Carbohydrate ligands and uses thereof

Abstract

The disclosure provides n Renal Tubule Targeting Carbohydrate (RENTAC) ligand of Formula I, where Formula I is L-CM. L is one or more linker group(s) covalently bound to a Carbohydrate Molecule, CM. The CM can be acylated lactobionic acid such as a fully acetylated lactobionic acid. The RENTAC ligand can be conjugated to one or more molecules of a pharmaceutical agent (PA), such as a large or small molecule pharmaceutical agent, to form a RENTAC conjugate. RENTACs (ligands and conjugates) of this disclosure can be used to target a pharmaceutical agent to the megalin or cubilin receptors in the kidney or to any place in the body where megalin or cubilin receptors are present.

Description

CARBOHYDRATE LIGANDS AND USES THEREOF CROSS REFERENCE TO RELATED APPLICATION This application claims priority to U.S. Provisional Application No.63 / 592,867 filed October 24, 2023, which is hereby incorporated by reference in its entirety. FIELD OF THE DISCLOSURE

[0001] This application is directed to modified-carbohydrate ligands and small molecule- carbohydrate conjugates, their methods of manufacture, compositions including the ligands and / or conjugates, and their uses. The ligands and conjugates are especially useful for improved targeting of kidney cells. BACKGROUND

[0002] Organs such as the kidneys and livers are important organs involved in critical body functions including metabolism, detoxification, excretion, synthesis of proteins and lipids, secretion of cytokines and growth factors and immune / inflammatory responses. More than 1 in 7 of US adults, or about 37 million people, are estimated to have chronic kidney disease CKD. Renal fibrosis is the final manifestation of chronic kidney disease. Other kidney diseases include cancer, IgA nephropathy, membranous nephropathy, and acute kidney injury.

[0003] Many therapeutics are delivered to body tissues that they are not meant to effect, which can result in unintended or harmful side effects. There is accordingly a need for safe and efficient delivery of therapeutic molecules (for example genetic sequences and active agents such as drugs including small molecules, genes, or proteins) to their target sites in the body including the kidneys. There is an immediate need for novel agents and methods for safe and efficient organ targeted delivery of therapeutic molecules. SUMMARY

[0004] There is an unmet need to develop clinical interventions for chronic kidney disease (CKD). A common pathological phenotype for CKD is kidney fibrosis and is considered as the final manifestation of CKD. Currently, there are no effective drugs against CKD. Being an excretory organ with complex architecture, applying existing drugs is also limiting for kidney and kidney-associated diseases. There is an immediate requirement for practical strategies for kidney-specific delivery of therapeutic drugs. To circumvent this issue, we havedesigned RENTAC (Renal tubule targeting carbohydrate) ligands and conjugates. Without wishing to be bound to any particular theory it is believed that RENTACs of this disclosure target a factor present on the surface of kidney-associated cells for uptake in renal tubules, for example, megalin and cubilin receptors. The RENTACs showed retention up to 96 hrs. The RENTACs of this disclosure are useful for treating kidney diseases and diseases in which megalin and / or cubilin receptors are present. The RENTACs of this disclosure are useful for delivering payloads / cargos such as drugs where drug action is in kidneys, such as acute and chronic kidney diseases, including fibrosis and polycystic kidney diseases.

[0005] This disclosure provides a Renal Tubule Targeting Carbohydrate (RENTAC) ligand of Formula I, where L-CM (I) L is one or more linker group(s) covalently bound to a CM; and CM is a carbohydrate moiety comprising 1 to 16 carbohydrate residues derived from a monosaccharide, a disaccharide, a trisaccharide, or a tetrasaccharide; where at least one carbohydrate residue is a group an acylated lactobionic acid, an acylated galactose, or a acylated cellobionic acid of the formula Owhere Ac is H or an acyl group (-(C=O)alkyl) having 2 to 10 carbon atoms, provided that not all Ac are H.

[0006] The disclosure also provides a RENTAC conjugate comprising the RENTAC ligand covalently bound to one or more molecules of a pharmaceutical agent (PA) to form the RENTAC conjugate of Formula IV: (PA)x-L-CM (IV) where x is 1-10.

[0007] The disclosure provides pharmaceutical composition comprising a RENTAC of this disclosure, e.g. a compound of Formula I and / or a conjugated compound of Formula IV, together with an excipient or carrier. The disclosure provides methods of treating disordersassociated with megalin / cubulin receptors comprising administering a therapeutically effective amount of a compound comprising a RENTAC of this disclosure, e.g. a conjugated compound of Formula IV, to a patient in need of such treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIGURE 1: Schematic of chemical synthesis of RENTAC ligands and solution–phase conjugation with 5-carboxytetramethylrhodamine (TAMRA). Fig.1A Synthesis scheme of RENTAC ligand (1-7). Step one comprises the synthesis (1-4) of the backbone, and the second step (5-7) involves the functionalization of the backbone using acetylated lactobionic acid (LBAAc). Fig.1B. Schematic of (7-9) solution-phase RENTAC ligand conjugation with TAMRA. The purity and identity of the TAMRA-RENTAC conjugated compound (a RENTAC conjugate) were confirmed by HPLC and Matrix-assisted laser desorption / ionization time-of-flight mass spectrometry (MALDI-TOF-MS), respectively. Data not shown.

