)4.56(br.s.,2H)4.84(br.s.,2H)5.15(s,1H)5.21(s,1 H)5.29(s,1H)5.38(s,1H)6.67(dd,J=9.50,2.50Hz,2H)6.83-6.97(m,1H)7 .10(m,J=9.60Hz,1H)7.19(d,J=9.40Hz,2H)7.24(d,J=7.91Hz,1H)7.26-7.3 4(m,4H)7.37(d,J=8.64Hz,1H)7.42(d,J=7.06Hz,1H)7.47(d,J=2.50Hz,2H) 7.51(br.s.,1H)7.61-7.70(m,2H)8.43(d,J=9.01Hz,1H)8.48-8.60(m,2H).

[0776] Preparation of compound 49

[0777]

[0778] Intermediate 49-1 was synthesized following published procedures [Reference: Koide et al. J. Am. Chem. Soc., 134(11), 5029–5031].

[0779] Compound 49 was synthesized from intermediates 49-1 and 19-5 following the order of general procedures X, XIV, and XV. HPLC-MS: m / z 1086.2 (for M + Calculated value: 1085.6). UV / Vis: λ max =705nm.

[0780] Preparation of compound 45

[0781]

[0782] Intermediate 45-1 was synthesized from commercially available starting materials by analogy with 49-1 as described in the literature (Koide, Y.; Urano, Y.; Hanaoka, K.; Piao, W.; Kusakabe, M.; Saito, N.; Terai, T.; Okabe, T.; Nagano, T. Am. Chem. Soc. 2012, 134(11), 5029-5031).

[0783] Compound 45 was synthesized from intermediates 45-1 and 19-5 following general procedures X, XIV, and XV. HPLC-MS: m / z 1114.3 (for M + Calculated value: 1113.6). UV / Vis: λ max =690nm.

[0784] Preparation of compound 48

[0785]

[0786] The intermediate silaxanthonone 48-1 was synthesized from commercially available starting materials by analogy with 49-1 as described in the literature (Koide, Y.; Urano, Y.; Hanaoka, K.; Piao, W.; Kusakabe, M.; Saito, N.; Terai, T.; Okabe, T.; Nagano, T. Am. Chem. Soc. 2012, 134(11), 5029–5031).

[0787] Compound 48 was synthesized from silaanthrone 48-1 and bromoanthracene 19-5 following General Procedures X, XIV, and XV. HPLC-MS: m / z 1194.3 (for M + Calculated value: 1193.7). UV / Vis: λ max =740nm.

[0788] Preparation of compound 56

[0789]

[0790] Intermediate 56-1 was synthesized from commercially available starting materials by analogy with 49-1 as described in the literature (Koide, Y.; Urano, Y.; Hanaoka, K.; Piao, W.; Kusakabe, M.; Saito, N.; Terai, T.; Okabe, T.; Nagano, T. Am. Chem. Soc. 2012, 134(11), 5029-5031).

[0791] General Procedure XVI. Preparation of Siloxamine Fluorophores by Lithium-Halogen Exchange with t-BuLi and TMEDA. Preparation of compound 56-2.

[0792] A solution of aryl bromide 19-5 (142 mg, 0.26 mmol) and TMEDA (0.02 mL, 0.13 mmol) in anhydrous THF (4 mL) was cooled to -78 ° C under argon. A solution of tert-butyl lithium in pentane (c = 1.52 M, 0.19 mL, 0.29 mmol) was added dropwise, and the mixture was stirred at -78 ° C for 5-15 minutes, followed by rapid addition of silanthone 56-1 (c = 0.075 M, 2.65 mL, 0.20 mmol) in the form of a solution in anhydrous THF. The mixture was stirred at -78 ° C for 5-30 minutes, then allowed to warm to room temperature. After 1 hour, the reaction was quenched with half-saturated NH4Cl, acidified with 0.1 M HCl (1 mL), and thoroughly extracted with DCM until the aqueous layer was colorless. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO 2 , gradient elution with 2% to 25% MeOH in DCM) to give bis-TBDMS diether 56-2 (83 mg, 27% yield, 56% brsm) as a dark blue solid.

[0793] General Procedure XVII-A. Double Amination of TBDMS Diether. Preparation of Compound 56-3.

[0794] A solution of intermediate 56-2 (83 mg, 0.09 mmol) in anhydrous DCM (9 mL) was treated with a 1 M solution of thionyl chloride in DCM (0.5 mL, 0.5 mmol) at room temperature for 16 hours. The solvent was then removed in vacuo, and the residue was rigorously dried under high vacuum to remove traces of thionyl chloride. This residue was dissolved in anhydrous MeCN (5 mL) and transferred to a slurry of APMA·HCl (330 mg, 1.85 mmol) and K2CO3 (511 mg, 3.7 mmol) in anhydrous MeCN (50 mL), which was pre-stirred at room temperature for at least 24 hours. NaI (8 mg, 0.05 mmol) was added to the suspension, and the mixture was stirred at room temperature for 2 hours, then filtered. The filtrate was concentrated in vacuo and the residue was purified by reverse phase flash chromatography (C18 SiO2, gradient elution 5% to 100% MeOH in water + 0.05% TFA). Yield: 9 mg (10%) as a blue oil.

[0795] Compound 56 was synthesized from intermediate 56-3 following General Procedure XV. HPLC-MS: m / z 1114.3 (for M + Calculated value: 1113.6). UV / Vis: λ max=665nm.

[0796] Preparation of compound 36

[0797]

[0798] Preparation of compound 36-1.

[0799] A mixture of methyl 2-bromo-3-methylbenzoate (10 g, 43 mmol), pinacol borane (9.7 mL, 66 mmol), triethylamine (19 mL, 131 mmol), S-Phos (1.4 g, 3.5 mmol) and Pd(MeCN)Cl2 (15.7 mg, 0.9 mmol) in degassed dioxane (200 mL) was heated at 60 ° C under argon for 16 hours. The reaction mixture was then filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, eluted with a gradient of 0% to 100% DCM in hexane) to provide the title compound 36-1 (11.2 g, 94% yield) as a white solid.

[0800] Preparation of compound 36-2.

[0801] A mixture of intermediate 36-1 (11.2 g, 40 mmol), N-bromosuccinimide (7.8 g, 44 mmol), AIBN (10 mg, 0.06 mmol) in 1,2-dichloroethane (180 mL) was refluxed for 16 hours. The reaction mixture was then concentrated under reduced pressure. The residue was triturated with cold (4 ° C) EtOAc and insoluble solids were discarded. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (SiO2, eluted with a gradient of 0% to 100% DCM in hexane). This provided the title compound 36-2 (10.2 g, 72% yield) as a white solid.

[0802] Preparation of compound 36-3.

[0803] Under argon, a solution of intermediate 36-2 (5.0 g, 14 mmol) in toluene (25 mL) was cooled to 0 ° C. Over 30 minutes, diisobutylaluminum hydride (c = 1M, in THF, 29.5 mL, 29.5 mmol) was added dropwise. The mixture was distributed, and the aqueous layer was thoroughly extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, gradient elution with 0% to 10% MeOH in DCM). This provided the title compound 36-3 (2.2 g, 69%) as a colorless oil.

[0804] Compound 36 was prepared from intermediates 21-2 and 36-3 following General Procedure V. HPLC-MS: m / z 1086.4 (for M + Calculated value: 1085.6). UV / Vis: λ max =660nm.

[0805] Preparation of compound 37

[0806]

[0807] Intermediate 37-1 was synthesized following published procedures (Colvin, AE et al., PCT International Application (2008), WO2008066921A2 June 5, 2008).

[0808] Compound 37 was prepared from intermediates 21-2 and 37-1 following General Procedure V. HPLC-MS: m / z 1326.2 (for M + Calculated value: 1325.5). UV / Vis: λ max =660nm.

[0809] Preparation of compounds 46, 47, 51, 52, 53, 55, 57, 58, and 60

[0810]

[0811] General Procedure XVIII. Protection of Boronic Acid with Neopentyl Glycol. Preparation of Compound 51-1

[0812] 4-Cyano-2-methylphenylboronic acid (906 mg, 5.6 mmol), 2,2-dimethyl-1,3-propanediol (641 mg, 6.15 mmol) and A mixture of molecular sieves (1 g) in anhydrous toluene (10 mL) was heated for 1 hour and then allowed to cool to room temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (SiO , gradient elution with 20% to 60% EtOAc in hexane). Yield: 1.054 g (82%) as a light yellow solid.

[0813] General Procedure XIX. Free Radical Bromination. Preparation of Compound 51-2.

[0814] A mixture of 4-cyano-2-methylphenylboronic acid neopentyl glycol ester 51-1 (229 mg, 1.0 mmol), N-bromosuccinimide (208 mg, 1.17 mmol) and AIBN (22 mg, 0.13 mmol) in CCl (20 mL) was refluxed for 20–30 minutes. Progress was monitored by TLC (DCM: hexane = 6: 4). The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO , eluted with 0% to 50% EtOAc in hexane) to provide the title compound 51-2 (312 mg, quantitative) as a turbid oil, which slowly crystallized after storage at room temperature.

[0815] Compound 51 was prepared from intermediates 21-2 and 51-2 following General Procedure V. During the reverse phase chromatography purification, the neopentyl glycol protecting group was spontaneously removed. HPLC-MS: m / z 1112.2 (for M + Calculated value: 1111.6). UV / Vis: λ max =660nm. 1 H NMR (400 MHz, MeOH-d4; mixture of two rotamers) δ ppm 8.53 (m, J = 9.4 Hz, 2H), 8.29-8.40 (m, 1H), 7.68-7.78 (m, 2H), 7.48-7.67 (m, 8H), 7.46 (d, J = 2.7 Hz, 2H), 7.18 (d, J = 9.1 Hz, 2H), 6.70 (dd, J = 9.7, 2.8 Hz, 2H), 5.43 (s, 1H), 5.33 (s, 1H), 5.25 (quin, J = 1.3 Hz, 1H), 5.18 (quin, J = 1.3 Hz, 1H), 5.06 (br. s., 2H) ),4.96(br.s.,2H),4.23(br.s.,2H),4.03(br.s.,2H),3.37(s,12H),3.12(t,J=6.1Hz,2H),2.98(t,J=6.2Hz,2H),2.88(dd ,J=8.0,6.6Hz,2H),2.71(dd,J=8.2,6.6Hz,2H),1.91-2.08(m,4H),1.77(s,3H),1.69(s,3H),0.82(br.s.,3H),0.63(s,3H).

[0816] Compounds 46, 47, 52, 53, 55, 57, 58, 60 were prepared from intermediate 21-2 and the corresponding boronic acid or neopentyl glycol boronate following general procedures XVIII, XIX, and V as outlined in the above schemes.

[0817] For compound 46: HPLC-MS: m / z 1098.3 (for M + Calculated value: 1097.6). UV / Vis: λ max =660nm.

[0818] For compound 47: HPLC-MS: m / z 1268.0 (for M + Calculated value: 1267.3). UV / Vis: λ max =660nm.

[0819] For compound 52: HPLC-MS: m / z 1198.2 (for M + Calculated value: 1197.5). UV / Vis: λ max =660nm. 1 H NMR (400 MHz, MeOH-d4; mixture of two rotamers) δ ppm 8.82 (s, 1H), 8.30 (d, J = 7.9 Hz, 2H), 7.79-7.88 (m, 1H), 7.67-7.78 (m, 2H), 7.45-7.67 (m, 6H), 7.39-7.45 (m, 3H), 6.98 (d, J = 2.7 Hz, 2H), 6.78 (dd, J = 9.3, 2.7 Hz, 2H), 5.44 (s, 1H), 5.36 (s, 1H), 5.22 (quin, J = 1.3 Hz, 1H), 5.18 (quin, J = 1.7 Hz, 1H), 5. .03(br.s,2H),4.25(br.s.,2H),4.07(br.s.,2H),3.15(t,J=6.6Hz,2H),3.06(t,J=6.6Hz,2H),2.94(s,12H),2.72-2.83 (m,2H),2.67(dd,J=9.3,7.2Hz,2H),1.99-2.08(m,2H),1.80(s,2H),1.75(s,3H),1.69(s,3H),0.60(s,3H),0.55(s,3H).

[0820] For compound 53: HPLC-MS: m / z 1276.2 (for M + Calculated value: 1275.6). UV / Vis: λ max =660nm. 1H NMR (400 MHz, MeOH-d4; mixture of two rotamers) δ ppm 8.83 (s, 1H), 8.47 (br. s., 1H), 8.14-8.26 (m, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.60-7.73 (m, 6H), 7.48-7.54 (m, 2H), 7.36-7.47 (m, 3H), 6.98 (d, J = 2.8 Hz, 2H), 6.81 (d, J = 7.2 Hz, 2H), 5.48 (s, 1H), 5.41 (s, 1H), 5.25 (quin, J = 1.3 Hz, 1H), 5.21 (quin, J = 1.3 Hz, 1H), 4.92 (br. s., 2H ),4.76(br.s.,2H),4.29(br.s,2H),4.17(br.s.,2H),3.16(t,J=6.6Hz,2H),3.10(t,J=6.6Hz,2H),2.95(s,12H),2.76-2.84(m,2H),2 .65-2.73(m,2H),2.64(s,6H),2.48(s,6H),2.00-2.11(m,2H),1.82-1.90(m,2H),1.79(s,3H),1.73(s,3H),0.61(s,3H),0.55(s,3H).

[0821] For compound 55: HPLC-MS: m / z 1276.1 (for M + Calculated value: 1275.6). UV / Vis: λ max =660nm. 1H NMR (400 MHz, MeOH-d4; mixture of two rotamers) δ ppm 8.83 (br. s., 1H), 8.54 (d, J = 9.1 Hz, 1H), 8.48 (d, J = 8.6 Hz, 1H), 7.79-7.87 (m, 2H), 7.67-7.77 (m, 2H), 7.51-7.59 (m, 3H), 7.32-7.51 (m, 3H), 7.42 (d, J = 2.7 Hz, 2H), 7.18 (d, J = 9.7 Hz, 2H), 6.66 (dd, J = 9.7, 2.5 Hz, 2H), 5.42 (s, 1H), 5.28 (s, 1H), 5.23 (s, 1H), 5.15 (s, 1H), 5. .06(br.s.,2H),4.64(br.s.,2H),4.31(br.s.,2H),4.03(br.s.,2H),3.34(s,12H),3.08-3.19(m,2H),2.95(s,6H),2.88(t,J=6.6Hz ,2H),2.57-2.66(m,4H),2.54(s,6H),1.90-2.10(m,2H),1.80-1.90(m,2H),1.75(s,3H),1.65(s,3H),0.80(br.s.,3H),0.66(s,3H).

[0822] For compound 57: HPLC-MS: m / z 1198.1 (for M + Calculated value: 1197.5). UV / Vis: λ max =660nm. 1H NMR (400 MHz, MeOH-d4; mixture of two rotamers) δ ppm 8.50-8.60 (m, 2H), 8.47 (d, J = 9.1 Hz, 1H), 8.28 (t, J = 9.6 Hz, 1H), 7.58-7.75 (m, 5H), 7.50-7.57 (m, 2H), 7.47 (d, J = 2.7 Hz, 2H), 7.36-7.49 (m, 2H), 7.14 (d, J = 9.5 Hz, 2H), 6.65 (dd, J = 9.5, 2.7 Hz, 2H), 5.35 (s, 1H), 5.27 (s, 1H), 5.19 (quin, J = 1.2 Hz, 1H), 5.12 (quin, J = 1.2 Hz, 1H), 1H),4.92(br.s.,2H),4.60(br.s.,2H),4.19(br.s.,2H),4.01(br.s.,2H),3.36(s,12H),3.07(t,J=6.6Hz,2H),2.95(t,J=6.6Hz,2H) ,2.74-2.83(m,2H),2.61-2.74(m,2H),1.87-2.03(m,2H),1.73-1.82(m,2H),1.71(s,3H),1.64(s,3H),0.88(br.s.,3H),0.64(s,3H).

[0823] For compound 58: HPLC-MS: m / z 1152.3 (for M + Calculated value: 1151.5). UV / Vis: λ max =660nm. 1H NMR (400 MHz, MeOH-d4; mixture of two rotamers) δ ppm 8.85 (br. s., 1H), 8.28-8.40 (m, 2H), 8.24 (dd, J = 8.4, 2.7 Hz, 2H), 7.88 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 9.1 Hz, 1H), 7.69-7.75 (m, 1H), 7.53-7.63 (m, 2H), 7.43 (d, J = 9.0 Hz, 2H), 7.34-7.52 (m, 3H), 6.98 (d, J = 2.7 Hz, 2H), 6.78 (dd, J = 9.0, 2.7 Hz, 2H), 5.46 (s, 1H), 5.39 (s, 1H), 5.22 (quin, J = 1. 3Hz,1H),5.19(quin,J=1.3Hz,1H),4.94(br.s,4H,overlapping with CD3OH signal),4.27(br.s,2H),4.13(br.s.,2H),3.17(t,J=6.6Hz,2H),2.94(s,12H),2.90-2.97(m,2H),2.75-2.86(m,2H),2.66-2.75(m,2H),2.00-2.12(m,2H),1.78-1.90(m,2H),1.76(s,3H),1.71(s,3H),0.60(s,3H),0.55(s,3H).

[0824] For compound 60: HPLC-MS: m / z 1122.2 (for M + Calculated value: 1121.6). UV / Vis: λ max =660nm. 1H NMR (400 MHz, MeOH-d4; mixture of two rotamers) δ ppm 8.50-8.61 (m, 2H), 8.39-8.50 (m, 1H), 7.58-7.69 (m, 2H), 7.45 (d, J = 2.7 Hz, 2H), 7.36-7.49 (m, 2H), 7.32 (d, J = 8.9 Hz, 1H), 7.15 (m, J = 8.4 Hz, 3H), 6.84-6.93 (m, 2H), 6.75-6.83 (m, 2H), 6.65 (dd, J = 9.7, 2.3 Hz, 2H), 5.38 (s, 1H), 5.29 (s, 1H), 5.21 (quin, J = 1.3 Hz, 1H), 5.14 (quin, J = 1.3 Hz, 1H) ,4.73(br.s.,2H),4.54(br.s.,2H),3.87(br.s,2H),3.75(s,3H),3.68(br.s,2H),3.35(s,12H),3.08(t,J=6.5Hz,2H),2.95(t,J=6.6Hz,2H),2 .93(s,3H),2.65-2.71(m,2H),2.57-2.65(m,2H),1.84-1.94(m,2H),1. 75(s,3H),1.69-1.74(m,2H),1.67(s,3H),0.87(br.s,3H),0.63(s,3H).

[0825] Preparation of compounds 39, 40, 43, and 44

[0826]

[0827] General Procedure XX. Preparation of PEG monomethacrylate. Compound 43-1.

[0828] Methacrylic anhydride (0.55mL, 3.46mmol) and triethylamine (0.55mL, 3.95mmol) are added successively to a solution of mono-Boc-protected PEG4 diamine (1.0g 2.97mmol) in chloroform (30mL), and the reaction mixture is stirred overnight at room temperature. The reaction mixture is then concentrated under reduced pressure, and the residue is dissolved in EtOAc (40mL). The solution is washed with 1N HCl (2 × 40mL), saturated NaHCO (40mL) and brine (40mL). The organic layer is dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by reverse phase flash chromatography (C18 SiO2, gradient elution with MeOH+0.05% TFA in water) to provide the desired intermediate (553mg, 46% yield) as a colorless oil. The purified oil (553 mg, 1.37 mmol) was dissolved in DCM (5 mL) and treated with TFA (10 mL) at room temperature for 3 hours, then the reaction mixture was concentrated under reduced pressure. The residue was dried under high vacuum to produce the desired PEG4-monomethylacrylamide 43-1 (750 mg, quantitative, TFA salt) as an amber oil. Following General Procedure XX, intermediates 39-1, 40-1, and 44-1 were prepared from the corresponding mono-Boc-protected oligo(ethylene glycol)diamines.

[0829] As outlined in the above schemes, compounds 39, 40, 43 and 44 were prepared from the corresponding amines 39-1, 40-1, 43-1 and 44-1 and the common intermediate diol 21-1 following general procedures XVII-A and XV.

[0830] For compound 39: HPLC-MS: m / z 1210.5 (for M + Calculated value: 1209.6). UV / Vis: λ max =660nm. 1H NMR(400MHz,DMSO-d6)δppm 8.41-8.54(m,2H),8.19(br.s.,1H),7.60-7.67(m,1H),7.51-7.60(m,2H),7.47(d,J=2.8Hz,2H),7.17-7.43(m,7H),6 .91-7.17(m,4H),6.71(dd,J=9.8,2.7Hz,2H),5.52-5.59(m,1H),5.54(s,1H),5.18-5.29(m,2H),4.67(br.s.,2H),4.6 0(br.s.,2H),3.94(br.s.,2H),3.76(br.s.,2H),3.31-3.38(m,8H),3.29(s,12H),3.22(t,J=6.5Hz,2H),3.12-3.19(m ,8H),3.10(t,J=6.5Hz,2H),2.69-2.77(m,2H),2.58-2.64(m,2H),1.75(s,3H),1.74(s,3H),0.69(s,3H),0.61(s,3H).

[0831] For compound 40: HPLC-MS: m / z 1297.7 (for M + Calculated value: 1298.5). UV / Vis: λ max =660nm.

[0832] For compound 43: HPLC-MS: m / z 1386.5 (for M + Calculated value: 1385.8). UV / Vis: λ max =660nm.

[0833] For compound 44: HPLC-MS: m / z 1474.4 (for M + Calculated value: 1473.8). UV / Vis: λ max =660nm.

[0834] Preparation of compound 50

[0835]

[0836] Intermediate 50-1 was prepared as described elsewhere (Suri, Jeff T. PCT Intl Appl. 2008014280, Jan. 31, 2008).

[0837] Compound 50 was prepared from intermediates 21-1 and 50-1 following general procedures XVII-A and V. The final compound was additionally purified by reverse phase flash chromatography (C18 SiO2, eluting with a gradient of MeCN in 10 mM aqueous NH4HCO3). HPLC-MS: m / z 1385.0 (for M+Na + Calculated value: 1385.5). UV / Vis: λ max =655nm.

[0838] Preparation of compound 23

[0839]

[0840] Compound 23 was synthesized from aldehyde 14-9 following a combination of general procedures VII and V as outlined in the above scheme. HPLC-MS: m / z 1057.0 (for M + Calculated value: 1057.6). UV / Vis: λ max =560nm.

[0841] Preparation of compound 22

[0842]

[0843] Scheme 2. Preparation of Compound 22

[0844] Preparation of 5-bromo-2,3,3-trimethylindolenine 22-9

[0845] A solution of 4-bromophenylhydrazine (10 g, 44.7 mmol), 3-methyl-2-butanone (9.6 mL, 89.5 mmol) in anhydrous EtOH (160 mL) and concentrated H2SO4 (5 mL) was refluxed under argon for 1 hour. The reaction mixture was then concentrated in vacuo to 80 mL, diluted with DCM, and transferred to a separatory funnel. The aqueous layer was discarded, and the organic layer was washed three times with saturated NaHCO3, water, and brine. The DCM portion was then dried over MgSO4 and concentrated in vacuo to produce the title product (5.1 g, 48%).

[0846] Preparation of 5-bromo-1,2,3,3-tetramethyl-3H-indolium iodide 22-10

[0847] A mixture of intermediate 22-9 (5.1 g, 21.4 mmol) and iodomethane (3.96 mL, 64.3 mmol) in acetonitrile (40 mL) was heated to 80 ° C. in a pressure flask for 16 hours to produce a light yellow precipitate. The reaction mixture was cooled to room temperature, diluted with diethyl ether, and then cooled to -78 ° C. The product was collected by filtration and rinsed with cold diethyl ether to produce the title product 22-10 (7.51 g, 93%).

[0848] Preparation of 1,3,3-trimethyl-2-[4-(phenylamino)-1,3-butadien-1-yl]-3H-indolium iodide 22-12

[0849] Under argon, a mixture of N-(3-phenylimino-1-propen-1-yl)aniline hydrochloride (1.61 g, 6.2 mmol) and 1,2,3,3-tetramethyl-3H-indolium iodide (750 mg, 2.49 mmol) in acetic anhydride (40 mL) was heated to 80 ° C for 20 minutes. The reaction mixture was then diluted with DCM and transferred to a separatory funnel. The organic layer was washed with water and brine, then dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, eluted with DCM and MeOH) to produce the title product 22-12 (439 mg, 41%).

[0850] Preparation of 5-bromo-2-[(5-(1,3-dihydro-1,3,3-trimethyl-2H-indol-2-ylidene)-1,3-pentadien-1-yl]-1,3,3-trimethyl-3H-indolium iodide 22-13

[0851] A mixture of sodium acetate (750 mg, 9.1 mmol), intermediate 22-12 (430 mg, 0.911 mmol) and 22-10 (1.03 g mg, 2.72 mmol) and pyridine (2 mL) in acetic anhydride (16 mL) was stirred for 1 hour. The reaction mixture was diluted with DCM and neutralized with saturated NaHCO . The mixture was then distributed and the DCM layer was washed twice with brine. The DCM portion was then dried over MgSO and concentrated in vacuo. The crude product was purified by flash chromatography (SiO , eluted with DCM and MeOH) to provide the title product 22-13 (311 mg, 58%).

[0852] Preparation of 5-{[9,10-bis(3-methacrylamidopropyl)aminomethyl]anthracen-2-yl}-2-[(5-(1,3-dihydro-1,3,3-trimethyl-2H-indol-2-ylidene)-1,3-pentadien-1-yl]-1,3,3-trimethyl-3H-indolium iodide 22-14

[0853] To a mixture of intermediate 35-7 (200 mg, 0.339 mmol), 22-13 (215 mg, 0.406 mmol) and cesium carbonate (331 mg, 1.01 mmol) in degassed EtOH (15 mL) and water (1 mL) was added palladium (II) acetate (7.6 mg, 0.034 mmol) and triphenylphosphine (36 mg, 0.136 mmol). The reaction mixture was refluxed under argon for 16 hours and then concentrated in vacuo. The residue was dissolved in DCM and washed with saturated NaHCO and brine. The DCM layer was dried over MgSO and concentrated in vacuo. The crude product was purified by reverse phase flash chromatography (C18 SiO2, eluted with a gradient of 0.09% HCl in MeOH). The combined and concentrated fractions were basified with saturated NaHCO3 and then triple extracted with DCM to isolate the pure product. The combined DCM layers were then dried over MgSO 4 and concentrated in vacuo to give the title product 22-14 (92 mg, 27%).

[0854] Preparation of compound 22

[0855] To a mixture of intermediate 22-14 (85 mg, 0.085 mmol) and K2CO3 (118 mg, 0.85 mmol) in anhydrous acetonitrile (6 mL) and anhydrous DCM (4 mL) was added 2-bromomethylphenylboronic acid (55 mg, 0.256 mmol). The reaction was stirred at room temperature under argon for 40 minutes, followed by addition of 2-bromomethylphenylboronic acid (36 mg, 0.168 mmol) with anhydrous MeOH (2 mL), and the resulting mixture was stirred for 2 hours. The reaction mixture was then concentrated to 10 mL in a vacuum and filtered. The precipitate was washed with DCM in addition. The filtrate was concentrated in a vacuum. The crude product was purified by reverse phase flash chromatography (C18SiO2, eluted with a gradient of 0.09% HCl in MeOH). The combined and concentrated fractions were alkalized with saturated NaHCO3 and then triple extracted with DCM to isolate the pure product. The combined DCM layers were then dried over MgSO 4 and concentrated in vacuo. The title compound 22 was precipitated by hexane and dried in vacuo (55 mg, 51%). HPLC-MS: m / z 1135.3 (for M + Calculated value: 1135.6). UV / Vis: λ max =660nm.

[0856] Preparation of Compound 80

[0857]

[0858] Compound 80 was synthesized from intermediates 35-7 and 22-13 following general procedures III, XII, III, and XV as outlined in the above scheme. HPLC-MS: m / z 1212.4 (for M+H + Calculated value: 1211.7). UV / Vis: λ max =650nm.

[0859] Preparation of compound 24

[0860]

[0861] Compound 24 was synthesized from intermediates 2-2 and 35-7 following general procedures III and V, substituting K 2 CO 3 for DIPEA as the base in the last step. HPLC-MS: m / z 1352.6 (for M+H + Calculated value: 1351.6). UV / Vis: λ max =650nm. 1 H NMR (400 MHz, DMSO-d6; some integrations were broadened and unresolved) δ ppm 8.66 (s, 2H), 8.59 (br. s., 1H), 8.55 (br. s., 2H), 8.44 (d, J = 8.9 Hz, 1H), 8.36 (m, J = 8.9 Hz, 1H), 7.70 (d, J = 6.0 Hz, 1H), 7.58-7.67 (m, 4H), 7.55 (m, J = 8.3 Hz, 1H), 7.46-7.53 (m, 2H), 7.43 (d, J = 7.4 Hz, 1H), 7.30-7.41 (m, 6H), 7.20-7.30 (m, 3H), 7.0 9-7.20(m,2H),5.43(br.s,1H),5.39(br.s,1H),5.14(quin,J=1.5Hz,1H),5.10(quin,J=1.5Hz,1H),4.50(br.s.,4H),3 .95(br.s.,2H),3.78(br.s.,2H),2.80(m,J=6.9Hz,4H),2.19(br.s.,4H),1.68(s,3H),1.63-1.83(m,20H),1.62(s,3H).

[0862] Preparation of Compound 78

[0863]

[0864] Compound 78 was synthesized from intermediate 35-7, 3-bromophenol and IR-780 following general procedures III, XV and VIII as outlined in the above scheme. HPLC-MS: m / z 1350.7 (for M + Calculated value: 1349.8). UV / Vis: λ max =780nm. 1 H NMR(400MHz,MeOH-d4)δppm 8.71(br.s.,1H),8.43-8.55(m,1H),8.38(d,J=7.2Hz,2H),8.11(d,J=14.4Hz,2H),7.76 (d,J=9.4Hz,1H),7.54-7.66(m,4H),7.46-7.54(m,2H),7.40-7.45(m,1H),7.36(t,J=7.4 Hz,2H),7.33(d,J=7.4Hz,2H),7.26(m,J=7.9Hz,5H),7.20-7.24(m,2H),7.18(t,J=7.1Hz ,2H),7.04-7.14(m,2H),6.22(d,J=14.2Hz,2H),5.35(s,1H),5.31(s,1H),5.14(quin,J= 1.3Hz,1H),5.15(quin,J=1.3Hz,1H),4.91(br.s.,2H),4.78(br.s.,2H),4.20(br.s.,2 H),4.08(t,J=7.2Hz,4H),3.84(br.s.,2H),3.01(t,J=6.5Hz,2H),3.04(t,J=6.7Hz,2H), 2.80(t,J=6.1Hz,4H),2.71-2.78(m,2H),2.63(dd,J=9.1,6.1Hz,2H),2.09(quin,J=5.7H z,2H),1.79-1.94(m,8H),1.66(s,3H),1.67(s,3H),1.40(s,12H),1.01(t,J=7.4Hz,6H).

[0865] Preparation of compound 79

[0866]

[0867] Compound 79 was synthesized from intermediate 78-2 and IR-783 following General Procedure VIII as outlined in the above scheme. HPLC-MS: m / z 769.5 (for [M+H] 2+ Calculated value: 769.4). UV / Vis: λ max =785nm.1 H NMR (400 MHz, MeOH-d4; an additional set of Cy7 signals is present in the spectrum) δ ppm 8.65 (br. s., 1H), 8.49 (d, J = 8.6 Hz, 1H), 8.38-8.47 (m, 1H), 8.44 (d, J = 14.1 Hz, 2H), 8.14-8.26 (m, 1H), 8.10 (d, J = 14.1 Hz, 2H), 7.79 (d, J = 9.1 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.52-7.61 (m, 4 H),7.51(d,J=7.3Hz,2H),7.45-7.49(m,1H),7.42(t,J=7.5Hz,2H),7.34-7.40(m,3H),7.22-7 .34(m,11H),7.16(t,J=7.4Hz,4H),6.33(d,J=14.1Hz,2H),6.26(d,J=14.1Hz,2H),5.33(s,1H ),5.31(s,1H),5.13(s,1H),5.11(s,1H),4.97(br.s.,2H),4.31(br.s.,2H),4.22(t,J=7.1Hz ,4H),4.14(t,J=6.3Hz,4H),3.92(br.s.,2H),3.35(s,3H),3.04(t,J=6.2Hz,2H),3.01(t,J=6 .6Hz,2H),2.88(s,12H),2.79-2.83(m,4H),2.76(t,J=5.6Hz,4H),2.67(m,J=8.4Hz,2H),2.02 -2.13(m,2H),1.81-2.02(m,22H),1.71-1.77(m,12H),1.65(s,3H),1.64(s,3H),1.39(s,12H)

[0868] Preparation of compound 84

[0869]

[0870] Aza-BODIPY monophenol 84-1 was prepared as described elsewhere (Jokic, T.; Borisov, SM; Saf, R.; Nielsen, DA; Kühl, M.; Klimant, I. Anal. Chem. 2012, 84(15), 6723-6730).

[0871] General Procedure XXI. Conversion of Phenols to Aromatic Triflates. Preparation of Compound 84-2.

[0872] Under an argon atmosphere, a solution of aza-BODIPY phenol 84-1 (250 mg, 0.49 mmol) and pyridine (0.08 mL, 1.0 mmol) in anhydrous DCM (8 mL) was cooled to -30 ° C. Trifluoromethanesulfonic anhydride (0.11 mL, 0.66 mmol) was added, and the reaction mixture was stirred at -30 ° C for 30 minutes. The reaction mixture was then quenched with 0.1 M HCl (5 mL) and saturated NH4Cl (5 mL), diluted with water (10 mL), and distributed with additional DCM (20 mL). The aqueous layer was discarded. The organic extract was washed with half-saturated NH4Cl (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, eluted with a 10% to 40% gradient of DCM in hexane). The desired triflate 84-2 was obtained as a dark purple solid (228 mg, 72% yield).

[0873] General Procedure XXII. Suzuki-Miyaura Coupling with Aromatic Triflates. Preparation of Compound 84-3.

[0874] A mixture of aza-BODIPY triflate 84-2 (68 mg, 0.105 mmol), anthraceneboronic acid 35-7 (173 mg, 0.33 mmol), K 3 PO 4 (134 mg, 0.63 mmol), Pd(OAc) 2 (5.6 mg, 0.025 mmol) and XantPhos (15 mg, 0.026 mmol) in degassed anhydrous THF (20 mL) was refluxed under argon atmosphere for 16 hours. The reaction mixture was then cooled to ambient temperature and stirred for 16 hours. After filtration (washing with MeOH), the filtrate was concentrated and the residue was purified by reverse phase flash chromatography (C18 SiO2, gradient elution with 60% to 100% MeOH in water + 0.05% TFA) to give the desired product (11.6 mg, 11%) as a dark blue solid.

[0875] Compound 84 was prepared from intermediate 84-3 following General Procedure XV. HPLC-MS: m / z 1251.4 (for M+H + Calculated value: 1250.6). UV / Vis: λ max =665nm.