[0009] FIGURE 2: TAMRA-RENTAC showed targeted accumulation in proximal convoluted tubules (PCT) in the mice kidney following subcutaneous administration. Biodistribution of TAMRA-RENTAC in C57BL / 6J mice at 10 mg / kg (or specified) subcutaneous dose. Fig.2A. Ex vivo IVIS (in vivo imaging system) images of the harvested liver (Li), lungs (Lu), heart (H), kidney (K), and spleen (S) depicting TAMRA-RENTAC biodistribution at indicated time points (2 and 4h). N=3 mice for each time point. Fig.2B. Quantitative analysis of TAMRA-RENTAC organ distribution at 2 and 4h. Plotted are the TAMRA average radiant efficiency (ps−1 cm−2 sr−1) / (μW cm−2). Data are presented as the mean ± SEM. Fig.2C. Confocal microscopic image of TAMRA-RENTAC kidney distribution at 2h following 2 mg / kg dosage.10x zoom-in images depicting TAMRA- RENTAC distribution in red and nuclear stain Hoechst dye in blue (scale bar: 100 μm). Statistical significance analysis was performed on GraphPad Prism software using two-way ANOVA analysis. A p-value >0.05 was considered significant. Presented significance levels *p < 0.05, **p < 0.01, ***p < 0.001 versus indicated treatment groups.

[0010] FIGURE 3: TAMRA-RENTAC targeted proximal convoluted tubules (PCT) in folic acid-induced fibrosis mice model and showed enhanced accumulation with severe kidney fibrosis. Mice were injected with folic acid (250mg / kg) intraperitoneal for kidney fibrosis induction, and biodistribution of TAMRA-RENTAC (10 mg / kg, subcutaneous) was studied after 2 weeks. Biodistribution of TAMRA and TAMRA- RENTAC in moderate (Fig.3A) and severe fibrotic mice (Fig.3B). Depicted are ex vivo IVIS (in vivo imaging system) images of the harvested liver (Li), lungs (Lu), heart (H),kidney (K), and spleen (S) showing TAMRA and TAMRA- RENTAC biodistribution at indicated time points (2, 4, and 24h). N=3 mice for each time point. Fig.3C. Quantitative analysis of TAMRA-RENTAC organ distribution in severe fibrotic mice at 4 and 24h. Plotted are the TAMRA average radiant efficiency (ps−1 cm−2 sr−1) / (μW cm−2). Data are presented as the mean ± SEM. Fig.3D. Comparison of kidney accumulation of TAMRA-RENTAC in normal, moderate fibrotic, and severe fibrotic mice at 4h. N=3 mice for each time point, and data presented as the mean ± SEM. Fig.3E. Kidney cell uptake of TAMRA-RENTAC in moderate fibrotic mice. Following in vivo treatment, PFA (paraformaldehyde)-fixed kidney cells were analyzed for TAMRA fluorescence by flow cytometry. Each circle in contour plots represents the 5% events, and the adjunct graphs are histogram plots of kidney cell uptake. Statistical significance analysis was performed on GraphPad Prism software using one-way ANOVA analysis. A p-value >0.05 was considered significant. Presented significance levels *p < 0.05, **p < 0.01, ***p < 0.001 versus indicated treatment groups.

[0011] FIGURE 4: Kidney distribution of TAMRA-RENTAC in folic acid-induced fibrosis mice model. Mice were injected with folic acid (250mg / kg) intraperitoneal for fibrosis induction in kidneys, and biodistribution of TAMRA-RENTAC (10 mg / kg, subcutaneous) was studied after 2 weeks. Fig.4A. Schematic illustration of biodistribution study in mice. Fig.4B. Mice organs were imaged for TAMRA fluorescence on IVIS (in vivo imaging system) imager for biodistribution studies. Depicted is the kidney / liver relative distribution of TAMRA-RENTAC at indicated time points (2 and 4h). Data are presented as the mean ± SEM and n=3 mice for each time point. Fig.4C. Depicted are ex vivo IVIS images of the harvested kidneys of normal and fibrotic mice representing kidney accumulation at 4h. N=3 mice for each time point. Fig.4D. Kidney cell uptake of TAMRA and TAMRA-RENTAC in severe fibrotic mice at indicated time points. PFA(paraformaldehyde)-fixed kidney cells (in vivo treated) were analyzed for TAMRA fluorescence by flow cytometry. Each circle in contour plots represents the 5% events, and the adjunct graphs are histogram plots of cellular uptake. DETAILED DESCRIPTION Chemical Description

[0012] Disclosed herein are agents such as a modified-carbohydrate ligand and small molecule-carbohydrate conjugates, compositions, and methods for targeted delivery of the conjugates to specific organs in a subject such as mammals, in particular humans, and more in particular the kidneys of a subject such as a human.

[0013] In an aspect, disclosed is a modified-carbohydrate ligand, also called as RENTAC (Renal tubule targeting carbohydrate) ligand, that can deliver diverse classes of drugs to the kidney.

[0014] In an aspect, disclosed is a small molecule-carbohydrate conjugate (also classed as a RENTAC conjugate), that can deliver diverse classes of small molecules (drugs) to the kidney.

[0015] In another aspect, disclosed is a composition including a modified-carbohydrate ligand and / or small molecule-carbohydrate conjugates for targeted delivery of the conjugates to specific organs in a subject such as mammals, in particular humans, and more in particular the kidneys of a subject such as a human.

[0016] In an aspect, disclosed is a modified-carbohydrate ligand (RENTAC ligand) of following formula: wherein CM is a carbohydrate carbohydrate residues derived froma monosaccharide, a disaccharide, a trisaccharide, or a tetrasaccharide, preferably wherein CM comprises a carbohydrate residue derived from a monosaccharide or a disaccharide, optionally wherein the carbohydrate moiety is fully or partially acylated on a hydroxy or amino group thereof with a C2to C15acyl group, preferably wherein the carbohydrate moiety is fully or partially acetylated on a hydroxy or amino group thereof; and L is a linker or backbone.

[0017] In an aspect, disclosed is a modified-carbohydrate ligand (RENTAC ligand), having a formula A: O wherein X1and X4or -CR1R2R3; X2and X3are each independently a bond, NR1, O, S, C=O, or CR1R2; G1, G2, G3, and G4are each independently a bond, or a functional group such as NR1, O, S, C=O, or CR1R2; R1, R2, and R3are each independently H, a substituted alkyl, unsubstituted alkyl, such as C1 to C10 alkyl, or CM; CM is a carbohydrate moiety comprising 1 to 16 carbohydrate residues derived from a monosaccharide, a disaccharide, a trisaccharide, or a tetrasaccharide, preferablywherein CM comprises a carbohydrate residue derived from a monosaccharide or a disaccharide, optionally wherein the carbohydrate moiety is fully or partially acylated on a hydroxy or amino group thereof with a C2to C15acyl group, preferably wherein the carbohydrate moiety is fully or partially acetylated on a hydroxy or amino group thereof; n1, n2, n3, and n2are each independently an integer between 0 to 20; wherein at least one from X1, X2, X3, and X4includes R1, R2, or R3with at least one CM.

[0018] In an aspect, disclosed is a modified-carbohydrate ligand (RENTAC ligand) is disclosed, having a formula A-1: 1) wherein R4and R5are C1 to C10 alkyl,X1and X4are each independently -NR1R2, -OR1, C=O, or -CR1R2R3; X2is a bond, O, NR1, or CR1R2; where R1, R2, and R3are each independently H, a substituted or unsubstituted C1 to C6alkyl, such as C1to C10alkyl, or CM; CM is a carbohydrate moiety comprising 1 to 16 carbohydrate residues derived from a monosaccharide, a disaccharide, a trisaccharide, or a tetrasaccharide, preferably wherein CL comprises a carbohydrate residue derived from a monosaccharide or a disaccharide, optionally wherein the carbohydrate ligand is fully or partially acylated on a hydroxy or amino group thereof with a C2to C15acyl group, preferably wherein the carbohydrate ligand is fully or partially acetylated on a hydroxy or amino group thereof; n1is 1 to 20; and n2is 0 to 20; wherein at least one from X1, X2, and X4includes R1, R2, or R3with at least one CM.

[0019] In an aspect the RENTAC ligands bear 1 to 8, or 1 to 5, or 2 to 5, or 2 to 4 carbohydrate moieties (residues). The number and type of carbohydrate moieties are selected to target the kidneys. For example, the carbohydrate ligand can be selected to target the Asialglycoprotein receptor (ASPGR) expressed on cells. ASGPR is a C-type lectin, primary expressed on the sinusoidal surface of hepatocytes. In an aspect the ligands bear 1 to 8, or 1 to 5, or 2 to 5, or 2 to 4 galactose residues to target the ASPGR on kidney cells. In an aspect the ligands bear 1 to 8, or 1 to 5, or 2 to 5, or 2 to 4 galactose amine (GalNAc) residues to target the ASPGR on kidney cells. In another aspect the ligands bear 1 to 8, or 1 to 5, or 2 to 5, or 2 to 4, or 2 to 3 lactobionic acid residues to target the ASPGR on kidney cells.

[0020] The carbohydrate moiety / moieties of the ligand can be fully or partially acylated on a hydroxy or amino group thereof with a C2 to C15 acyl group. For example, the carbohydrate moiety can be fully or partially acetylated on a hydroxy or amino group. The acetylation of a carbohydrate moeity can be performed using an acetylating reagent such as acetic anhydride, acetyl chloride, mixed anhydrides, acids with coupling agents such as DCC or like reagents and a base such as triethyl amine, pyridine, DIEA, DMAP or the like, or an organic, inorganic, or polymeric base as used in the art. In an aspect, the carbohydrate ligand is a GalNAc residue that is fully or partially acylated, preferably acetylated, preferably fully acetylated. Alternatively, the carbohydrate moiety is a lactobionic acid residue that is fully or partially acylated, preferably acetylated, preferably fully acetylated.

[0021] In an embodiment, the RENTAC ligand is:.

[0023] In an embodiment, the RENTAC ligand is:.

[0024] In an e rtially acetylated. In an embodiment, the acetyl can be any alkyne up to C6 / C8.

[0025] In an aspect, disclosed is a small molecule-carbohydrate conjugate (RENTAC conjugate) is disclosed, having a formula B: L wherein CM is a carbohydrateis a linker or a bond or a backbone as disclosed herein, and SM is a small molecule.

[0026] In an aspect, disclosed is a small molecule-carbohydrate conjugate (RENTAC conjugate) is disclosed, having a formula C: O wherein SM is a - COOR1, or -or CR1R2; G1, G2, G3, and G4are each independently a bond, or a functional group such as NR1, O, S, C=O, or CR1R2; R1, R2, and R3are each independently H, a substituted alkyl, unsubstituted alkyl, such as C1 to C10 alkyl, or CM; CM is a carbohydrate moiety comprising 1 to 16 carbohydrate residues derived from a monosaccharide, a disaccharide, a trisaccharide, or a tetrasaccharide, preferably wherein CM comprises a carbohydrate residue derived from a monosaccharide or a disaccharide, optionally wherein the carbohydrate moiety is fully orpartially acylated on a hydroxy or amino group thereof with a C2to C15acyl group, preferably wherein the carbohydrate moiety is fully or partially acetylated on a hydroxy or amino group thereof; n1, n2, n3, and n2are each independently an integer between 0 to 20; wherein at least one from X1, X2, X3, and X4includes R1, R2, or R3with at least one CM..