[0876] Preparation of compound 85

[0877]

[0878] Aza-BODIPY monophenol 85-1 was prepared as described elsewhere (Jokic, T.; Borisov, SM; Saf, R.; Nielsen, DA; Kühl, M.; Klimant, I. Anal. Chem. 2012, 84(15), 6723-6730).

[0879] By analogy with the preparation of compound 85, compound 85 was prepared from 85-1 following general procedures XXI, XXII and XV as outlined in the above scheme. HPLC-MS: m / z 1251.4 (for M+H + Calculated value: 1250.6). UV / Vis: λ max =660nm.

[0880] Preparation of compound 26

[0881]

[0882] Compound 26 was prepared from 1,4-dibromobenzene and intermediates 11-3 and 35-7 by general procedures X, III, and V as outlined in the above scheme. HPLC-MS: m / z 1138.5 (for M + Calculated value: 1137.6). UV / Vis: λ max =650nm.

[0883] Preparation of compound 27

[0884]

[0885] Compound 27 was prepared from 1,4-dibromo-2,5-dimethylbenzene and intermediates 11-3 and 35-7 by general procedures X, III, and V as outlined in the above schemes. HPLC-MS: m / z 1166.5 (for M + Calculated value: 1165.6). UV / Vis: λ max =655nm.

[0886] Preparation of compound 28

[0887]

[0888] Preparation of compound 28-1.

[0889] A mixture of 6-diethylaminonaphthalene-1-ol (174 mg, 0.81 mmol) and 4-bromobenzaldehyde (75 mg, 0.0.41 mmol) in pure trifluoromethanesulfonic acid (2 mL) was heated at 105 ° C in a sealed vial for 2 hours. The reaction mixture was then cooled to room temperature and diluted with DCM: water = 1: 1 (50 mL). The layers were separated and the aqueous layer was extracted with DCM (3 × 15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (C18 SiO2, eluted with 80% MeOH + 0.05% TFA in water). Yield: 50 mg (8.5%), dark blue powder.

[0890] Compound 28 was synthesized from intermediates 28-1 and 35-7 following general procedures III and XV as outlined in the above schemes. HPLC-MS: m / z 1252.3 (for M + Calculated value: 1251.7). UV / Vis: λ max =685nm.

[0891] Preparation of compound 33

[0892]

[0893] Intermediate 33-1 was synthesized as described in the literature (Cherevatskaya, M. et al. Angew. Chem. Int. Ed., 51(17), 4062-4066, 2012).

[0894] Compound 33 was synthesized from intermediates 33-1 and 35-7 following general procedures III and V as outlined in the above scheme. HPLC-MS: m / z 1200.4 (for M + Calculated value: 1199.6). UV / Vis: λ max =585nm. 1H NMR (400MHz, CDCl3) δppm 8.35(d,J=9.3Hz,1H),8.26(d,J=8.8Hz,1H),7.70-7.85(m,3H),7.59-7.68(m,4H),7.51-7.58(m,2H),7.31-7.51(m,8H),7.20(s,2 H),5.37(s,1H),5.34(s,1H),5.13(s,1H),5.11(s,1H),4.58(br.s.,2H),4.53(s,2H),3.94(br.s.,2H),3.58(t,J=5.5Hz,4H),3.54 (t,J=5.5Hz,4H),3.39-3.42(m,2H),3.09(t,J=6.3Hz,4H),2.82(t,J=5.8Hz,4H),2.57(t,J=7.5Hz,2H),2.48(t,J=7.5Hz,2H),2.1 5(quin,J=6.0Hz,4H),2.00(quin,J=6.0Hz,4H),1.72(s,3H),1.70(s,3H),1.56-1.64(m,2H),1.45-1.54(m,2H),1.21-1.31(m,4H).

[0895] Preparation of compound 42

[0896]

[0897] Compound 42 was synthesized from 1,3-diiodobenzene and intermediate 11-3 following general procedures X, III, and XV as outlined in the above scheme. HPLC-MS: m / z 1138.3 (for M + Calculated value: 1137.6). UV / Vis: λ max =650nm. 1H NMR(400MHz,MeOH-d4)δppm 8.39(d,J=9.0Hz,1H),8.36(d,J=8.7Hz,1H),8.22-8.33(m,2H),7.89(d,J=7.9Hz,1H),7.71-7.84(m,2H),7.52-7. 70(m,5H),7.25-7.47(m,11H),7.08-7.25(m,3H),6.97(d,J=2.9Hz,1H),6.79(dd,J=9.7,2.9Hz,2H),5.38(s,1H), 5.34(s,1H),5.20(quin,J=1.4Hz,1H),5.14(quin,J=1.4Hz,1H),4.79(s,4H),4.15(br.s.,2H),3.89(br.s.,2H), 3.33(s,12H),2.65-2.75(m,2H),2.58(m,J=7.6Hz,2H),1.74-1.89(m,4H),1.72(s,3H),1.67(s,3H),0.63(s,6H).

[0898] Preparation of compound 59

[0899]

[0900] Compound 59 was synthesized from intermediates 42-2 and 51-2 following General Procedure V. HPLC-MS: m / z 1188.2 (for M + Calculated value: 1187.6). UV / Vis: λ max =650nm.

[0901] Preparation of compound 61

[0902]

[0903] Compound 61 was synthesized from 1,3-diiodobenzene and intermediates 49-1 and 35-7 following general procedures X, III, and XV as outlined in the above scheme. HPLC-MS: m / z 1162.2 (for M + Calculated value: 1161.6). UV / Vis: λ max =705nm.

[0904] Preparation of compound 62

[0905]

[0906] Compound 62 was synthesized from 1,3-diiodobenzene and intermediates 45-1 and 35-7 following general procedures X, III, and XV as outlined in the above scheme. HPLC-MS: m / z 1190.3 (for M + Calculated value: 1189.6). UV / Vis: λ max =680nm.

[0907] Preparation of compounds 54 and 71

[0908]

[0909] Preparation of compound 54-1

[0910] A solution of aryl bromide 19-5 (6.0 g, 11 mmol) and TMEDA (0.8 mL, 5.3 mmol) in anhydrous THF (100 mL) was cooled to -78°C under argon. To this solution was added tert-BuLi (c = 1.52 M in pentane, 8 mL, 12 mmol) dropwise over 5 minutes, and the mixture was stirred at -78°C for 5 minutes before the rapid addition of trimethyl borate (1.6 mL, 14.4 mmol). The reaction mixture was allowed to warm to room temperature and then quenched with MeOH (5 mL). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (SiO2, gradient elution with 5% to 20% EtOAc in hexanes). The desired boronic acid 54-1 was obtained as a light yellow solid (4.87 g, 87% yield).

[0911] General Procedure XXIII. Suzuki-Miyaura coupling with unprotected boronic acid. Preparation of compound 54-2

[0912] A suspension of anthraceneboronic acid 54-1 (1.0 g, 2.0 mmol) and 2,4-dibromothiophene (0.17 mL, 1.5 mmol) in degassed EtOH (80 mL) was refluxed under argon until all solids were dissolved. Pd(PPh 3 ) 4 (50 mg, 0.043 mmol) and 2M Na 2 CO 3 aqueous solution (2.1 mL, 4.2 mmol) were added and refluxed under argon for 4 hours. The solvent was then removed under reduced pressure and the residue was dissolved in DCM (50 mL) and purified by The filtrate was concentrated and the residue was purified by flash chromatography (SiO 2 , 10% to 40% DCM in hexanes gradient elution). The title compound 54-2 was obtained as a bright yellow solid (565 mg, 60% yield).

[0913] Compound 54 was prepared from intermediates 54-2 and 11-3 following general procedures XVI, XVII-A, and XV as outlined in the above schemes. HPLC-MS: m / z 1144.1 (for M + Calculated value: 1143.6). UV / Vis: λ max =660nm. 1 H NMR(400MHz,MeOH-d4)δppm 8.34(d,J=8.6Hz,1H),8.27(d,J=8.6Hz,1H),8.19(d,J=8.2Hz,1H),7.82(d,J=9.0Hz,1H),7.58-7.64(m,2H),7.53-7.58(m,4H),7.46-7.53 (m,1H),7.41(d,J=2.8Hz,2H),7.38-7.44(m,2H),7.29-7.38(m,4H),7.16-7.24(m,1H),7.08(t,J=7.2Hz,1H),6.86(dd,J=9.8,2.9Hz,2H), 5.35(s,1H),5.36(s,1H),5.17(quin,J=1.3Hz,2H),4.68(br.s,2H),4.65(br.s,2H),4.09(br.s.,2H),3.91(br.s.,2H),3.36(s,12H),3.0 2(t,J=6.5Hz,2H),2.92-2.99(m,2H),2.65-2.74(m,2H),2.53-2.65(m ,2H),1.77-1.89(m,2H),1.67-1.76(m,2H),1.70(s,6H),0.65(s,6H).

[0914] Compound 71 was prepared from intermediate 54-1 and 2,4-dibromo-5-methylthiophene following the same reaction sequence as outlined for compound 54. HPLC-MS: m / z 1158.2 (for M + Calculated value: 1157.6). UV / Vis: λ max =660nm. 1H NMR(400MHz,MeOH-d4)δppm 8.35(d,J=8.9Hz,1H),8.23(d,J=8.8Hz,1H),8.28(d,J=9.1Hz,1H),7.78(d,J=9.4Hz,1H),7.49(d,J=9.8Hz,2H),7.47-7.60(m,4H),7.41 (d,J=2.8Hz,2H),7.37-7.43(m,1H),7.28-7.37(m,4H),7.17-7.25(m,2H),7.10(td,J=7.5,1.1Hz,1H),6.89(dd,J=9.6,2.8Hz,2H),5.36 (s,2H),5.17(quin,J=1.3Hz,2H),4.70(br.s.,4H),4.09(br.s.,2H),3.92(br.s,2H),3.37(s,12H),3.02(t,J=6.6Hz,2H),2.94-3.00(m ,2H),2.65-2.72(m,2H),2.62(m,J=5.6Hz,2H),2.28(s,3H),1.81-1.89(m,2H),1.70(s,6H),1.65-1.75(m,2H),0.66(s,3H),0.64(s,3H).

[0915] Preparation of Compound 96

[0916]

[0917] Compound 96 was prepared from compounds 54-4 and 53-2 following General Procedure V as outlined in the above scheme. HPLC-MS: m / z 1358.2 (for M + Calculated value: 1357.6). UV / Vis: λ max =662nm.

[0918] Preparation of compound 63

[0919]

[0920] Compound 63 was prepared from 2-bromo-4-iodotoluene and intermediates 54-1 and 11-3 following general procedures XXIII, XVI, XVII-A and XV as outlined in the above schemes. HPLC-MS: m / z 1152.3 (for M + Calculated value: 1151.6). UV / Vis: λ max =650nm. 1H NMR(400MHz,MeOH-d4)d ppm 8.47(br.s.,1H),8.14-8.30(m,2H),8.04(d,J=7.9Hz,1H),7.81(d,J=7.7Hz,1H), 7.71(d,J=9.5Hz,1H),7.58(d,J=1.8Hz,1H),7.51(d,J=8.2Hz,1H),7.31-7.51(m,5 H),7.29(d,J=2.8Hz,2H),7.15-7.23(m,2H),7.18(d,J=9.6Hz,2H),7.03-7.15(m, 3H), 6.70 (dd, J=9.7, 2.9Hz, 2H), 5.29 (quin, J=0.8Hz, 1H), 5.22 (quin, J=0.8Hz, 1H ),5.10(quin,J=1.3Hz,1H),5.02(quin,J=1.3Hz,1H),4.58(br.s,2H),4.54(br.s ,2H),3.98(br.s.,2H),3.74(s,2H),3.23(s,12H),2.89(t,J=6.6Hz,2H),2.74(t,J =6.9Hz,2H),2.51-2.62(m,2H),2.37-2.49(m,2H),2.05(s,3H),1.65-1.76(m,4H) ,1.63(m,J=1.5,0.7Hz,3H),1.55(dd,J=1.5,1.0Hz,3H),0.54(s,3H),0.53(s,3H).

[0921] Preparation of compound 64

[0922]

[0923] Compound 64 was prepared from intermediates 63-3 and 53-2 following General Procedure V. HPLC-MS: m / z 1366.3 (for M + Calculated value: 1365.6). UV / Vis: λ max =650nm. 1H NMR (600 MHz, MeOH-d4; mixture of two rotamers) δ ppm 8.12-8.31 (m, 2H), 7.86-8.03 (m, 3H), 7.71-7.77 (m, 2H), 7.60-7.71 (m, 6H), 7.53-7.60 (m, 3H), 7.47-7.53 (m, 1H), 7.36-7.44 (m, 2H), 7.30-7.36 (m, 2H), 6.88 (d, J = 8.3 Hz, 1H), 5.47 (s, 1H), 5.35 (s, 1H), 5.26 (s, 1H), 5.14 (s, 1H), 4.70 (b r.s,4H),3.36(s,12H),3.08(br.s.,2H),2.96(br.s.,2H),2.69-2.77(m,4H),2.67-2.69(m,4H),2.65(br.s,6H),2. 48(br.s,6H),1.87-1.98(m,2H),1.79-1.85(m,2H),1.78(s,3H),1.71(s,3H),1.66(s,3H),0.68(s,3H),0.64(s,3H).

[0924] Preparation of compound 65

[0925]

[0926] Compound 65 was prepared from intermediates 63-2 and 43-1 following general procedures XVII-A and XV as outlined in the above schemes. HPLC-MS: m / z 1476.3 (for M + Calculated value: 1475.8). UV / Vis: λ max =650nm.

[0927] Preparation of compound 69

[0928]

[0929] Compound 69 was prepared from intermediates 63-1 and 56-1 following general procedures XVI, XVII-A and XV as outlined in the above schemes. HPLC-MS: m / z 1204.3 (for M + Calculated value: 1203.7). UV / Vis: λ max =660nm. 1H NMR(400MHz,MeOH-d4)δppm 8.15-8.44(m,2H),7.94-8.05(m,1H),7.85-7.94(m,2H),7.78-7.85(m,1H),7.69-7.78(m,3H),7.54-7.69(m,8H),7.27- 7.38(m,1H),7.19(d,J=10.3Hz,2H),6.75(d,J=9.7Hz,2H),5.28(br.s,1H),5.29(br.s,1H),5.14(br.s,1H),5.10(br.s. ,1H),4.80(br.s.,2H),3.69(t,J=6.1Hz,4H),3.18-3.27(m,2H),3.23(s,6H),3.00-3.16(m,8H),2.94(t,J=6.6Hz,2H),2 .18(s,3H),2.06-2.15(m,4H),1.90-2.06(m,2H),1.74-1.90(m,2H),1.58(s,3H),1.59(s,3H),0.80(s,3H),0.80(s,3H).

[0930] Preparation of Compound 82

[0931]

[0932] Bis-allylsilaxanthonone 82-1 was prepared as described in the literature (Umezawa, K.; Yoshida, M.; Kamiya, M.; Yamasoba, T.; Urano, Y. Nat. Chem. 2016, 9(3), 279–286).

[0933] Intermediate 82-2 was prepared from Intermediates 63-1 and 82-1 following General Procedure XVI.

[0934] General Procedure XXIV. Double deallylation of Si-xanthene. Preparation of Compound 82-3

[0935] A general method for deallylating silicon-substituted xanthene dyes is described in the literature (Umezawa, K.; Yoshida, M.; Kamiya, M.; Yamasoba, T.; Urano, Y. Nat. Chem. 2016, 9(3), 279–286). According to this method, the bis-allyl intermediate 82-2 (158 mg, 0.166 mmol) was dissolved in MeOH (5 mL) and treated with excess solid NaBH4 until the color turned yellow-green (gas was released after the addition of NaBH4). The mixture was stirred for another 10 minutes, then quenched with water, and the resulting slurry was partitioned with EtOAc. The aqueous layer was discarded, and the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in degassed DCM (10 mL). 1,3-Dimethylbarbituric acid (DMBA; 245 mg, 1.57 mmol) and Pd(PPh3)4 (43 mg, 0.037 mmol) were added and the mixture was stirred at ambient temperature for 16 hours. Chlorobenzoquinone (49 mg, 0.20 mmol) was then added and after stirring for 20 minutes, the reaction mixture was The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (SiO 2 , gradient elution with 2% to 30% MeOH in DCM). The desired intermediate 82-3 was obtained as a dark blue solid (150 mg, quantitative yield).

[0936] Compound 82 was prepared from intermediate 82-3 following general procedures XVII-A and XV as outlined in the above schemes. HPLC-MS: m / z 1123.9 (for M+H + Calculated value: 1123.6). UV / Vis: λ max =624nm. 1H NMR(400MHz,MeOH-d4)δppm 8.63(br.s.,1H),8.35(d,J=8.3Hz,1H),8.30(d,J=9.1Hz,1H),8.16(d,J=8.5Hz,1H),7.93(d,J=6.8Hz,1H),7.84(d,J=8.7Hz,1H),7.65(s,1H ),7.61(d,J=8.0Hz,1H),7.43-7.55(m,3H),7.39(d,J=7.5Hz,1H),7.21-7.33(m,7H),7.07-7.17(m,3H),6.65(dd,J=9.4,2.2Hz,2H),5.40(s, 1H),5.33(s,1H),5.21(s,1H),5.12(s,1H),4.73(br.s.,2H),4.65(br .s.,2H),4.13(br.s.,2H),3.80(s,2H),3.02-3.11(m,6H),3.01(t,J=6 .6Hz,2H),2.89(t,J=6.6Hz,2H),2.65-2.73(m,2H),2.52-2.61(m,2H), 2.16(s,3H),1.78-1.88(m,4H),1.74(s,3H),1.66(s,3H),0.59(s,6H).