[0027] In an aspect, disclosed is a small molecule-carbohydrate conjugate (RENTAC conjugate) is disclosed, having a formula C-a or C-b: a) b) wherein SM is a are eachindependently H or a substituted or unsubstituted C1 to C10 alkyl, X1and X4are each independently a bond, NR1, O, S, -NR1R2, -OR1, C=O, or -CR1R2R3; X2is O, NR1, or CR1R2; where R1, R2, and R3are each independently H, a substituted or unsubstituted C1 to C6 alkyl, such as C1to C10alkyl, or CM; CM is a carbohydrate moiety comprising 1 to 16 carbohydrate residues derived from a monosaccharide, a disaccharide, a trisaccharide, or a tetrasaccharide, preferably wherein CL comprises a carbohydrate residue derived from a monosaccharide or a disaccharide, optionally wherein the carbohydrate ligand is fully or partially acylated on a hydroxy or amino group thereof with a C2to C15acyl group, preferably wherein the carbohydrate ligand is fully or partially acetylated on a hydroxy or amino group thereof; n1 is 1 to 20; and n2is 0 to 20; wherein at least one from X1, X2, and X4includes R1, R2, or R3with at least one CM.

[0028] In an aspect the conjugates (RENTAC conjugates) bear 1 to 8, or 1 to 5, or 2 to 5, or 2 to 4 carbohydrate moieties (residues). The number and type of carbohydrate moieties are selected to target the kidneys. For example, the carbohydrate ligand can be selected to target the Asialglycoprotein receptor (ASPGR) expressed on cells. ASGPR is a C-type lectin, primary expressed on the sinusoidal surface of hepatocytes. In an aspect the conjugates bear 1 to 8, or 1 to 5, or 2 to 5, or 2 to 4 galactose residues to target the ASPGR on kidney cells. In an aspect the conjugates bear 1 to 8, or 1 to 5, or 2 to 5, or 2 to 4 galactose amine (GalNAc)residues to target the ASPGR on kidney cells. In another aspect the conjugates bear 1 to 8, or 1 to 5, or 2 to 5, or 2 to 4, or 2 to 3 lactobionic acid residues to target the ASPGR on kidney cells.

[0029] The carbohydrate ligand(s) of the conjugate can be fully or partially acylated on a hydroxy or amino group thereof with a C2 to C15 acyl group. For example, the carbohydrate ligand can be fully or partially acetylated on a hydroxy or amino group. The acetylation of a carbohydrate ligand can be performed using an acetylating reagent such as acetic anhydride, acetyl chloride, mixed anhydrides, acids with coupling agents such as DCC or like reagents and a base such as triethyl amine, pyridine, DIEA, DMAP or the like, or an organic, inorganic, or polymeric base as used in the art. In an aspect, the carbohydrate ligand is a GalNAc residue that is fully or partially acylated, preferably acetylated, preferably fully acetylated. Alternatively, the carbohydrate ligand is a lactobionic acid residue that is fully or partially acylated, preferably acetylated, preferably fully acetylated.

[0030] The carbohydrate ligands can be covalently attached to the small molecule by an optional backbone linker as shown in Formula B, C, C-a, and C-b. A variety of linkers can be used, but in general contain at least two functional groups, for example at least two amino groups, one or more for reaction with the carbohydrate ligand(s) and one or more for reaction with the small molecule. The amino groups can be selectively protected as known in the art and as described in the Examples. The liker or backbone can include moieties to modify properties such as solubility. For example, lysine and arginine residues can be present in a backbone.

[0031] In an aspect as shown in Formula C, C-a, and C-b, a group G1, G2,G3, or G4can be optionally present. G1can be a moiety to connect the linker / backbone to the small molecule, for example a moiety having 1 to 20 carbon atoms, and optionally one or more reactive groups such as hydroxy, carboxy, thio, or amino. In another aspect, G1, G2,G3, or G4can be a functional moiety. The functional moiety G1, G2,G3, or G4can provide a structural feature to the conjugates that can impart a desired function such as stearic separation from a binding ligand, enhancing hydrophilicity or hydrophobicity, facilitating absorption, of the conjugates, facilitating distribution of the conjugate in the body, or other functions advantageous in medicinal chemistry and drug design. The functional moiety can be linked between the linker / backbone and the small molecule. In an aspect, a functional moiety G1, G2, G3, or G4is, for example, a residue of a polyethylene glycol, a polypropylene glycol, or a polyethylene- propylene glycol. In an aspect, G1or G2, or both can be polyethylene glycol (PEG) group. The PEG group can contain 1 to 25 ethylene glycol residues (-OCH2CH2O-) that canterminate in a free hydroxy, amino, ether, or like functional moiety. The which is optionally bonded to a carbohydrate moiety, a linker / backbone or structure of a conjugate.

[0032] The disclosure provides a Renal Tubule Targeting Carbohydrate (RENTAC) ligand of Formula I: L-CM (I)

[0033] Within Formula I the following conditions are met.

[0034] L is one or more linker group(s) covalently bound to a CM.

[0035] CM is a carbohydrate moiety comprising 1 to 16 carbohydrate residues derived from a monosaccharide, a disaccharide, a trisaccharide, or a tetrasaccharide; where at least one carbohydrate residue is a group an acylated lactobionic acid, an acylated galactose, or a acylated cellobionic acid of the formula O OAcid where Ac is H or an acyl group (-(C=O)alkyl) having 2 to 10 carbon atoms, provided that not all Ac are H.

[0036] The disclosure also includes a RENTAC ligand wherein the CM is a carbohydrate moiety of Formula (I-A): A)

[0037] bond or a straight or branched C1-C16alkylene optionally containing one or more double or triple bonds in which one or more CH2 groups is replaced by NR1, S, or O where R1is H or C1-C4alkyl and which C1-C16 alkylene is optionally substituted by one or more groups independently chosen from halo, hydroxyl, oxo, and cyano.

[0038] G5is hydrogen or a straight or branched C1-C10alkyl optionally containing one or more double or triple bonds in which one or more CH2 groups is replaced by NR1, S, or O where R1is H or C1-C4alkyl and which C1-C10alkyl is optionally substituted by one or more groups independently chosen from halo, hydroxyl, oxo, and cyano.

[0039] X1, X2, X3and X4, are independently chosen at each occurrence from NR2, CR2R3, OR2, or SR2where R3is hydrogen or C1-C4 alkyl; and R2is

[0040] Or, X2is group of the formulaAcO

[0042] m2 is an integer chosen from 0 to 4.

[0043] n1 and n4 are integers independently chosen from 0 – 10; such that up to 4 X groups may be present at any position on the G group bearing the same number (up to 4 X1groups may be bound to G1, up to 4 X2groups may be bound to G2, up to 4 X3groups may be bound to G3, and up to 4 X4groups may be bound to G4).

[0044] In embodiments of this disclosure, one or more of the following conditions are met. Any of the following conditions may be combined so long as a stable compound results. (i) The Ac is an acetyl group (-(C=O)CH3) at all occurrences. (ii) Ac are non-hydrogen. ` (iii) CM comprises a Lactobionic acid group. (iv) CM is a carbohydrate moiety in which each X3and X4are NR1. (v) CM is a moiety in which each G5is hydrogen or acyl group (-(C=O)alkyl). (vi) G5is hydrogen or acetyl. (vii) m3 is 3, X3is NR2and G5is H at all occurrences.

[0045] The disclosure includes a RENTAC ligand in which CM is a carbohydrate moiety in which m1, m2, and n1 are all 0 and G2is a bond, i.e. a group of the Formula I-BB).

[0046] In some embo mula: .

[0047] In some embodiments, theof the formula I-C .in Formula I-C R3and R4are independently chosen at each occurrence from hydrogen, halogen, hydroxyl, amino, cyano, C1-C2alkyl, C1-C2alkoxy, mono- or di-C1-C2alkylamino, C1-C2haloalkyl, C1-C2haloalkoxy or R3and R4are taken together to form an oxo group. Alternatively, R3and R4are both hydrogen at all occurrences.

[0048] In some embodiments, the CM moiety is a group of the formula O H .

[0049] In some embodiments, the CM moiety is a group of the formula .

[0050] In someformula

[0051] In some embodiments, the CM moiety is a group of formula I-D .

[0052] In someformula I-E, where In Formula I-E, R3from hydrogen, halogen, hydroxyl, amino, cyano, C1-C2alkyl, C1-C2alkoxy, mono- or di-C1-C2alkylamino, C1-C2haloalkyl, C1-C2haloalkoxy or R3and R4are taken together to form an oxo group.

[0053] In some embodiments, the CM moiety is a group of the formulaO O H .

[0054] In.

[0055] In.

[0056] The RENTAC ligand’s of this disclosure can include a Linker. The Linker group, L, can comprises a straight or branched C1-C20alkylene optionally containing one or more double or triple bonds in which one or more CH2groups is replaced by NR6, CR7R8, S, or O,and which C1-C20alkylene is optionally substituted by one or more groups independently chosen from halo, hydroxyl, oxo, and cyano.

[0057] R6is H or C1-C4alkyl, R7and R8are joined to form a 3- to 7-membered cycloalkyl group or 3- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently chosen from N, O, and S; and which straight or branched C1-C20alkylene optionally comprises one or more 3- to 7- membered carbocylic rings and one or more 3- to 7-membered heterocyclic rings containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, which carbocyclic and heterocyclic rings are optionally substituted with halogen, hydroxyl, cyano, amino, C1-C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, and C1- C2haloalkoxy.

[0058] In some embodiments, the Linker group L is a straight or branched C1-C16alkylene optionally containing one or more double or triple bonds in which one or more CH2 groups is replaced by NR6, CR7R8, S, or O, and which C1-C16alkylene is optionally substituted by one or more groups independently chosen from halo, hydroxyl, oxo, and cyano and which has an amino group (NR6) at bound to the first and final carbon of the C1-C16alkylene.

[0059] In some embodiments the Linker group comprises a polyethylene glycol, a polypropylene glycol, or a polyethylene-propylene glycol of 2 to 12 repeating units.

[0060] In some embodiments the Linker group is one of the following groups: (i) where p is an integer from 0 to 20 and in which any CH2group is substituted with oxo or replaced by NR6, S, SO, or SO2. (ii) The Linker . (iii) Thegroupsgroups chosen from ester, amide, -CO-, -S-, -SO-, -SO2- NR6, and O. (iv) The Linker is a covalent bond between the Active Agent and Carbohydrate Moiety (CM).