[0937] Preparation of Compound 104

[0938]

[0939] Compound 104 was isolated as a side product during the synthesis of compound 82 according to General Procedure XV on a 150 mg scale. HPLC-MS: m / z 1258.0 (for M+H + Calculated value: 1257.6). UV / Vis: λ max =639nm. 1H NMR(400MHz,MeOH-d4)δppm 8.44(m,J=9.7,9.7Hz,2H),8.23-8.32(m,1H),7.84-8.00(m,2H),7.67(br.s.,1H),7.50-7.63(m,4H),7.39-7.48(m,2H),7.09 -7.37(m,11H),7.03(dd,J=8.8,4.0Hz,1H),6.95(d,J=9.0Hz,1H),6.75-6.89(m,2H),6.63(dd,J=6.9,3.0Hz,1H),5.39(s,1H) ,5.32(s,1H),5.20(s,1H),5.12(br.s.,1H),4.20(br.s.,2H),3.89(br.s.,2H),3.34-3.43(m,4H),3.03(br.s.,6H),2.90(br .s.,2H),2.69-2.83(m,4H),2.55-2.66(m,2H),2.11-2.19(m,3H),1.87(br.s.,4H),1.73(s,3H),1.65(s,3H),0.50(br.s,6H).

[0940] Preparation of compounds 83, 117, 118 and 119

[0941]

[0942] Compounds 117-2 and 118-2 were prepared from 3-fluoro-2-methylphenylboronic acid and 5-fluoro-2-methylphenylboronic acid, respectively, following general procedures XVIII and XIX.

[0943] Compounds 83, 117, 118, and 119 were prepared from common intermediate 82-4 and benzyl bromides 51-2, 117-2, 118-2, and 57-2, respectively, following General Procedure V. The neopentyl glycol protecting group was spontaneously removed during reverse phase chromatography purification.

[0944] For compound 83: HPLC-MS: m / z 1174.1 (for M+H + Calculated value: 1173.6). UV / Vis: λ max =625nm. 1H NMR(400MHz,MeOH-d4)δppm 8.66(br.s.,1H),8.41(d,J=9.5Hz,1H),8.45(d,J=8.4Hz,1H),8.30(d,J=7.8Hz,1H),8.06(d,J=1.3Hz,1H),8.01(s,1H),7.96(m,J=8.7Hz, 2H),7.47-7.73(m,7H),7.32-7.46(m,3H),7.23(d,J=2.3Hz,2H),6.66(dd,J=9.4,2.3Hz,2H),5.48(s,1H),5.41(s,1H),5.27(quin,J=1.3Hz ,1H),5.20(quin,J=1.3Hz,1H),4.98(br.s.,2H),4.59(br.s,2H),4.29(br.s.,2H),4.05(br.s.,2H),3.35(s,6H),3.04-3.12(m,2H),2.99 (t,J=6.5Hz,2H),2.83-2.92(m,2H),2.72-2.83(m,2H),2.16(s,3H),1 .87-1.98(m,4H),1.79(s,3H),1.72(s,3H),0.60(s,3H),0.58(s,3H).

[0945] For compound 117: HPLC-MS: m / z 1160.2 (for M+H + Calculated value: 1159.6). UV / Vis: λ max =624nm. 1H NMR (400MHz, 1% TFA-d in MeOH-d4) δppm 8.54(br.s.,1H),8.38-8.49(m,2H),8.16-8.24(m,1H),7.96(d,J=10.1Hz,1H),7.65-7.74(m,2H),7.57-7.6 5(m,2H),7.36-7.51(m,3H),7.14-7.31(m,7H),6.65(d,J=9.6Hz,2H),5.32(s,1H),5.29(s,1H),5.22(br.s. ,2H),5.14-5.20(m,3H),5.11(quin,J=1.5Hz,1H),4.53(br.s,2H),4.37(br.s.,2H),3.06(br.s.,6H),2.88 -3.04(m,8H),2.17(s,3H),1.83-1.97(m,4H),1.65(s,3H),1.61(s,3H),0.60(br.s.,3H),0.59(br.s.,3H).

[0946] For compound 118: HPLC-MS: m / z 1160.3 (for M+H + Calculated value: 1159.6). UV / Vis: λ max =624nm. 1H NMR (400MHz, 1% TFA-d in MeOH-d4) δppm 8.43(d,J=8.9Hz,2H),8.36(d,J=8.6Hz,1H),8.12-8.24(m,1H),7.99(d,J=8.9Hz,1H),7.81-7.87(m,1H),7.70-7.76(m,1H),7.60-7.66( m,1H),7.64(d,J=7.9Hz,2H),7.68(d,J=1.9Hz,2H),7.38(dd,J=9.4,2.7Hz,1H),7.24(br.s.,5H),7.12-7.19(m,2H),6.66(dd,J=9.6,2. 3Hz,2H),5.29-5.36(m,4H),5.25(br.s,2H),5.18(quin,J=1.3Hz,1H),5.14(quin,J=1.3Hz,1H),4.55(br.s.,2H),4.44(br.s.,2H),3.0 7(br.s.,6H),3.01-3.11(m,4H),2.92-3.01(m,4H),2.18(s,3H),1.82-1.97(m,4H),1.65(s,3H),1.62(s,3H),0.60(s,3H),0.59(s,3H).

[0947] For compound 119: HPLC-MS: m / z 1260.2 (for M+H + Calculated value: 1259.6). UV / Vis: λ max =624nm. 1H NMR (400MHz, 1% TFA-d in MeOH-d4) δppm 8.57(br.s.,1H),8.45(d,J=8.4Hz,1H),8.38(d,J=9.4Hz,1H),8.22(d,J=8.2Hz,1H),7.97(d,J=8.3Hz,1H),7.84-7.91(m,2H),7.76(d,J=7.5 Hz,1H),7.66-7.73(m,4H),7.64(d,J=8.2Hz,2H),7.57-7.62(m,2H),7.24(br.s.,4H),6.65(dd,J=9.5,2.5Hz,2H),5.37(s,1H),5.32(s,1H),5 .22(br.s.,2H),5.19(quin,J=1.5Hz,1H),5.17(br.s.,2H),5.13(quin,J=1.5Hz,1H),4.51(br.s.,2H),4.32(br.s.,2H),3.07(br.s.,6H),3. 01-3.12(m,4H),2.98(t,J=6.4Hz,2H),2.87-3.00(m,2H),2.17(s,3H), 1.86-1.98(m,4H),1.68(s,3H),1.63(s,3H),0.61(s,3H),0.59(s,3H).

[0948] Preparation of Compound 101

[0949]

[0950] Compound 101 was prepared from intermediates 82-3 and 43-1 following general procedures XVII-A and XV as outlined in the above schemes. HPLC-MS: m / z 1448.1 (for M+H + Calculated value: 1447.8). UV / Vis: λ max =626nm. 1H NMR (400 MHz, MeOH-d4; the signals of the two methylene groups overlap with the CD3OH signal) δ ppm 8.80-8.97 (m, 1H), 8.37-8.66 (m, 3H), 7.87-8.04 (m, 2H), 7.50-7.64 (m, 4H), 7.32-7.43 (m, 2H), 7.13-7.31 (m, 8H), 7.02-7.11 (m, 2H), 6.64 (dd, J = 9.5, 2.7 Hz, 2H), 5.64 (quin, J = 1.0 Hz, 1H), 5.63 (quin, J = 1.0 Hz, 1H), 5.30 (quin, J = 1.5 Hz, 1H). (quin,J=1.5Hz,1H),3.58-3.69(m,6H),3.34-3.55(m,32H),3.21(s,3H),3.05-3.10(m,2H),3.05(s,3H),2.91(br.s.,2H) ,2.73-2.84(m,2H),2.16(s,3H),1.88(dd,J=1.5,1.0Hz,3H),1.87(dd,J=1.5,1.0Hz,3H),0.53-0.61(m,3H),0.57(s,3H).

[0951] Preparation of compounds 105 and 106

[0952]

[0953] Compounds 105 and 106 were prepared following General Procedure V from common intermediate 101-1 and benzyl bromide 51-2 or 57-2, respectively.

[0954] For compound 105: HPLC-MS: m / z 1498.7 (for M+H + Calculated value: 1497.8). UV / Vis: λ max =624nm.

[0955] For compound 106: HPLC-MS: m / z 1583.7 (for M+H + Calculated value: 1584.7). UV / Vis: λ max =624nm.

[0956] Preparation of Compound 109

[0957]

[0958] Compound 109 was prepared from intermediates 54-2 and 82-1 following general procedures XVI, XXIV, XVII-A and XV as outlined in the above schemes. HPLC-MS: m / z 1116.3 (calculated: 1115.5). UV / Vis: λ max =628nm. 1 H NMR (400MHz, MeOH-d4; acidified with TFA-d) δppm 8.74(br.s.,1H),8.39-8.52(m,2H),8.34(br.s.,1H),7.40-7.70(m,8H),7.15-7 .38(m,8H),7.05-7.13(m,1H),6.71(d,J=9.9Hz,2H),5.36(s,2H),5.18(s,2H),4. 99(br.s.,2H),4.17(br.s.,2H),3.99(br.s.,2H),3.08(s,6H),2.99-3.06(m,4H) ,2.77(br.s.,2H),2.70(br.s.,2H),1.85-1.96(m,4H),1.70(s,6H),0.59(s,6H).

[0959] Preparation of compound 89

[0960]

[0961] Compound 89 was prepared from intermediates 19-5 and 82-1 following general procedures XVI, XXIV, XVII-A, and XV as outlined in the above schemes. Tetraboronic acid was obtained as the major product instead of the expected diboronic acid. HPLC-MS: m / z 1302.2 (for M + Calculated value: 1301.7). UV / Vis: λ max =664nm.

[0962] Preparation of compound 66

[0963]

[0964] Compound 66 was prepared from 2-bromo-6-iodotoluene and intermediates 54-1 and 11-3 following general procedures XXIII, XVI, XVII-A and XV as outlined in the above schemes. HPLC-MS: m / z 1152.3 (for M + Calculated value: 1151.6). UV / Vis: λ max =650nm. 1H NMR(400MHz,MeOH-d4)δppm 8.51(s,1H),8.40-8.47(m,1H),8.38(d,J=10.0Hz,1H),7.50-7.65(m,6H),7.36-7.45(m,2H),7.40(d,J=3.2Hz,2H),7.21-7.36(m,5 H),7.31(d,J=9.5Hz,2H),7.17(m,J=6.7Hz,2H),6.87(dd,J=9.8,2.7Hz,2H),5.37(s,1H),5.34(s,1H),5.18(m,J=1.7,1.7,1.7,1.7 Hz,2H),4.94(br.s,2H),4.82(br.s.,2H),4.17(br.s,2H),3.95(br.s,2H),3.37(s,12H),3.04(t,J=6.9Hz,2H),3.00(t,J=6.4Hz,2 H),2.73-2.82(m,2H),2.57-2.71(m,2H),2.04(s,3H),1.88-1.97(m,2H),1.79-1.88(m,2H),1.70(s,6H),0.65(s,3H),0.61(s,3H).

[0965] Preparation of compound 67

[0966]

[0967] Compound 67 was prepared from intermediates 66-3 and 53-2 following General Procedure V. HPLC-MS: m / z 1366.4 (for M + Calculated value: 1365.6). UV / Vis: λ max =650nm.

[0968] Preparation of compound 73

[0969]

[0970] Compound 73 was prepared from 3-bromo-5-iodotoluene and intermediates 54-1 and 11-3 following general procedures XXIII, XVI, XVII-A and XV as outlined in the above schemes. HPLC-MS: m / z 1152.3 (for M + Calculated value: 1151.6). UV / Vis: λ max =650nm. 1H NMR (400 MHz, MeOH-d4; mixture of two rotamers) δ ppm 8.25-8.39 (m, 2H), 8.07-8.20 (m, 2H), 7.75-7.84 (m, 2H), 7.61 (m, J = 5.0 Hz, 2H), 7.47-7.54 (m, 1H), 7.39-7.46 (m, 3H), 7.37 (m, J = 3.2 Hz, 3H), 7.26-7.34 (m, 3H), 7.18-7.25 (m, 3H), 7.15 (d, J = 5.6 Hz, 1H), 6.78 (dd, J = 9.7, 2.9 Hz, 2H), 5.36 (s, 1H), 5.34 (s, 1H), 5.17-5. 21(m,1H),5.11-5.16(m,1H),4.61(br.s.,4H),4.06(br.s,2H),3.83(br.s,2H),2.97-3.03(m,2H),2.90-2.95(m,12H),2.85(t,J=6 .3Hz,2H),2.63-2.70(m,2H),2.61(s,3H),2.49-2.59(m,2H),1.78-1.85(m,2H),1.73-1.78(m,2H),1.65-1.69(m,6H),0.63(s,6H).

[0971] Preparation of Compound 74

[0972]

[0973] Compound 74 was prepared from intermediates 73-3 and 53-2 following General Procedure V. HPLC-MS: m / z 1366.6 (for M + Calculated value: 1365.6). UV / Vis: λ max =650nm. 1H NMR(400MHz,MeOH-d4)δppm 8.23(s,1H),8.16-8.26(m,1H),8.06-8.15(m,1H),7.96-8.06(m,1H),7.52-7.79(m,11H),7.41(d,J=3.0Hz,2H),7.45(d,J= 9.9Hz,2H),7.25(s,1H),6.89(d,J=9.3Hz,2H),5.45(s,1H),5.34(br.s.,1H),5.24(s,1H),5.13(br.s.,1H),4.48-4.70(m, 4H),4.38(br.s,2H),3.91(br.s.,2H),3.36(s,12H),3.00(s,3H),2.95-3.05(m,2H),2.85-2.95(m,2H),2.65-2.74(m,4H), 2.63(br.s.,6H),2.47(br.s,6H),1.84-1.94(m,2H),1.77(s,3H),1.72-1.84(m,2H),1.66(s,3H),0.68(s,3H),0.65(s,3H).

[0974] Preparation of Compound 102

[0975]

[0976] Compound 102 was prepared from intermediates 73-1 and 82-1 following general procedures XVI, XXIV, XVII-A and XV as outlined in the above schemes. HPLC-MS: m / z 1123.9 (for M+H + Calculated value: 1123.6). UV / Vis: λ max =623nm. 1H NMR(400MHz,MeOH-d4)δppm 8.23-8.45(m,2H),7.94-8.21(m,3H),7.53-7.69(m,2H),7.39-7.46(m,2H),7.36(d,J=8.6Hz,2H),7.33-7.39(m,1H),7.2 5-7.33(m,4H),7.15-7.25(m,4H),6.86(d,J=2.6Hz,2H),6.67(dd,J=8.8,2.4Hz,2H),5.32(br.s.,1H),5.29(br.s,1H),5. 15(br.s.,1H),5.06(br.s.,1H),4.50-4.69(m,4H),4.36-4.50(m,2H),4.09(br.s.,2H),2.86-3.01(m,4H),2.78(s,6H), 2.57-2.70(m,2H),2.45-2.55(m,2H),2.38(s,3H),1.72-1.81(m,4H),1.68(s,3H),1.61(s,3H),0.56(s,3H),0.52(s,3H).

[0977] Preparation of compound 75

[0978]

[0979] Compound 75 was prepared from 1,5-dibromo-2,4-dimethylbenzene and intermediates 54-1 and 11-3 following general procedures XXIII, XVI, XVII-A and XV as outlined in the above schemes. HPLC-MS: m / z 1166.4 (for M + Calculated value: 1165.6). UV / Vis: λ max =650nm. 1H NMR (400 MHz, MeOH-d4; mixture of two rotamers) δ ppm 8.45-8.53 (m, 2H), 8.25-8.44 (m, 2H), 7.63 (d, J = 9.3 Hz, 1H), 7.52-7.60 (m, 2H), 7.49 (d, J = 6.8 Hz, 1H), 7.44 (s, 1H), 7.40 (dd, J = 6 .8,2.0Hz,1H),7.37(d,J=2.9Hz,2H),7.33(d,J=9.7Hz,2H),7.17-7.31(m,4H),7.06- 7.17(m,3H),6.84(dd,J=9.7,2.9Hz,2H),5.36(br.s.,1H),5.35(s,1H),5.19(quin,J =1.3Hz,1H),5.15(quin,J=1.3Hz,1H),4.91(br.s.,2H),4.75(br.s.,2H),4.18(br.s .,2H),3.83(br.s,2H),3.34(s,12H),3.03(t,J=6.5Hz,2H),2.91(t,J=6.4Hz,2H),2. 76(dd,J=9.0,6.7Hz,2H),2.58(dd,J=8.5,6.7Hz,2H),2.49(s,3H),2.11(s,3H),1.84 -1.96(m,2H),1.75-1.84(m,2H),1.72(s,3H),1.68(s,3H),0.61(s,3H),0.58(s,3H).

[0980] Preparation of compounds 76, 94 and 95.

[0981]

[0982] Compound 95-2 was prepared from 2-methyl-4-(morpholinosulfonyl)phenylboronic acid following general procedures XVIII and XIX.

[0983] As outlined in the above scheme, compounds 76, 94, and 95 were prepared following General Procedure V from common intermediate 75-3 and benzyl bromides 53-2, 68-2, and 95-2, respectively.

[0984] For compound 76: HPLC-MS: m / z 1380.4 (for M + Calculated value: 1379.6). UV / Vis: λ max =650nm. 1H NMR(400MHz,MeOH-d4)δppm 8.46(br.s.,1H),8.34-8.41(m,1H),8.22-8.30(m,1H),7.74-7.78(m, 1H),7.63-7.72(m,3H),7.47-7.62(m,6H),7.44(s,1H),7.35-7.38(m, 2H),7.30-7.35(m,1H),7.34(s,1H),7.28(br.s,1H),6.88(dd,J=9.6,2.7Hz,2H),5.40(s,1H),5.40(s,1H),5.22(quin,J=1.3Hz,1H),5.18( quin,J=1.3Hz,1H),4.91(br.s.,2H),4.27(br.s.,2H),4.08(br.s.,2H),3.36(s,12H),3.05(t,J=6.6Hz,2H),2.94(t,J=6.7Hz,2H),2.77-2 .86(m,2H),2.68-2.73(m,2H),2.55(s,6H),2.52(s,3H),2.47(s,6H), 2.12(s,3H),1.80-1.95(m,4H),1.73(s,3H),1.71(s,3H),0.61(s,6H).