[0061] The disclosure includes a RENTAC ligand, having any of the following structures:O H H2N N O N H , ,or

[0062] e scosue aso cu es a ga s as scose ere, covalently bound to one or more molecules of a Pharmaceutical Agent (PA) to provide a Pharmaceutical Agent / RENTAC ligand conjugate also called as RENTAC conjugate of Formula IV(PA)x-L-CM where x is 1-10 (Formula IV).

[0063] In an embodiment the Pharmaceutical Agent is 5-carboxytetramethylrhodamine (TAMRA) a fluorescent molecule if the formula:

[0064] An example of a conjugated to a RENTACligand is O H HNNO.be class I (high solubility, high permeability) pharmaceutical agent, a class I (Low solubility, high permeability) pharmaceutical agent, a class III (high solubility, low permeability) pharmaceutical agent, or a class IV (low solubility, low permeability) pharmaceutical agent. Pharmaceutical agents of these four classes have been set forth in M9 Biopharmaceutical classification system-based biowavers, Guidance for Industry, US Dept. of Health and Human Services, FDA, May 2021. The pharmaceutical agent (PA) can also be a drug useful for treating kidney disorders, such as kidney stones, polycystic kidney disease, kidney fibrosis. The pharmaceutical agent can be a large molecule (MW > 500 D) such as a recombinant protein or monoclonal antibody or a small molecule (MW < 500 K). For example, the pharmaceutical agent can be sunitinib, gemcitabine, cabozantinib, temsirolimus, interferon, avelumab, axitinib, belzutifan, bevacizumab, everolimus, ipilimumab, Lenvatinibmesylate, nivolumab, pazopanib HCl, or pembrolizumab, pirfenidone, lademirsen, nintedanib, PRM-151, epigallocatedchin gallate, ziritaxestat, pentoxifylline, berberine, betulinic acid, celastrol, curcumin, salidroside, polydatin, resveratrol, finerenone, empagliflozin, nedosiran, budesonide, difelikefalin, or any combinations thereof. Pharmaceutical agent are bound to the Linker (L) at any point available for chemical reaction with the liker. Conjugation can be via a single covalent bond, an O atom, a NH, ester, or carboxamide linker. Methods of Treatment

[0066] In an embodiment, the RENTAC conjugate can deliver diverse classes of drugs / small molecules to the kidney. In an embodiment, the small molecule can include any suitable therapeutic agent. For example, TAMRA, kielin, tolvaptan, nintedanib, paclitaxel, bleomycin, cyclosporin, cisplatin, romidepsin, doxorubicin, docetaxel, danunorubicin, vincristine, methotrexate, cyclophosphamide, venetoclax, hydroxyurea, mercaptopurine, prednisolone, cytarabine, pirfenidone, or any combination thereof. Other therapeutic agents can be found in the Merck Index published by the Royal Society of Chemistry published in print and online at https: / / www.rsc.org / merck-index.

[0067] In an embodiment, a modified-carbohydrate ligand RENTAC (Renal tubule targeting carbohydrate) can deliver diverse classes of drugs to the kidney. The RENTAC ligands consist of a linker and targeting moiety acetylated lactobioninc acid (LBAAc). The linker facilitates the conjugation of the ligand with the drugs / cargo molecule. In an embodiment, a small molecule, TAMRA (5-carboxytetramethylrhodamine) fluorescent molecule is conjugated with RENTAC ligand to afford a kidney-targeted delivery in C57BL / 6J mice. The RENTACs (ligands and / or conjugates) targeted a factor present on the surface of kidney-associated cells, for example, the megalin and cubilin receptors in the proximal convoluted tubules of the kidney. It showed prolonged high retention in normal and fibrosis mice models compared to unconjugated TAMRA. The RENTAC ligand has pharmaceutical applications for kidney-targeted delivery of small molecules, RNA medicine, and diagnostic applications.

[0068] Although different technologies have been tested for renal targeting, most of them are based on passive targeting. For nanotechnological applications low glomerular filtration cutoff is a significant hurdle for delivering the active ingredients to the kidney tubules. The RENTAC ligand-drug conjugates (RENTAC conjugates) disclosed herein will easily cross the glomerulus barrier and actively uptaken in renal tubules by receptor-mediated endocytosis. The ligand synthesis is straightforward, scalable, and adaptable for diverseclasses of drugs. Also, in recent years, there is a surge in the clinical application of receptor- targeted active delivery over nanotechnology applications for other organ-specific deliveries. Moreover, lactobionic acid has been reported as an excipient in various pharmaceutical formulations.

[0069] Based on our in vitro & in vivo assessments RENTACs disclosed herein actively targeted the megalin cubilin receptors in kidney tubular cells and showed kidney-specific distribution following systemic administration in healthy and fibrotic mice. No such carbohydrate / modified carbohydrate ligands have been reported previously for kidney tubule-specific delivery of small molecular drugs. Like other ligand-targeting moieties such as GalNAc, Lactobionic acid has shown robust safety profile without toxicities.