[0985] For compound 94: HPLC-MS: m / z 1256.1 (for M + Calculated value: 1255.6). UV / Vis: λ max =651nm.

[0986] For compound 95: HPLC-MS: m / z 1464.2 (for M + Calculated value: 1463.7). UV / Vis: λ max =650nm.

[0987] Preparation of compound 77

[0988]

[0989] Compound 77 was prepared from 2-bromo-4-iodoanisole and intermediates 54-1 and 11-3 following general procedures XXIII, XVI, XVII-A and XV as outlined in the above schemes. HPLC-MS: m / z 1168.4 (for M + Calculated value: 1167.6). UV / Vis: λ max =650nm. 1H NMR(400MHz,MeOH-d4)δppm 8.77(d,J=2.4Hz,1H),8.38-8.49(m,2H),8.26(m,J=8.0Hz,1H),8.05(d,J=9.5Hz,1H),7.62-7.69(m,1H),7.49-7.62(m,3H),7.47(d,J=8. 0Hz,1H),7.42(m,J=8.7Hz,1H),7.26-7.39(m,4H),7.17-7.24(m,2H),7.14(d,J=8.7Hz,2H),6.93(d,J=2.9Hz,2H),6.85(d,J=8.6Hz,1H), 6.71(dd,J=8.6,2.9Hz,2H),5.38(s,2H),5.18(s,2H),4.94(br.s.,4H),4.29(br.s.,2H),4.02(s,2H),3.20(s,3H),3.02-3.0(m,4H),2.9 3(s,12H),2.79-2.86(m,2H),2.70-2.78(m,2H),1.98-2.08(m,2H),1 .90-1.96(m,2H),1.71(s,3H),1.70(s,3H),0.57(s,3H),0.45(s,3H).

[0990] Preparation of compounds 92, 93, 97 and 116

[0991]

[0992] As outlined in the above scheme, compounds 92, 93, 97 and 116 were prepared following General Procedure V from common intermediate 77-3 and benzyl bromides 53-2, 95-2, 60-2 and 117-2, respectively.

[0993] For compound 92: HPLC-MS: m / z 1382.1 (for M + Calculated value: 1381.6). UV / Vis: λ max =650nm.

[0994] For compound 93: HPLC-MS: m / z 1466.3 (for M + Calculated value: 1465.6). UV / Vis: λ max =651nm.

[0995] For compound 97: HPLC-MS: m / z 1228.3 (for M + Calculated value: 1227.6). UV / Vis: λ max =651nm.1 H NMR (400 MHz, MeOH-d4; mixture of rotamers) δ ppm 8.75-8.83 (m, 1H), 8.35-8.47 (m, 2H), 7.93-8.03 (m, 1H), 7.92-8.07 (m, 1H), 7.65 (br. s., 1H), 7.42-7.56 (m, 3H), 7.31-7.37 (m, 2H), 7.16 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 2.7 Hz, 2H), 6.86 (br. s., 1H), 6.72-6.82 (m, 5H), 6.68 (m, J = 8.9, 2.7, 2.7H z,1H),5.33-5.38(m,2H),5.13-5.20(m,2H),4.59-4.72(m,4H),3.81-3.83(m,3H),3.80(s,3H),3.55-3.63(m,4H),3.1 6(s,3H),3.00-3.10(m,4H),2.92(s,12H),2.66(s,4H),1.67-1.75(m,3H),1.67-1.75(m,3H),0.57(s,3H),0.45(s,3H).

[0996] For compound 116: HPLC-MS: m / z 1204.2 (for M + Calculated value: 1203.6). UV / Vis: λ max =655nm. 1H NMR (400MHz, 1% TFA-d in MeOH-d4) δppm 8.48(br.s.,1H),8.41(d,J=10.1Hz,1H),8.39(d,J=10.7Hz,1H),8.18(d ,J=9.6Hz,1H),7.96(d,J=9.3Hz,2H),7.59-7.72(m,3H),7.45-7.52(m,2 H),7.42(d,J=8.8Hz,2H),7.37(d,J=2.8Hz,2H),7.34(d,J=9.7Hz,2H),7.22(t,J=8.4Hz,1H),7.11(t,J=9.1Hz,1H),6.80(dd,J=9.7,2.9Hz,2H),5 .32(s,1H),5.30(s,1H),5.25(br.s.,2H),5.21(br.s.,2H),5.16(quin,J=1.3Hz,1H),5.12(quin,J=1.3Hz,1H),4.56(br.s,2H),4.42(br.s.,2H) ,3.85(s,3H),3.35(s,12H),3.01-3.10(m,4H),2.96(m,J=6.6,6.6Hz,4H ),1.85-1.98(m,4H),1.64(s,3H),1.61(s,3H),0.64(s,3H),0.62(s,3H).

[0997] Preparation of Compound 98

[0998]

[0999] Compound 98 was prepared from intermediates 77-2 and 43-1 following general procedures XVII-A and XV as outlined in the above schemes. HPLC-MS: m / z 1492.4 (for M + Calculated value: 1491.8). UV / Vis: λ max =652nm. 1H NMR(400MHz,MeOH-d4)δppm 8.87(br.s.,1H),8.58(d,J=9.5Hz,1H),8.54(d,J=9.4Hz,1H),8.50(d,J=7.0Hz,1H),8.1 0(d,J=8.8Hz,1H),7.93(d,J=9.1Hz,1H),7.79(d,J=2.3Hz,1H),7.52-7.61(m,2H),7.43( d,J=8.8Hz,2H),7.38(s,1H),7.34-7.37(m,4H),7.20-7.25(m,3H),7.03-7.17(m,3H),6. 78(dd,J=9.7,2.8Hz,2H),5.64(quin,J=1.0Hz,1H),5.62(quin,J=1.0Hz,1H),5.31(quin ,J=1.5Hz,1H),5.30(quin,J=1.5Hz,1H),5.00(br.s.,2H),4.97(br.s.,2H),4.08(br.s, 2H),3.83(s,3H),3.84(br.s,2H),3.67(br.s.,2H),3.46-3.58(m,13H),3.34-3.45(m,15 H),3.33(s,12H),3.24-3.29(m,2H),3.17-3.23(m,4H),2.94(br.s,2H),2.79(t,J=4.9Hz ,2H),1.88(dd,J=1.5,1.0Hz,3H),1.86(dd,J=1.5,0.9Hz,3H),0.63(s,3H),0.58(s,3H).

[1000] Preparation of Compound 99

[1001]

[1002] Compound 99 was prepared from intermediates 77-1 and 82-1 following general procedures XVI, XXIV, XVII-A and XV as outlined in the above schemes. HPLC-MS: m / z 1140.0 (for M+H + Calculated value: 1139.6). UV / Vis: λ max =627nm. 1H NMR (400 MHz, MeOH-d4; two rotamers) δ ppm 8.62(br.s.,1H),8.39(d,J=8.6Hz,1H),8.34(d,J=9.5Hz,1H),8.21(d,J=8.4Hz ,1H),8.03(d,J=9.5Hz,1H),7.85(d,J=8.9Hz,1H),7.61-7.68(m,2H),7.47-7.5 8(m,3H),7.40(d,J=8.8Hz,2H),7.31-7.37(m,2H),7.26-7.31(m,3H),7.18-7.2 3(m,2H),7.10-7.17(m,2H),6.63(dd,J=9.5,2.6Hz,2H),5.39(s,1H),5.34(s,1 H),5.21(quin,J=1.5Hz,1H),5.13(quin,J=1.5Hz,1H),4.80(br.s.,2H),4.74( br.s.,2H),4.16(br.s.,2H),3.86(br.s,2H),3.84(s,3H),3.04(s,6H),3.02(t ,J=5.6Hz,2H),2.90(t,J=5.7Hz,2H),2.70-2.76(m,2H),2.55-2.63(m,2H),1.8 0-1.90(m,4H),1.73-1.75(m,3H),1.65-1.67(m,3H),0.60(s,3H),0.55(s,3H).

[1003] Preparation of Compound 100

[1004]

[1005] Compound 100 was prepared from intermediates 99-4 and 57-2 following General Procedure V. HPLC-MS: m / z 1276.0 (for M+H + Calculated value: 1275.6). UV / Vis: λ max =625nm.

[1006] Preparation of Compound 110

[1007]

[1008] Ge-xanthone 110-1 was prepared as described in the literature (AN Butkevich et al., Chem.-A Eur. J. 2017, 23, 12114–12119).

[1009] Compound 110 was prepared from intermediates 63-1 and 110-1 following general procedures XVI, XVII-A, and XV as outlined in the above schemes. HPLC-MS: m / z 1198.4 (for M + Calculated value: 1197.6). UV / Vis: λ max =639nm. 1 H NMR (400 MHz, MeOH-d4) δ ppm 8.68(br.s.,1H),8.31-8.43(m,2H),8.21(d,J=8.2Hz,1H),7.95(d,J=8.3Hz,1 H),7.87(d,J=8.9Hz,1H),7.68(d,J=1.6Hz,1H),7.62(d,J=8.2Hz,1H),7.43-7. 58(m,4H),7.35(d,J=2.9Hz,2H),7.24-7.32(m,2H),7.29(d,J=9.6Hz,2H),7.1 0-7.23(m,4H),6.77(dd,J=9.7,2.9Hz,2H),5.40(s,1H),5.34(s,1H),5.22(qui n,J=1.5Hz,1H),5.13(quin,J=1.5Hz,1H),4.77(br.s.,2H),4.70(br.s.,2H), 4.14(br.s.,2H),3.83(s,2H),3.32(s,12H),3.02(t,J=6.5Hz,2H),2.86(t,J=6 .6Hz,2H),2.69-2.76(m,2H),2.53-2.60(m,2H),2.15(s,3H),1.84(s,4H),1.7 4(dd,J=1.5,1.0Hz,3H), 1.66(dd,J=1.5,1.0Hz,3H), 0.79(s,3H), 0.77(s,3H).

[1010] Preparation of compounds 111–113 .

[1011]

[1012] As outlined in the above scheme, compounds 111, 112, and 113 were prepared following General Procedure V from common intermediate 110-3 and benzyl bromides 53-2, 57-2, and 60-2, respectively.

[1013] For compound 111: HPLC-MS: m / z 1412.3 (for M + Calculated value: 1411.6). UV / Vis: λ max =638nm. 1H NMR(400MHz,MeOH-d4)δppm 8.69(br.s.,1H),8.33(br.s.,1H),8.16(br.s,1H),7.92-8.02(m,2H),7.72-7.80(m,2H),7.65-7.71(m,2H),7.57-7.63(m,3H),7.49-7 .57(m,3H),7.33-7.40(m,5H),6.87(dd,J=9.9,2.6Hz,2H),5.47(s,1H),5.35(s,1H),5.26(quin,J=1.5Hz,1H),5.14(quin,J=1.5Hz,1H ),4.61-4.75(m,4H),4.37(br.s.,2H),3.91(br.s.,2H),3.34(s,12H),2.98(t,J=6.2Hz,2H),2.87-2.93(m,2H),2.67-2.74(m,4H),2.6 3(br.s.,6H),2.35(br.s.,6H),2.16(s,3H),1.89-1.99(m,2H),1.74-1.82(m,2H),1.78(s,3H),1.67(s,3H),0.83(s,3H),0.79(s,3H).

[1014] For compound 112: HPLC-MS: m / z 1334.3 (for M + Calculated value: 1333.5). UV / Vis: λ max =638nm. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.73(br.s.,1H),8.44(t,J=8.1Hz,2H),8.30(d,J=8.0Hz,1H),8.04(d,J=6.1 Hz,1H),7.98(d,J=7.9Hz,1H),7.93(d,J=9.3Hz,1H),7.64-7.72(m,3H),7.51 -7.63(m,3H),7.48-7.51(m,1H),7.46(d,J=7.8Hz,1H),7.40(d,J=7.8Hz,1H) ,7.36(d,J=2.8Hz,2H),7.28(d,J=9.6Hz,2H),6.78(dd,J=9.7,2.9Hz,2H),5.4 3(s,1H),5.35(s,1H),5.23(quin,J=1.5Hz,1H),5.14(quin,J=1.5Hz,1H),4. 94(br.s.,4H),4.31(br.s.,2H),4.03(br.s.,2H),3.34(s,12H),3.03(t,J=6 .5Hz,2H),2.91(t,J=6.4Hz,2H),2.78-2.85(m,2H),2.67-2.74(m,2H),2.15( s,3H),1.85-1.94(m,4H),1.76(s,3H),1.67(s,3H),0.79(s,3H),0.79(s,3H).

[1015] For compound 113: HPLC-MS: m / z 1258.3 (for M + Calculated value: 1257.6). UV / Vis: λ max =638nm. 1H NMR(400MHz,MeOH-d4)δppm 8.69(br.s.,1H),8.41(br.s.,2H),8.29(br.s.,1H),7.89-7.97(m,1H),7.84(br. s.,1H),7.69(br.s.,1H),7.60(d,J=8.2Hz,1H),7.41-7.56(m,3H),7.34(d,J=2.8H z,2H),7.29(d,J=9.6Hz,2H),6.92(d,J=2.4Hz,1H),6.83-6.88(m,1H),6.80(d,J= 7.9Hz,1H),6.75(dd,J=9.7,2.8Hz,2H),6.72-6.77(m,1H),6.68(d,J=8.0Hz,1H),5 .40(s,1H),5.34(s,1H),5.22(s,1H),5.15(s,1H),4.63(br.s,2H),4.59(br.s,2H ),3.89(s,2H),3.73(s,3H),3.68(br.s.,2H),3.59(br.s.,3H),3.32(br.s,12H),3 .04(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.60-2.69(m,2H),2.49-2.56(m,2H),2 .14(s,3H),1.77-1.87(m,4H),1.75(s,3H),1.69(s,3H),0.79(s,3H),0.78(s,3H).

[1016] Preparation of Compound 120

[1017]

[1018] Compound 120 was prepared from intermediates 77-1 and 110-1 following general procedures XVI, XVII-A, and XV as outlined in the above schemes. HPLC-MS: m / z 1214.1 (for M + Calculated value: 1213.6). UV / Vis: λ max =644nm. 1H NMR (400 MHz, MeOH-d4; a mixture of rotamers in a ratio of 1:0.29) δ ppm 8.66 (br. s., 1H), 8.40 (d, J = 9.1 Hz, 1H), 8.36 (d, J = 9.6 Hz, 1H), 8.24 (d, J = 8.5 Hz, 1H), 8.05 (dd, J = 8.6, 2.2 Hz, 1H), 7.87 (d, J = 9.4 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.4 7-7.58(m,3H),7.38-7.43(m,2H),7.36(d,J=9.7Hz,2H),7.31(d,J=2.8Hz,2H),7 .23-7.30(m,2H),7.08-7.22(m,4H),6.76(dd,J=9.7,2.9Hz,2H),5.40(s,1H),5.3 4(quin,J=0.9Hz,1H),5.21(quin,J=1.3Hz,1H),5.14(quin,J=1.3Hz,1H),4.83( br.s.,2H),4.76(br.s.,2H),4.17(br.s.,2H),3.85(br.s,2H),3.83(s,3H),3.31 (s,12H),3.02(t,J=6.6Hz,2H),2.86(t,J=6.6Hz,2H),2.71-2.78(m,2H),2.55-2. 63(m,2H),1.80-1.91(m,4H),1.74(s,3H),1.66(s,3H),0.79(s,3H),0.74(s,3H).

[1019] Preparation of Compound 121

[1020]

[1021] Compound 121 was prepared from intermediates 120-2 and 57-2 following General Procedure V. HPLC-MS: m / z 1350.2 (for M + Calculated value: 1349.5). UV / Vis: λ max =644nm. 1H NMR(400MHz,MeOH-d4)δppm 8.64-8.73(m,1H),8.43(br.s.,2H),8.33(m,J=18.6Hz,1H),8.07(dd,J=8.7,2.1Hz,1H),7.90(d,J=9.3Hz,1H),7.64-7.74(m,3H),7.45-7.62(m,7H),7.37(d,J=9.7Hz,2H),7.31(d,J=2.8Hz,2H),6.75(dd,J=9.7,2.8Hz,2H),5.41(s,1H),5.33(s,1H),5.21(s,1H),5.11-5.15(m,1H),4.91(br.s.,4H),4.31(br.s.,2H),4.05(br.s.,2H),3.82(s,3H),3.32(s,12H),3.01(t,J=6.6Hz,2H),2.89(t,J=6.1Hz,2H),2.75-2.83(m,2H),2.64-2.73(m,2H),1.82-1.91(m,4H),1.74(s,3H),1.66(s,3H),0.79(s,3H),0.74(s,3H)。

[1022] Preparation of Compound 86

[1023]

[1024] Preparation of compound 86-1

[1025] To a suspension of 3-bromo-5-iodobenzoic acid (6.0 g, 18.4 mmol) in anhydrous DCM (20 mL) was added oxalyl chloride (6.5 mL, 75.8 mmol) dropwise, followed by a catalytic amount of DMF (5 drops; gas release was observed shortly after the addition of DMF). The reaction mixture was stirred at ambient temperature for 30 minutes, after which the suspension became a clear orange solution. The solvent was removed under reduced pressure. The residue was fully dried under high vacuum, then redissolved in anhydrous DCM (30 mL), and while cooling the reaction mixture with an ice / water bath (0 ° C), it was added dropwise to a mixture of 2-amino-2-methylpropan-1-ol (5.05 g, 56.7 mmol) and anhydrous DCM (20 mL). The reaction mixture was allowed to reach ambient temperature and stirred for 3 hours. The resulting suspension was filtered, and the white precipitate was washed with DCM (30 mL) in addition. The combined filtrate and washings were concentrated under reduced pressure to provide a crude amide intermediate in the form of a red oil. This intermediate was dissolved in pure thionyl chloride (13 mL) and the mixture was stirred at ambient temperature for 2 hours. Excess thionyl chloride was then removed in vacuo and the resulting residue was purified by flash chromatography (SiO , gradient elution with 5% to 10% EtOAc in hexanes). The product (6.16 g, 89% yield) was obtained as a white crystalline solid.

[1026] As outlined in the above schemes, compound 86-3 was obtained from oxazoline 86-1, anthraceneboronic acid 54-1, and silaxanthrone 11-3 following general procedures XXIII and XVI (without the addition of TMEDA for the latter).

[1027] General Procedure XVII-B. Double Amination of TBDMS Diether. Preparation of Compound 86-4

[1028] At ambient temperature, a solution of bis-TBDMS ether 86-3 (40 mg, 0.041 mmol) in anhydrous DCM (2 mL) was treated with 1 M SOCl in DCM (0.25 mL, 0.25 mmol) for 16 hours. The solvent was then removed under reduced pressure, and the residue was fully dried under high vacuum. The crude residue was dissolved in anhydrous DCM (2 mL) and added dropwise to a mixture of 2-(methylaminomethyl)phenylboronic acid (110 mg, 0.67 mmol), KCO (100 g, 0.72 mmol) and NaI (6 mg, 0.04 mmol) in anhydrous DMF (3 mL). The mixture was stirred for 16 hours at ambient temperature. The mixture was then filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase flash chromatography (C18 SiO2, eluted with 5% to 75% MeOH+0.05% TFA gradient in water). The title compound (24 mg, 52% yield) was obtained as a dark blue oil.

[1029] Preparation of compound 86-5

[1030] Oxazoline 86-4 (24 mg, 0.021 mmol) was dissolved in 6N HCl (5 mL) and the mixture was heated at 80 ° C for 16 hours. The reaction mixture was then diluted with saturated NH4Cl and neutralized with 25% NH3 (aq.) to a pH of approximately 3–4. The aqueous mixture was extracted with DCM, and the combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was further purified by reverse phase flash chromatography (C18 SiO2, eluting with a gradient of 5% to 75% MeOH in water + 0.05% TFA) to produce the title compound (11.7 mg, 52% yield) as a dark blue solid.

[1031] Preparation of Compound 86

[1032] A mixture of carboxylic acid 86-5 (11.7 mg, 0.011 mmol), EDC·HCl (7.5 mg, 0.04 mmol), HOBt hydrate (2.15 mg, 0.014 mmol), APMA·HCl (6.5 mg, 0.036 mmol) and DIPEA (0.02 mL, 0.11 mmol) in anhydrous DMF (1 mL) was stirred at ambient temperature for 16 h. The reaction mixture was then diluted with water, acidified with TFA, and directly loaded onto a C18 SiO2 column for flash chromatography purification (eluting with a gradient of 5% to 100% MeOH in water + 0.05% TFA). The title compound (8.2 mg, 62% yield) was obtained as a dark blue amorphous solid. HPLC-MS: m / z 1084.1 (for M + Calculated value: 1083.6). UV / Vis: λ max =650nm. 1H NMR(400MHz,MeOH-d4)δppm 8.35(br.s.,2H),8.02-8.15(m,2H),7.97(br.s.,1H),7.84-7.93(m,2H),7.72-7.82(m,2H),7.67(m,J=6.1Hz,3H),7.56-7. 63(m,3H),7.46-7.56(m,2H),7.43(d,J=2.9Hz,2H),7.30(d,J=9.7Hz,2H),7.22-7.36(m,1H),6.84(dd,J=9.7,2.8Hz,2H),5 .70(s,1H),5.59(br.s,2H),5.55(br.s,2H),5.35(quin,J=1.3Hz,1H),4.81(br.s,2H),4.84(br.s,2H),3.56(t,J=5.7Hz,2 H), 3.39 (t, J = 6.5Hz, 2H), 3.36 (s, 12H), 2.83 (s, 3H), 2.78 (s, 3H), 1.91-1.95 (m, 2H), 1.92 (s, 3H), 0.66 (s, 3H), 0.65 (s, 3H).

[1033] Preparation of compound 25

[1034]

[1035] Intermediate 25-1 was prepared from 1-bromo-4-[2-(trimethylsilyl)ethynyl]benzene and Intermediate 11-3 following General Procedure X followed by basic treatment.

[1036] General Procedure XXV. Sonogashira coupling. Preparation of compound 25-2.

[1037] A mixture of aryl alkyne 25-1 (250 mg, 0.61 mmol), aryl bromide 35-6 (374 mg, 0.73 mmol), Pd(PPh 3 ) 2 Cl 2 (43 mg, 0.06 mmol), copper (I) iodide (12 mg, 0.06 mmol) and triethylamine (2 mL) in degassed THF (15 mL) was refluxed under argon for 16 hours. The reaction mixture was then concentrated under reduced pressure, the residue was dissolved in MeOH, and the mixture was purified by HPLC. The filtrate was concentrated again, and the residue was purified by reverse phase flash chromatography (C18 SiO2, eluting with a gradient of MeOH+0.25% HCl in water) to provide the title compound 25-2 (78 mg, 15%) as a brown oil.

[1038] Compound 25 was prepared from intermediate 25-2 following General Procedure V as outlined in the above scheme. HPLC-MS: m / z 1162.4 (for M + Calculated value: 1161.6). UV / Vis: λ max =650nm.

[1039] Preparation of compound 81

[1040]

[1041] Intermediate 81-1 was prepared from intermediate 54-1 and ethyl 5-bromo-2-thiophenecarboxylate following general procedure XXIII. Intermediate 81-3 was prepared following published procedures (Grimm, JB; Brown, TA; Tkachuk, AN; Lavis, LDACS Cent. Sci. 2017, 3(9), 975–985).

[1042] General Procedure XXVI-A. Preparation of compound 81-4.

[1043] According to the general method described in the literature (Grimm, JB; Brown, TA; Tkachuk, AN; Lavis, LDACS Cent. Sci. 2017, 3 (9), 975–985), a solution of intermediate 81-3 (46.7 mg, 0.10 mmol) in anhydrous THF (3 mL) was cooled to –78°C under an argon atmosphere. Tert-butyl lithium (1.52 M in pentane, 0.29 mL, 0.44 mmol) was added dropwise to the solution. The bright yellow reaction mixture was stirred at –78°C for 3 minutes and then warmed to –20°C. A solution of ethyl ester 81-1 (140 mg, 0.225 mmol) in anhydrous THF (3 mL) was slowly added, and the reaction mixture was warmed to ambient temperature and stirred for 16 hours. The reaction was quenched with half-saturated NH4Cl, acidified with 1M HCl until dark green, and thoroughly extracted with DCM. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, gradient elution with 0 to 25% MeOH in DCM) to give the desired product (28 mg, 32%) as a dark green solid.

[1044] Compound 81 was prepared from intermediate 81-4 following general procedures XVII-A and XV. HPLC-MS: m / z 1144.1 (for M + Calculated value: 1143.6). UV / Vis: λ max =670nm.

[1045] Preparation of compound 90.

[1046]

[1047] Intermediate 90-1 was prepared from Intermediate 54-1 and ethyl 2-bromothiazole-4-carboxylate following General Procedure XXIII.

[1048] General Procedure XXVI-B. Preparation of compound 90-2.

[1049] Under an argon atmosphere, a mixture of TMEDA (0.05 mL, 0.33 mmol) and a stock solution of bis-(2-bromo-5-[N,N-dimethylamino]phenyl)dimethylsilane 81-3 (0.10 M in anhydrous THF, 3 mL, 0.30 mmol) was cooled to –78°C. Tert-butyllithium (1.52 M in pentane, 0.87 mL, 1.32 mmol) was added dropwise. The bright yellow reaction mixture was stirred at –78°C for 3 minutes and then allowed to warm to –20°C. After 5 minutes, a solution of MgBr2 (0.20 M in anhydrous THF, prepared from MgBr2·Et2O, 3.3 mL, 0.66 mmol) was added, and the mixture was stirred for 20 minutes. A solution of 90-1 in anhydrous THF (0.10 M, 2.6 mL, 0.26 mmol) was then quickly added. The reaction mixture immediately turned deep red. The mixture was allowed to warm to ambient temperature and stirred for 30 minutes. The reaction was then quenched with saturated NH4Cl, acidified with 1M HCl until dark green, and thoroughly extracted with DCM. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, gradient elution with 2 to 20% MeOH in DCM) to produce the desired product (59 mg, 25%) as a dark green solid.

[1050] Compound 90 was prepared from intermediate 90-2 following general procedures XVII-A and XV as outlined in the above schemes. HPLC-MS: m / z 1145.1 (for M + Calculated value: 1144.6). UV / Vis: λ max =667nm. 1H NMR(400MHz,MeOH-d4)δppm 8.38(s,2H),8.19(d,J=8.9Hz,2H),7.88(s,1H),7.57-7.70(m,5H),7.46-7.53(m,3H),7.44(d,J=2.8Hz,2H),7.37-7.42 (m,2H),7.28-7.36(m,1H),7.32(d,J=9.6Hz,2H),6.85(dd,J=9.9,2.8Hz,2H),5.33(s,1H),5.31(br.s.,1H),5.17(quin, J=1.5Hz,1H),5.16(quin,J=1.5Hz,1H),5.09(br.s.,2H),5.05(br.s.,2H),4.38(br.s.,2H),4.18(br.s.,2H),3.38(s,1 2H), 3.09 (t, J = 6.3Hz, 2H), 2.95-3.04 (m, 4H), 2.84 (br.s., 2H), 1.91 (br.s., 4H), 1.66 (s, 3H), 1.65 (s, 3H), 0.66 (s, 6H).

[1051] Preparation of Compound 103

[1052]

[1053] Intermediate 103-1 was prepared from Intermediate 54-1 and methyl 5-bromo-2-fluorobenzoate following General Procedure XXIII.

[1054] Compound 103 was prepared from intermediates 103-1 and 81-3 following general procedures XXVI-B, XVII-A, and XV. HPLC-MS: m / z 1156.0 (for M + Calculated value: 1155.6). UV / Vis: λ max =662nm. 1H NMR(400MHz,MeOH-d4)δppm 8.76(br.s,1H),8.72(dd,J=7.4,2.3Hz,1H),8.45(d,J=7.3Hz,2H),8.28( d,J=8.4Hz,1H),7.99(d,J=9.1Hz,1H),7.58(d,J=8.3Hz,4H),7.46(dd,J=7 .1,1.8Hz,1H),7.40(d,J=2.4Hz,1H),7.28-7.37(m,4H),7.25(d,J=8.9Hz, 2H),7.18(d,J=5.4Hz,2H),6.93(d,J=2.8Hz,1H),6.87(dd,J=11.2,8.4Hz, 1H),6.84(dd,J=9.9,2.7Hz,1H),6.77(dd,J=9.0,2.8Hz,1H),5.38(s,2H) ,5.18(s,2H),4.92(br.s.,2H),4.25(br.s.,2H),3.97(s,2H),3.03-3.10( m,4H),2.95(s,12H),2.76-2.83(m,2H),2.68-2.76(m,2H),1.96-2.06(m,2 H),1.85-1.94(m,2H),1.71(s,3H),1.70(s,3H),0.51(s,3H),0.48(s,3H).

[1055] Preparation of Compound 107

[1056]

[1057] Intermediate 107-1 was synthesized from Intermediate 54-1 and methyl 5-bromo-3-fluoro-2-methylbenzoate following General Procedure XXIII.

[1058] General Procedure XXVI-C. Preparation of compound 107-2.

[1059] A solution of intermediate 81-3 (0.2 M in anhydrous THF, 3 mL, 0.60 mmol) and TMEDA (0.20 mL, 1.33 mmol) was cooled to -78 ° C under an argon atmosphere. Tert-butyl lithium (1.57 M in pentane, 1.6 mL, 2.5 mmol) was added dropwise to the solution. The reaction mixture was stirred at -78 ° C for 15 minutes, and a solution of methyl ester 107-1 (320 mg, 0.51 mmol) in anhydrous THF (5 mL) was slowly added. The reaction mixture was allowed to warm to ambient temperature and stirred for 30 minutes. The reaction was quenched with half-saturated NH4Cl, acidified with 1M HCl until dark blue, and thoroughly extracted with DCM. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO 2 , gradient elution with 0 to 25% MeOH in DCM) to give the desired product (259 mg, 55%) as a dark blue solid.

[1060] Compound 107 was prepared from intermediates 107-2 and 107-3 following general procedures XVII-A and XV as outlined in the above schemes. HPLC-MS: m / z 1170.1 (for M + Calculated value: 1169.6). UV / Vis: λ max =661nm. 1H NMR (400 MHz, MeOH-d4; for the rotamers with a ratio of 2:3, there are two sets of signals, and one set of signals is listed) δ ppm 8.73 (br.s, 1H), 8.44 (t, J = 9.4 Hz, 2H), 8.22-8.33 (m, 1H), 7.88 (d, J = 8.9 Hz, 1H), 7.79 (d, J = 10.2 Hz, 1H), 7.47-7.63 (m, 4H), 7.40 (d, J = 2.8 Hz, 2H), 7.37-7.42 (m, 1H), 7.32 (m, J = 6.5 Hz, 2H), 7.27 (d, J = 9.6 Hz, 2H), 7.25-7.29 (m, 1H), 7.09-7.23 (m, 3H), 6.83 (dd, J=9.7,2.9Hz,2H),5.39(s,1H),5.34(s,1H),5.21(quin,J=1.5Hz,1H),5.14(qu in,J=1.5Hz,1H),4.14(br.s.,2H),3.87(br.s,2H),3.34(s,12H),3.00-3.08(m ,2H),2.86(t,J=5.8Hz,2H),2.68-2.81(m,2H),2.53-2.63(m,2H),2.07(d,J=1. 7Hz,3H),1.80-1.91(m,4H),1.73(s,3H),1.67(s,3H),0.63(s,3H),0.62(s,3H).

[1061] Preparation of Compound 108

[1062]

[1063] Compound 108 was prepared from intermediates 107-3 and 57-2 following General Procedure V. HPLC-MS: m / z 1306.3 (for M + Calculated value: 1305.6). UV / Vis: λ max =661nm. 1H NMR(400MHz,MeOH-d4)δppm 8.76(br.s.,1H),8.46(t,J=7.6Hz,2H),8.33(d,J=8.2Hz,1H),8.03(s,1H ),7.92(d,J=9.4Hz,1H),7.82(d,J=10.5Hz,1H),7.51-7.72(m,6H),7.47(m ,J=6.3Hz,2H),7.41(d,J=2.9Hz,2H),7.27(d,J=9.3Hz,2H),6.82(dd,J=9. 7,2.9Hz,2H),5.41(s,1H),5.35(s,1H),5.22(quin,J=1.5Hz,1H),5.15(qu in,J=1.5Hz,1H),4.98(br.s.,2H),4.95(br.s.,2H),4.28(br.s.,2H),4. 03(br.s.,2H),3.35(s,12H),3.03(t,J=6.5Hz,2H),2.90(t,J=6.4Hz,2H), 2.77-2.84(m,2H),2.66-2.74(m,2H),2.07(d,J=1.7Hz,3H),1.83-1.93(m, 4H), 1.74 (dd, J=1.5, 1.0Hz, 3H), 1.67 (dd, J=1.5, 1.0Hz, 3H), 0.63 (s, 6H).

[1064] Preparation of compound 114

[1065]

[1066] Intermediate 114-1 was prepared from Intermediate 54-1 and methyl 4-bromo-2-thiophenecarboxylate following General Procedure XXIII.

[1067] Compound 114 was prepared from intermediates 114-1 and 81-3 following general procedures XXVI-C, XVII-A, and XV. HPLC-MS: m / z 1144.2 (for M + Calculated value: 1143.6). UV / Vis: λ max =673nm. 1H NMR (400MHz, 1% TFA-d in MeOH-d4) δppm 8.26-8.40(m,2H),8.26(s,1H),8.14(d,J=9.1Hz,1H),8.04(br.s.,1H),7.68-7.80(m,4H),7.60-7.67(m,3H),7.57(d,J=9 .7Hz,2H),7.54-7.60(m,1H),7.42-7.48(m,1H),7.45(d,J=2.9Hz,1H),7.23-7.33(m,1H),6.89(dd,J=9.7,2.9Hz,2H),5.49 (s,1H),5.37(br.s.,2H),5.33(s,1H),5.29(br.s.,2H),5.24(s,1H),5.16(s,1H),5.11(s,1H),4.64(br.s.,4H),3.40(s,1 2H),3.02-3.19(m,6H),2.98(t,J=5.9Hz,2H),1.92-2.01(m,2H),1.75-1.88(m,2H),1.63(s,3H),1.57(s,3H),0.67(s,6H).