[0070] The disclosure includes methods of treating diseases and disorders in a patient comprising administering a therapeutically effective amount of a compound comprising a RENTAC of this disclosure, e.g. conjugated to a pharmaceutical agent via a linker such as a compound of Formula IV, to a patient in need thereof. The disease or disorder can be kidney cancer, kidney fibrosis, kidney stones, or polycystic kidney disease. EXAMPLES Example 1. Synthesis of acetylated lactobionic acid ligand for kidney-targeted delivery (RENTAC ligand)

[0071] Figure 1A shows a schematic of chemical synthesis of RENTAC ligands. The acetylated lactobionic acid, called RENTAC ( Renal tubule targeting carbohydrate), was synthesized with a terminal amino group (Figure 1A, compound 7). The amino group was introduced to facilitate the conjugation with cargo using solution phase synthesis. First, N- Boc-1,6-hexanediamine (1) and Fmoc-Lys(Fmoc)-OH (Figure 1A, compound 2) was conjugated through amide linkage followed by Fmoc deprotection using piperidine / DMF solution. This results in forming an N-Boc-1,6 diamino hexane-lysine linker (Figure 1A, compound 4). Lactobionic acid (Figure 1A, compound 5) was converted into lactone in situ by refluxing with methanol and a catalytical amount of trifluoracetic acid (TFA). Further, the lactone form in the presence of triethylamine reacted with N-Boc-1,6 diamino hexane-lysine (Figure 1A, compound 4), and the reaction mixture was acetylated and purified over silica. Finally, the Boc was deprotected from ligand intermediate (Figure 1A, compound 6) using TFA: DCM (40:60 v / v) mixture yielding the synthesis of RENTAC ligand (Figure 1A, compound 7). All the reaction intermediates were characterized comprehensively by ESI-MS,1H, and13C NMR analysis.Example 2. Solution phase conjugation of RENTAC ligand with TAMRA (5- carboxytetramethylrhodamine) (RENTAC conjugate)

[0072] Figure 1B shows solution–phase conjugation with 5-carboxytetramethylrhodamine (TAMRA). For preliminary investigation intended for in vivo biodistribution, RENTAC ligands was conjugated with TAMRA fluorescent dye. As depicted Figure 1B,conjugation was performed using a solution-phase amide bond formation between NH2 of RENTAC (7) ligands and the carboxylic group of the TAMRA dye (8). The TAMRA-RENTAC (9) conjugates were purified using RP-HPLC and characterized by Matrix-assisted laser desorption / ionization time- of-flight mass spectrometry (MALDI-TOF-MS) and analyzed for HPLC purity (Figures 1C and ID). Example 3. In vivo biodistribution of TAMRA- RENTAC (a RANTAC conjugate) after systemic delivery

[0073] To test the biodistribution of small molecules, TAMRA-RENTAC conjugates were tested in wild-type mice post-systemic delivery.10 mg / kg of TAMRA-RENTAC was injected subcutaneously in the mice and performed IVIS imaging to detect the fluorescent signal in various indicated organs (Figure 2A). TAMRA (10 mg / kg equiv. of TAMRA- RENTAC) was also administered only as a control. Inventors performed short-time course studies (2 and 4 hr), as, like most small molecules, TAMRA has a high elimination rate in vivo. As expected, any fluorescent signal was not detected in the mice treated with TAMRA after 4 hours post-administration (Figure 2A and B). It was noted significant fluorescence in the kidney in mice treated with TAMRA-RENTAC conjugates after 2 and 4 hours. Consistent with the prior observation, a fluorescence signal was noted only in the kidney and not in the other indicated organs.

[0074] The flow cytometry analysis was also performed on the total kidney cells and confirmed that TAMRA-RENTAC conjugate shows higher biodistribution (60-70% more) than the TAMRA alone (Figure 2C).

[0075] The results were confirmed by performing cryosection imaging on the kidneys at 2mg / kg dose. Following in vivo treatment, PFA (paraformaldehyde)-fixed kidney cells were analyzed for TAMRA fluorescence by flow cytometry. Depicted values are the percentage of the TAMRA-positive cell population. N=3 mice for each time point, and data presented as the mean ± SEM. (Data not shown).

[0076] The cell-specific staining was also performed in the kidneys and it was found that TAMRA-RENTAC conjugate targets significantly in the PCT. The results shown here indicated that the RENTAC ligand delivered small molecules exceptionally in the kidneys.Confocal immunofluorescence (2F) imaging was used to determine the localization of TAMRA-RENTAC in different kidney regions.60x zoom-in images at 24h in which red was used to depict the TAMRA-RENTAC distribution, green was used as nephron region-specific marker, and blue was used as a nuclear stain, were obtained. Nephron-specific IF antibodies that have a green signal were used as follows: aquaporin-2 (AQP2) in collecting duct, megalin (MEG) in proximal convoluted tubules (PCT), Chloride channel-K (CLC-K) in distill convoluted tubules (DCT) and collecting ducts, and Tamm-Horsfall protein (THP) in thick ascending limb (TAL) of the loop of Henle. Data not shown. Example 4. In vivo biodistribution of TAMRA- RENTAC in fibrotic mice after systemic delivery

[0077] Next, the targeting efficacy of TAMRA-RENTAC was evaluated in a kidney fibrosis mice model. C57BL / 6J mice were injected with folic acid (250 mg / kg) intraperitoneally to induce fibrosis in proximal tubules (Figure 4A). After two weeks, mice were injected with 10 mg / kg of TAMRA-RENTAC subcutaneously. Next, IVIS imaging was performed to detect the fluorescent signal in various indicated organs (Figure 3A and 3B).