[1068] Preparation of compound 115

[1069]

[1070] Compound 108 was prepared from intermediates 107-3 and 57-2 following General Procedure V. HPLC-MS: m / z 1279.9 (for M + Calculated value: 1279.5). UV / Vis: λ max =673nm. 1H NMR (400MHz, 1% TFA-d in MeOH-d4) δppm 8.60(br.s.,1H),8.46(d,J=9.1Hz,1H),8.40(d,J=8.5Hz,1H),8.32(d,J=8.2Hz,1H),8.28(d,J=1.2Hz,1H),8.09(d,J=9.1Hz,1H),7.76-7.83(m ,2H),7.69-7.74(m,2H),7.64-7.68(m,2H),7.61(s,2H),7.60(d,J=9.9 Hz,2H),7.52-7.56(m,2H),7.50(s,1H),7.42(d,J=2.9Hz,2H),7.37(d,J =8.3Hz,1H),6.88(dd,J=9.7,2.8Hz,2H),5.38(s,1H),5.33(s,1H),5.18(br.s,2H),5.15(s,2H),5.05(br.s.,2H),4.39(br.s.,2H),4.35(br.s .,2H),3.39(s,12H),3.07(t,J=6.4Hz,2H),2.99(t,J=6.4Hz,1H),2.84 -2.95(m,4H),1.82-1.97(m,4H),1.70(s,3H),1.65(s,3H),0.65(s,6H).

[1071] Preparation of Compound 91

[1072]

[1073] The synthesis of intermediate 91-1 was performed according to published procedures (JB Grimm, TA et al., ACS Cent. Sci. 2017, 3, 975-985).

[1074] Preparation of compound 91-2

[1075] Intermediate 91-2 was synthesized following a modified method of Grimm et al. (JB Grimm, TA et al., ACS Cent. Sci. 2017, 3, 975–985). A mixture of TMEDA (0.20 mL, 1.33 mmol) and a 0.1 M solution of diarylsilane 91-1 in anhydrous THF (4.6 mL, 0.46 mmol) was cooled to −78° C. under argon. Tert-butyl lithium (1.52 M in pentane, 1.4 mL, 2.13 mmol) was added dropwise and the mixture was stirred vigorously for 5 minutes. The reaction was then transferred to a −20° C. cooling bath and allowed to equilibrate for 10 minutes. A solution of magnesium bromide (0.2 M in anhydrous THF, prepared from MgBr2·Et2O, 5.1 mL, 1.02 mmol) and a solution of lithium chloride (0.5 M in anhydrous THF, 2.0 mL, 1.0 mmol) were then added, and the mixture was stirred at –20°C for 10 minutes. A solution of methyl 5-bromo-2-methylbenzoate (1 M in anhydrous THF, 0.46 mL, 0.46 mmol) was rapidly injected, and the reaction mixture was allowed to warm to ambient temperature overnight. The reaction was then quenched with saturated NH4Cl (50 mL), acidified with 1 M HCl (5 mL), and extracted with DCM (3 x 30 mL). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The dark blue residue was purified by flash chromatography (SiO2, 2% to 25% MeOH in DCM gradient). Yield: 51 mg (21%) as a dark blue solid.

[1076] Compound 91 was synthesized from intermediate 91-2 following general procedures III and XV. HPLC-MS: m / z 1175.9 (for M + Calculated value: 1175.6). UV / Vis: λ max =652nm.

[1077] Preparation of Compound 68

[1078]

[1079] Preparation of compound 68-1.

[1080] A solution of aryl bromide 19-6 (555 mg, 1.02 mmol) and TMEDA (0.17 mL, 1.14 mmol) in anhydrous THF (4 mL) was cooled to -78 ° C under argon. To this solution was added t-BuLi (c = 1.52 M in cyclohexane, 0.74 mL, 1.12 mmol) dropwise. After 5 minutes, p-toluenesulfonyl azide (13.6% w / w in toluene, 1.6 mL, 0.99 mmol) was added dropwise over 2 minutes. The reaction mixture was stirred at -78 ° C for 30 minutes, then quenched with water (10 mL) and allowed to warm to room temperature. Saturated NH4Cl (10 mL) and DCM (15 mL) were added with vigorous stirring, and the layers were separated. The aqueous layer was discarded, and the organic layer was washed with saturated NaHCO3 and brine. The solution was then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO 2 , gradient elution with 2% to 30% DCM in hexanes) to provide 2-azidoanthracene 68-1 (442 mg, 85% yield) as a yellow solid. The product was stored at -20° C. under argon in the dark.

[1081] General Procedure XXVII. Copper-catalyzed alkyne-azide cycloaddition. Preparation of compound 68-2.

[1082] A mixture of aryl alkyne 25-1 (86 mg, 0.19 mmol), aryl azide 68-1 (97 mg, 0.19 mmol), copper (II) sulfate pentahydrate (9.5 mg, 0.038 mmol), TBTA (20 mg, 0.038 mmol) and (L)-sodium ascorbate (15 mg, 0.075 mmol) in anhydrous DMF (10 mL) was stirred at room temperature for 16 hours. The reaction mixture was then diluted with ethyl acetate (75 mL) and washed with NH4Cl aqueous solution (saturated solution diluted with water 1:10, 100 mL), 5% w / w LiCl aqueous solution (100 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, gradient elution with 2% to 10% MeOH in DCM). This provided the title intermediate 68-2 as a dark blue solid (78 mg, 43% yield).

[1083] Compound 68 was prepared from intermediate 68-2 following general procedures XVII-A and XV as outlined in the above schemes. HPLC-MS: m / z 1205.3 (for M + Calculated value: 1204.6). UV / Vis: λ max =650nm.

[1084] Preparation of compound 29

[1085]

[1086] Intermediate 29-1 was prepared from intermediate 35-6 and ethynyltrimethylsilane following General Procedure XXV followed by basic treatment.

[1087] Compound 29 was prepared from intermediates 29-1 and 2-2 following general procedures XXV and V as outlined in the above schemes. HPLC-MS: m / z 1376.6 (for M+H + Calculated value: 1375.6). UV / Vis: λ max =650nm.

[1088] Preparation of Compound 70

[1089]

[1090] The preparation of intermediate 70-1 was achieved based on procedures reported for similar compounds (Bertozzi, CR; Shieh, P. US Patent 9410958).

[1091] Preparation of compound 70-1.

[1092] A solution of 3-bromo-4-methylaniline (1.10 g, 5.9 mmol) in anhydrous THF (30 mL) was cooled to -78 ° C under an argon atmosphere. LiHMDS (1.05 M in THF, 11.8 mL, 12.4 mmol) was added dropwise over 10 minutes. The reaction mixture was allowed to warm to ambient temperature, stirred for 15 minutes, and then cooled back to -78 ° C under an argon atmosphere. Chlorotrimethylsilane (1.6 mL, 12.6 mmol) was added dropwise over 10 minutes, and the reaction mixture was allowed to warm to ambient temperature and stirred for 1 hour. The solvent was then removed under reduced pressure. The resulting residue was suspended in hexane, filtered, and the filtrate was concentrated under reduced pressure. After being fully dried under high vacuum, the crude product 70-1 (1.85 g, 95% yield) was obtained as a brown-orange liquid. The product was used in the next step without further purification.

[1093] Preparation of compound 70-2.

[1094] The crude TMS-protected aniline 70-1 (1.85 g, 5.6 mmol) was dissolved in anhydrous THF (15 mL), and the solution was cooled to -78 ° C under an argon atmosphere. Tert-BuLi (1.52 M in pentane, 4.5 mL, 6.84 mmol) was added dropwise, and the solution was stirred at -78 ° C for 30 minutes. A solution of silanthone 11-3 (0.075 M in THF, 55 mL, 4.13 mmol) was then quickly added, and the reaction mixture was allowed to warm to ambient temperature. After stirring for 1 hour, the reaction was quenched with 1M HCl (16 mL), and the mixture was concentrated under reduced pressure. The residue was neutralized with saturated NaHCO 3 (100 mL), and the aqueous slurry was then extracted with DCM (5×25 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO 2 , gradient elution with 2 to 20% MeOH in DCM) to provide the desired Si-rhodamine 70-2 as a blue solid (0.75 g, 40% yield).

[1095] Preparation of compound 70-3.

[1096] A solution of aniline 70-2 (0.20 g, 0.44 mmol) in a mixture of 2:1 (v / v) glacial acetic acid and water was cooled to 0 ° C. To this mixture was added NaNO2 (46 mg, 0.67 mmol) as a solid, and the mixture was stirred at 0 ° C for 5 minutes, followed by the addition of NaN3 (60 mg, 0.92 mmol). The reaction mixture was allowed to warm to ambient temperature over 1.5 hours, at which point the reaction was complete. The reaction mixture was slowly poured into a 20% (w / v) Na2CO3 aqueous solution (100 mL), and the resulting slurry was extracted with DCM (3 ×). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Without purification, the desired product 70-3 was obtained as a dark blue solid (190 mg, 86%).

[1097] Compound 70 was prepared from intermediates 70-3 and 29-1 according to general procedures XXVII and XV as outlined in the above schemes. HPLC-MS: 1219.3 (for M + Calculated value: 1218.6). UV / Vis: λ max =650nm. 1H NMR(400MHz,MeOH-d4)δppm 9.05(br.s.,1H),8.62(br.s.,1H),8.04-8.32(m,4H),7.85-8.02(m,2H),7.71(d,J=8.8Hz,1H),7.42-7.50(m,3H),7.37-7.42(m,3 H),7.26-7.37(m,5H),7.24(d,J=9.6Hz,2H),7.14(t,J=6.6Hz,1H),6.82(d,J=9.1Hz,2H),5.36(s,1H),5.30(s,1H),5.15(quin,J= 1.3Hz,1H),5.10(quin,J=1.2Hz,1H),4.42-4.71(m,4H),4.00(br.s.,4H),3.33(s,12H),2.92-3.03(m,2H),2.84-2.92(m,2H),2.6 0-2.68(m,2H),2.54-2.60(m,2H),2.18(s,3H),1.77-1.84(m,2H),1.75(s,2H),1.69(s,3H),1.64(s,3H),0.63(s,3H),0.65(s,3H).

[1098] Preparation of compound 72

[1099]

[1100] Compound 72 was synthesized by the same procedure described for compound 70 starting from 4-bromoaniline and intermediates 11-3 and 29-1 (see above scheme). HPLC-MS: 1205.5 (for M + Calculated value: 1204.6). UV / Vis: λ max =650nm.

[1101] Preparation of compound 32

[1102]

[1103] Compound 32 was prepared from 4-iodobenzaldehyde, 2,4-dimethylpyrrole and intermediate 29-1 following general procedures VII, XXV and V as outlined in the above scheme. HPLC-MS: m / z 1102.0 (for M+H + Calculated value: 1101.6). UV / Vis: λ max =500nm. 1H NMR(400MHz,MeOH-d4)δppm 8.42(d,J=8.5Hz,2H),8.28(d,J=8.8Hz,2H),7.85(d,J=8.0Hz,2H),7.48-7.63(m,4H),7.44(d,J=8.0Hz,2 H),7.36-7.48(m,3H),7.20-7.36(m,4H),6.09(s,2H),5.37(s,1H),5.35(s,1H),5.20(quin,J=1.5Hz,1H) ,5.16(quin,J=1.5Hz,1H),4.51-4.76(m,4H),4.04(br.s.,2H),3.97(s,2H),3.02(t,J=7.0Hz,4H),2.67( t,J=7.4Hz,2H),2.56-2.63(m,2H),2.51(s,6H),1.74-1.90(m,4H),1.72(s,3H),1.70(s,3H),1.52(s,6H).

[1104] Preparation of compound 34

[1105]

[1106] Compound 34 was prepared from benzene-1,4-diboronic acid and intermediates 1-2 and 35-6 following general procedures III (twice) and V as outlined in the above scheme. HPLC-MS: m / z 1212.6 (for M + Calculated value: 1211.7). UV / Vis: λ max =635nm. 1H NMR (400MHz, CDCl3) δppm 8.14-8.44(m,5H),8.08(br.s.,1H),7.95(br.s.,1H),7.83(t,J=8.3Hz,3H),7.68(d,J=7.9Hz,1H),7. 30-7.51(m,15H),7.07-7.15(m,3H),5.86(d,J=14.0Hz,2H),5.37(s,2H),5.34(s,1H),5.32(s,1H),5.1 1(br.s,2H),5.09(br.s,2H),4.54(s,2H),4.51(s,2H),3.94(br.s,3H),3.92(br.s,3H),3.39-3.43(m ,2H),2.88-2.93(m,2H),2.46-2.62(m,4H),1.82(s,12H),1.69(s,3H),1.67(s,3H),1.52-1.63(m,4H).

[1107] Preparation of compound 30

[1108]

[1109] Compound 30 was prepared from 4-ethynylphenylboronic acid and intermediates 2-2 and 35-6 following general procedures XXV, III, and V as outlined in the above schemes. HPLC-MS: m / z 1452.0 (for M+H + Calculated value: 1451.7). UV / Vis: λ max =650nm. 1 H NMR(400MHz,MeOH-d4)δppm 8.45(d,J=14.0Hz,2H),7.90-8.04(m,3H),7.72-7.75(m,1H),7.60-7.70(m,3H),7.37 -7.59(m,13H),7.16-7.37(m,7H),6.78(d,J=14.0Hz,2H),5.38(s,1H),5.37(s,1H),5 .17(br.s,1H),5.15(s,1H),4.40-4.53(m,4H),3.09(t,J=7.2Hz,4H),3.03(t,J=6.6H z, 4H), 2.41 (quin, J = 7.7Hz, 4H), 1.68-1.72 (m, 3H), 1.67 (s, 3H), 1.26-1.33 (m, 16H).

[1110] Preparation of compound 31

[1111]

[1112] Intermediate 31-1 was prepared from Intermediate 14-4 following General Procedure XIX.

[1113] Preparation of compound 31-2

[1114] A mixture of bis-bromomethylanthracene 31-1 (520 mg, 1.33 mmol), APMA HCl (711 mg, 4.0 mmol) and potassium carbonate (1.57 g, 8.0 mmol) in anhydrous DMF (40 mL) was stirred at room temperature for 5 hours. The solvent was then removed under reduced pressure. The residue was resuspended in a minimum amount of MeOH and filtered. The filtrate was diluted with 0.1 M HCl and purified by reverse phase flash chromatography (C18 SiO2, MeOH + 0.25% HCl gradient in water). This provided intermediate 31-2 (118 mg, 17%) as a yellow oil.

[1115] Intermediate 31-3 was prepared from 31-2 following General Procedure V.

[1116] Preparation of compound 31.

[1117] A mixture of carboxylic acid 31-3 (11 mg, 0.014 mmol), Cy5 amine 2-3 (11 mg, 0.015 mmol), HOBt (2 mg, 0.015 mmol), EDC (3 mg, 0.016 mmol) and triethylamine (3 mg, 0.03 mmol) in anhydrous DCM (4 mL) was stirred at room temperature for 24 hours. The reaction mixture was then concentrated, and the residue was purified by reverse phase flash chromatography (C18SiO2, eluted with a gradient of MeOH from 10% to 100% in water). This provided compound 31 (15 mg, 70% yield) as a dark blue solid. HPLC-MS: m / z 1487.9 (for M+H + Calculated value: 1484.7). UV / Vis: λ max =650nm.

[1118] Preparation of compound 38

[1119]

[1120] Preparation of compound 38-1

[1121] A mixture of 2-bromo-9,10-dimethylanthracene 35-2 (2.5 g, 8.8 mmol), acetyl chloride (0.89 mL, 13.7 mmol) and anhydrous aluminum chloride (1.68 g, 12.6 mmol) in anhydrous DCM (200 mL) was stirred at ambient temperature for 24 hours. Water (200 mL) was then added and the layers were separated. The aqueous layer was further extracted with DCM (4×100 mL). The combined extracts were dried over anhydrous MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO 2 , gradient elution with 0 to 100% DCM in hexanes). The product was obtained as a bright yellow solid; a mixture of 6-acetyl and 7-acetyl regioisomers in a ratio of approximately 1:5 (2.74 g, 95%).

[1122] Preparation of compound 38-2

[1123] A mixture of intermediate 38-1 (2.74 g, 9.6 mmol), N-bromosuccinimide (3.76 g, 21 mmol) and AIBN (5 mg, 0.03 mmol) was refluxed in anhydrous CCl4 (120 mL) for 3 hours. The reaction mixture was then concentrated under reduced pressure. The residue was triturated with MeOH (200 mL). The collected solid was dried under high vacuum to yield the desired product 38-2 (3.27 g, 70%) as a yellow-orange powder.

[1124] Preparation of compound 38-3

[1125] Solid intermediate 38-2 (3.0 g, 6.2 mmol) was added to a suspension of APMA·HCl (9.9 g, 56 mmol) and K2CO3 (21 g, 155 mmol) in a mixture of anhydrous DCM and MeCN (1:1 v / v, 200 mL), which was pre-stirred at ambient temperature for 3 hours. The reaction mixture was vigorously stirred at ambient temperature for 18 hours. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18SiO2, gradient elution with 0 to 25% MeOH in 0.1% HCl). Yield: 2.2 g (59%) of the free base as a yellow solid; approximately 8:3 mixture of regioisomers.

[1126] Compound 38 was prepared from 38-3 and 26-1 according to general procedures XII, III and V as outlined in the above scheme. HPLC-MS: m / z 1180.2 (for M + Calculated value: 1179.6). UV / Vis: λ max =650nm.

[1127] Preparation of compound 41

[1128]

[1129] Preparation of compound 41-1

[1130] A mixture of 2,6-dibromoanthraquinone (5.24 g, 14.4 mmol) and CsF (2.40 g, 15.8 mmol) in anhydrous DMSO (300 mL) was heated at 140 ° C in an argon atmosphere in a sealed container for 6 hours, and the mixture was then cooled to ambient temperature. Diethylamine (3.0 mL, 2.1 mmol) and K2CO3 (3.98 g, 28.8 mmol) were added, and the reaction was continued at 50 ° C for 48 hours. The reaction mixture was then diluted with water (1.5 L) and extracted with DCM (5 × 200 mL). The combined extracts were washed with brine and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, eluted with a gradient of 0 to 100% EtOAc in hexane). Product 41-1 was obtained as a red solid (1.63 g, 32%).

[1131] Preparation of compound 41-2

[1132] Under an argon atmosphere, a solution of anthraquinone 41-1 (1.63 g, 5.68 mmol) in anhydrous THF (100 mL) was cooled to -78 ° C. MeLi (1.6 M, 7.8 mL, 12.5 mmol) was added dropwise over 10 minutes, and the reaction was continued at -78 ° C for 1 hour. The reaction mixture was then warmed to room temperature and quenched with saturated NH4Cl. The slurry was diluted with water and extracted with ether. The extract was concentrated under reduced pressure, and the residue was purified by flash chromatography (SiO2, eluted with 0 to 25% EtOAc gradient in DCM). The purified intermediate diol was dissolved in THF (30 mL) and added dropwise to a mixture of SnCl2 (9.48 g, 42 mmol) in 1M HCl (20 mL) and ether (100 mL) at ambient temperature. The reaction mixture was stirred for 1.5 hours, then diluted with water (100 mL) and basified to pH approximately 4 with 1 M NaOH. The layers were separated and the aqueous layer was extracted with DCM. The combined ether layer and DCM extracts were concentrated under reduced pressure, and the residue was purified by flash chromatography (SiO , gradient elution with 0% to 20% MeOH in DCM). Yield: 118 mg (6%) as an orange solid.

[1133] As outlined in the above scheme, compound 41 was synthesized from intermediate 41-2 following the order of general procedures XIX, XI, XIII, X, XIV and XV. HPLC-MS: m / z 1133.4 (for M+ Calculated value: 1132.6). UV / Vis: λ max =660nm.

[1134] Preparation of compounds 87 and 88

[1135]

[1136] According to the method described in the literature (Myochin, T.; Hanaoka, K.; Iwaki, S.; Ueno, T.; Komatsu, T.; Terai, T.; Nagano, T.; Urano, Y. Am. Chem. Soc. 2015, 137(14), 4759–4765), silanthone 87-2 was synthesized from diiodosilanthone 87-1 and 1-Boc-piperazine.

[1137] Intermediate 87-3 was synthesized from bromoanthracene 19-5, silaxanthrone 87-2, and 2-(aminomethylamino)phenylboronic acid following General Procedures XVI and XVII-B as outlined in the above schemes.

[1138] Preparation of compound 87-4

[1139] A solution of the bis-Boc protected intermediate 87-3 (66.4 mg, 0.054 mmol) in...

Claims

1. A compound of formula (IV): (IV), or a tautomer or salt thereof, wherein: R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 11 、R 12 and R 14 Each is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C 10 Heteroalkyl, halogen, -C(O)R', -COOR', -C(O)NH2, -C(O)NR'R", -CF3, -CN, -SO3H, -SO2CF3, -SO2R', -SO2NR'R", -N(R')2, -N(R')3 + , -NO2, -OR', -NHC(O)R', -OC(O)R' or phenyl, wherein R' and R" are each independently H or C1-C6 alkyl; or R' and R" together with the nitrogen atom form a 5- or 6-membered heterocyclic ring optionally containing one additional heteroatom selected from S, O or N; R 2 and R 15 Each independently is H or C1-C6 alkyl; R 9 and R 10 are independently H, C1-C6 alkyl or -NHC(O)C(CH3)CH2; L 1 and L 3 is independently a bond or a linker group selected from: C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C2-C 20 heteroalkylene; L 2 yes 、 、 or a phenylene group substituted by at least one substituent selected from halogen, C1-C3 alkyl or C1-C3 alkoxy; Y 1 Selected from -Ge(R d )(R e )-or-Si(R d )(R e )-, where R d and R e Each is H, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy or C6-C 10 aryloxy; R 20 、R 21 、R 23 and R 24 are each independently H, C1-C6 alkyl or optionally substituted by -B(OR 2 )2 substituted benzyl; R 22 、R 25 、R 26 and R 27 Each independently is H or C1-C6 alkyl; Alternatively, (R 21 and R 20 ) and / or (R 23 and R 24 ) together with the nitrogen atom to which they are attached, form a 6-, 5- or 4-membered saturated or partially saturated ring; Alternatively, (R 21 and R 22 )、(R 24 and R 25 )、(R 23 and R 27 ) and / or (R 26 and R 20 ) together with the atoms to which they are attached, form a 6- or 5-membered saturated, unsaturated or partially saturated ring; Provided that the compound is not: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and ， wherein the C2-C 10 Heteroalkyl and C2-C 20 The heteroalkyl group in heteroalkylene refers to the corresponding alkyl group in which one or more chain carbon atoms have been replaced by a heteroatom selected from N, O, S and P.

2. A compound of formula (IV): (IV), or a tautomer or salt thereof, wherein: R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 11 、R 12 and R 14 Each is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C 10 Heteroalkyl, halogen, -C(O)R', -COOR', -C(O)NH2, -C(O)NR'R", -CF3, -CN, -SO3H, -SO2CF3, -SO2R', -SO2NR'R", -N(R')2, -N(R')3 + , -NO2, -OR', -NHC(O)R', -OC(O)R' or phenyl, wherein R' and R" are each independently H or C1-C6 alkyl; or R' and R" together with the nitrogen atom form a 5- or 6-membered heterocyclic ring optionally containing one additional heteroatom selected from S, O or N; R 2 and R 15 Each independently is H or C1-C6 alkyl; R 9 and R 10 are independently H, C1-C6 alkyl or -NHC(O)C(CH3)CH2; L 1 and L 3 is independently a linker group selected from: -(CH2CH2O) n CH2-, -CH2(CH2CH2O) n -, -(CH2CH2O)nCH2CH2-, -CH2CH2(CH2CH2O) n -, (CH2CH2O) n -, where n is an integer between 1 and 10; L 2 yes 、 、 or a phenylene group substituted by at least one substituent selected from halogen, C1-C3 alkyl or C1-C3 alkoxy; Y 1 Selected from -Ge(R d )(R e )-or-Si(R d )(R e )-, where R d and R e Each is H, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy or C6-C 10 aryloxy; R 20 、R 21 、R 23 and R 24 are each independently H, C1-C6 alkyl or optionally substituted by -B(OR 2 )2 substituted benzyl; R 22 、R 25 、R 26 and R 27 Each independently is H or C1-C6 alkyl; Alternatively, (R 21 and R 20 ) and / or (R 23 and R 24 ) together with the nitrogen atom to which they are attached, form a 6-, 5- or 4-membered saturated or partially saturated ring; Alternatively, (R 21 and R 22 )、(R 24 and R 25 )、(R 23 and R 27 ) and / or (R 26 and R 20 ) together with the atoms to which they are attached, form a 6- or 5-membered saturated, unsaturated or partially saturated ring; Provided that the compound is not: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and ， wherein the C2-C 10 The heteroalkyl group in heteroalkyl means the corresponding alkyl group in which one or more chain carbon atoms have been replaced by a heteroatom selected from N, O, S and P.

3. The compound of claim 1, wherein Y 1 Yes-Si(R d )(R e )-, where R d and R e Each is H, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy or C6-C 10 Aryloxy.

4. The compound of claim 1, wherein Y 1 Yes-Ge(R d )(R e )-, where R d and R e Each is H, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy or C6-C 10 Aryloxy.

5. The compound according to claim 1, wherein the compound has the following formula (IV-IA): (IV-IA), or a tautomer or salt thereof, wherein: R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 11 、R 12 and R 14 Each is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C 10 Heteroalkyl, halogen, -C(O)R', -COOR', -C(O)NH2, -C(O)NR'R", -CF3, -CN, -SO3H, -SO2CF3, -SO2R', -SO2NR'R", -N(R')2, -N(R')3 + , -NO2, -OR', -NHC(O)R', -OC(O)R' or phenyl; R' and R" are each independently H or C1-C6 alkyl; or R' and R" can form together with the nitrogen atom to which they are attached a 5- or 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains one additional heteroatom selected from S, O or N; R d and R e Each is H, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy or C6-C 10 aryloxy; R 2 and R 15 Each independently is H or C1-C6 alkyl; R 9 and R 10 are independently H, C1-C6 alkyl or -NHC(O)C(CH3)CH2; L 1 and L 3 is independently a bond or a linker group selected from: C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C2-C 20 heteroalkylene; L 2 yes 、 、 or a phenylene group substituted by at least one substituent selected from halogen, C1-C3 alkyl or C1-C3 alkoxy; R 20 、R 21 、R 23 and R 24 are each independently H, C1-C6 alkyl or optionally substituted by -B(OR 2 )2 substituted benzyl; R 22 、R 25 、R 26 and R 27 Each independently is H or C1-C6 alkyl; Alternatively, (R 21 and R 20 ) and / or (R 23 and R 24 ) together with the nitrogen atom to which they are attached, form a 6-, 5- or 4-membered saturated or partially saturated ring; Alternatively, (R 21 and R 22 )、(R 24 and R 25 )、(R 23 and R 27 ) and / or (R 26 and R 20 ) together with the atoms to which they are attached form a 6- or 5-membered saturated, unsaturated or partially saturated ring, wherein the C2-C 10 Heteroalkyl and C2-C 20 The heteroalkyl group in heteroalkylene refers to the corresponding alkyl group in which one or more chain carbon atoms have been replaced by a heteroatom selected from N, O, S and P.

6. The compound of claim 5, wherein L 1 and L 3 is independently a linker group selected from: -(CH2CH2O) n CH2-, -CH2(CH2CH2O) n -, -(CH2CH2O)nCH2CH2-, -CH2CH2(CH2CH2O) n -, (CH2CH2O) n -, where n is an integer between 1 and 5.

7. The compound according to claim 1, wherein the compound has the following structure: (IV-IB), or a tautomer or salt thereof, wherein: R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 11 、R 12 and R 14 Each is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C 10 Heteroalkyl, halogen, -C(O)R', -COOR', -C(O)NH2, -C(O)NR'R", -CF3, -CN, -SO3H, -SO2CF3, -SO2R', -SO2NR'R", -N(R')2, -N(R')3 + , -NO2, -OR', -NHC(O)R', -OC(O)R' or phenyl; R' and R" are each independently H or C1-C6 alkyl; or optionally, R' and R" in -SO2NR'R" can form together with the nitrogen atom to which they are attached a 5- or 6-membered heterocyclic ring, wherein the heterocyclic ring optionally contains one additional heteroatom selected from S, O or N; R d and R e Each is H, C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy or C6-C 10 aryloxy; R 2 and R 15 Each independently is H or C1-C6 alkyl; R 9 and R 10 are independently H, C1-C6 alkyl or -NHC(O)C(CH3)CH2; L 1 and L 3 is independently a bond or a linker group selected from: C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C2-C 20 heteroalkylene; L 2 yes 、 、 or phenylene substituted by at least one substituent selected from C1-C3 alkyl, C1-C3 alkoxy or halogen; R 20 、R 21 、R 23 and R 24 are each independently H, C1-C6 alkyl or optionally substituted by -B(OR 2 )2 substituted benzyl; R 22 、R 25 、R 26 and R 27 Each independently is H or C1-C6 alkyl; Alternatively, (R 21 and R 20 ) and / or (R 23 and R 24 ) together with the nitrogen atom to which they are attached, form a 6-, 5- or 4-membered saturated or partially saturated ring; Alternatively, (R 21 and R 22 )、(R 24 and R 25 )、(R 23 and R 27 ) and / or (R 26 and R 20 ) together with the atoms to which they are attached form a 6- or 5-membered saturated, unsaturated or partially saturated ring, wherein the C2-C 10 Heteroalkyl and C2-C 20 The heteroalkyl group in heteroalkylene refers to the corresponding alkyl group in which one or more chain carbon atoms have been replaced by a heteroatom selected from N, O, S and P.

8. The compound of claim 7, wherein L 1 and L 3 is independently a linker group selected from: -(CH2CH2O) n CH2-, -CH2(CH2CH2O) n -, -(CH2CH2O)nCH2CH2-, -CH2CH2(CH2CH2O) n -, (CH2CH2O) n -, where n is an integer between 1 and 5.

9. The compound of claim 1, wherein L 2 It is a phenylene group substituted by halogen, C1-C3 alkyl or C1-C3 alkoxy.

10. The compound of claim 1, wherein L 2 yes 、 or .

11. The compound of claim 1, wherein L 2 Selected from 、 、 、 、 、 、 、 or .

12. The compound of claim 1, wherein R d and R e Each is a methyl group.

13. The compound of claim 1, wherein R 10 It is -NHC(O)C(CH3)CH2.

14. The compound of claim 1, wherein R 9 It is -NHC(O)C(CH3)CH2.

15. The compound of claim 1, wherein L 1 It is C1-C 10 Alkylene or C2-C 20 Heteroalkylene.

16. The compound of claim 2, wherein L 1 is -(CH2CH2O) n CH2-, -(CH2CH2O) n CH2CH2- or -(CH2CH2O) n -.

17. The compound of claim 1, wherein L 3 It is C1-C 10 Alkylene or C2-C 20 Heteroalkylene.

18. The compound of claim 2, wherein L 3 is -CH2(CH2CH2O) n -、-CH2CH2-(CH2CH2O) n 、-(CH2CH2O) n CH2-, -(CH2CH2O) n CH2CH2- or -(CH2CH2O) n -.

19. The compound of claim 1, wherein L 1 and L 3 It is –CH2-CH2-CH2- or -(CH2CH2O)4CH2CH2-.

20. The compound of claim 1, wherein R 11 、R 14 and R 12 It’s H.

21. The compound of claim 1, wherein R 22 、R 25 、R 26 and R 27 It’s H.

22. The compound of claim 1, wherein R 1 、R 5 and R 6 It’s H.

23. The compound of claim 1, wherein R 3 、R 4 、R 7 and R 8 At least one of them is selected from C1-C3 alkyl, -CF3, C1-C3 alkoxy, halogen, -SO2NR'R", -CN or -NO2.

24. The compound of claim 1, wherein R 3 、R 4 、R 7 and R 8 At least one of them is selected from methyl, -CF3, methoxy, halogen, -SO2N(Me)2, -SO2NHMe, -CN, -NO2 or .

25. The compound of claim 1, wherein R 2 and R 15 Each is H.

26. The compound of claim 1, wherein R 20 、R 21 、R 23 and R 24 are each independently H, C1-C4 alkyl or optionally substituted by -B(OR 2 )2 substituted benzyl; or alternatively, (R 21 and R 22 )、(R 24 and R 25 )、(R 23 and R 27 ) and / or (R 26 and R 20 ) together with the atoms to which they are attached form a 6- or 5-membered saturated, unsaturated or partially saturated ring.

27. The compound of claim 1, wherein R 20 、R 21 、R 23 and R 24 are each independently H, C1-C6 alkyl or optionally substituted by -B(OR 2 )2-substituted benzyl.

28. The compound of claim 1, selected from ； ； ； ； or ;or its tautomers or salts.

29. The compound of claim 1, selected from ； ； ； ； or .

30. The compound of claim 1, selected from ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ; ;or ;or its tautomers or salts.

31. The compound of claim 1, selected from ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ; ;or 。 32. The compound of claim 1, selected from 、 、 、 、 、 or a salt thereof.

33. A composition comprising any one of the compounds of claims 1-32.

34. A sensor for detecting an analyte comprising a polymer, wherein the polymer comprises one or more residues of a compound according to any one of claims 1-32.

35. The sensor of claim 34, wherein the polymer is a hydrogel.

36. A sensor as claimed in claim 34 or claim 35, wherein the compound has excitation and emission wavelengths in the NIR optical window of mammalian skin.

37. The sensor of claim 34, wherein the compound has an absorption maximum between 500 nm and 900 nm and an emission maximum between 600 nm or 1000 nm.

38. The sensor of claim 34, wherein the residue of the compound is present at a concentration of 0.01 mM to 20 mM.

39. The sensor of claim 38, wherein the residue of the compound is present at a concentration of 1 mM, 5 mM, 10 mM, or 20 mM.

40. The sensor of claim 34, wherein the polymer further comprises residues of hydroxyethyl methacrylate (HEMA), N,N-dimethylacrylamide, or polyethylene glycol diacrylamide.

41. The sensor of claim 34, wherein the polymer further comprises residues of [2-(acryloyloxy)ethyl]trimethylammonium chloride, 2-carboxyethyl acrylate, or polyethylene glycol diacrylamide.

42. The sensor of claim 34, wherein the polymer further comprises residues of N,N-dimethylacrylamide, acrylamide, or polyethylene glycol diacrylamide.

43. The sensor of claim 34, wherein the analyte is glucose.

44. The sensor of claim 34, wherein the sensor produces a detectable luminescent signal when placed under the skin of a mammalian subject.

45. The sensor of claim 44, wherein the sensor produces a detectable luminescent signal when placed under the skin of a mammalian subject at a depth of up to 5 mm.

46. The sensor of claim 44, wherein the sensor generates a detectable luminescent signal when placed under the skin of a mammalian subject at a depth greater than 1 mm.

47. The sensor of claim 44, wherein the mammalian subject is a human.

48. The sensor of claim 44, wherein the sensor is stable in mammalian tissue for greater than 1 week.

49. The sensor of claim 44, wherein the sensor is stable in mammalian tissue for longer than one month.

50. The sensor of claim 44, wherein the sensor is stable in mammalian tissue for greater than 1 year.

51. The sensor of claim 44, wherein the sensor is tissue-integrated, wherein the term tissue-integrated means that the material, when integrated into living tissue, remains in close proximity to blood vessels of the tissue.

52. The sensor of claim 34, further comprising catalase.

53. Use of a compound according to any one of claims 1 to 32 or a composition according to claim 33 in the preparation of a sensor for measuring blood glucose concentration in a mammalian subject.

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