[0078] Confocal immunofluorescence (IF) imaging was used to view the localization of TAMRA-RENTAC in different kidney regions of severe fibrotic mice.60x zoom-in images were obtained at 24h. Red color was used to depict the TAMRA-RENTAC distribution, green was used as the nephron region-specific marker, and blue as nuclear stain DAPI (Data not shown). Nephron-specific IF antibodies (green): aquaporin-2 (AQP2) in collecting duct, megalin (MEG) in proximal convoluted tubules (PCT), Chloride channel-K (CLC-K) in distill convoluted tubules (DCT) and collecting ducts, and Tamm-Horsfall protein (THP) in thick ascending limb (TAL) of the loop of Henle show localization of the TAMRA-RENTAC molecule to each of these regions. (Data not shown.) Statistical significance analysis was performed on GraphPad Prism software using one-way ANOVA analysis. A p-value >0.05 was considered significant. Presented significance levels *p < 0.05, **p < 0.01, ***p < 0.001 versus indicated treatment groups.

[0079] Biodistribution was studied in moderate and severe fibrotic mice, considering folic acid induces variable fibrosis in tubular epithelial cells in the rodents. Like normal mice, kidney-specific distribution of TAMRA-RENTAC (4 and 24h) was noticed in fibrotic mice (Figure 3A and 3B). Any significant change was not noticed in the fluorescent signal in the kidneys in the fibrotic mice over 4 to 24h (Figure 3C). An increase in kidney / liver ratio of fluorescence signal was noticed from 5.90 at 2h to 12.15 at 4h (Figure 4B). Interestingly, TAMRA-RENTAC showed 5 and 8-fold enhanced retention in the severe fibrotic micekidneys compared to mice with moderate fibrosis and in the normal mice, respectively (Figure 3D and Figure 4C). Inventors further confirmed increased retention of RENTAC conjugates in the mice with severe fibrosis via flow cytometry analysis of kidney cells. Fluorescence-activated cell sorting (FACS) analysis of whole kidney cells showed enhanced cellular distribution of TAMRA-RENTAC (70-80%) compared to TAMRA (2%) both at 4 and 24h (Figure 3E and Figure 4D). The cell-specific staining was performed in the fibrotic kidneys and confirmed that TAMRA-RENTAC conjugate targets significantly in the PCT (Figure 4F). Moreover, the distribution of TAMRA fluorescence was noticed in PCT, DCT, and collecting ducts in severe fibrotic mice. Our results here indicated that the RENTAC ligand has the potential to deliver the cargos significantly in the fibrotic kidneys with enhanced retention.

[0080] Embodiments disclosed here are not limiting of the subject matter and is merely exemplary. Various other components may be included and called upon for providing for aspects of the teachings herein. For example, additional materials, combinations of materials and / or omission of materials may be used to provide for added embodiments that are within the scope of the teachings herein. Other Embodiments

[0081] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims.

[0082] For reasons of completeness, various aspects of the disclosure are set out in the following numbered clauses:

[0083] Clause 1: An Renal Tubule Targeting Carbohydrate (RENTAC) ligand of the Formula I, where L-CM (I) L is one or more linker group(s) covalently bound to a CM; and CM is a carbohydrate moiety comprising 1 to 16 carbohydrate residues derived from a monosaccharide, a disaccharide, a trisaccharide, or a tetrasaccharide.

[0084] Clause 2: The RENTAC ligand of clause 1, wherein at least one carbohydrate residue is a group an acylated lactobionic acid, an acylated galactose, or a acylated cellobionic acid of the formulaO O AcOwhere or an group provided that not all Ac are H.

[0085] Clause 3: The RENTAC ligand of clause 1, wherein the CM is a carbohydrate moiety of Formula (I-A), where A)or branched C1-C16alkylene optionally containing one or more double or triple bonds in which one or more CH2 groups is replaced by NR1, S, or O where R1is H or C1-C4alkyl and which C1-C16 alkylene is optionally substituted by one or more groups independently chosen from halo, hydroxyl, oxo, and cyano; G5is hydrogen or a straight or branched C1-C10alkyl optionally containing one or more double or triple bonds in which one or more CH2 groups is replaced by NR1, S, or O where R1is H or C1-C4alkyl and which C1-C10alkyl is optionally substituted by one or more groups independently chosen from halo, hydroxyl, oxo, and cyano; X1, X2, X3and X4, are independently chosen at each occurrence from NR2, CR2R3, OR2, or SR2where R3is hydrogen or C1-C4 alkyl; and R2isAcO orX2is group of the formulam2 is an integer chosen from 0 to 4; and n1 and n4 are integers independently chosen from 0 – 10;such that up to 4 X groups may be present at any position on the G group bearing the same number (up to 4 X1groups may be bound to G1, up to 4 X2groups may be bound to G2, up to 4 X3groups may be bound to G3, and up to 4 X4groups may be bound to G4).

[0086] Clause 4: The RENTAC ligand of clause 1, 2, or 3, wherein Ac is an acetyl group (- (C=O)CH3) at all occurrences.

[0087] Clause 5: The RENTAC ligand of any one of clauses 1-4, where all Ac are non- hydrogen.

[0088] Clause 6: The RENTAC ligand of any one of clauses 1 to 5 wherein the CM comprises a Lactobionic acid group.

[0089] Clause 7: The RENTAC ligand of any one of clauses 3 to 6, wherein the CM is a carbohydrate moiety in which m1, m2, and n1 are all 0 and G2is a bond, i.e. a group of the Formula I-B . one of clauses 3 or 7, wherein the CM is acarbohydrate moiety in which each X3and X4are NR1

[0091] Clause 9: The RENTAC ligand of any one of clauses 3 to 8, wherein the CM is a moiety in which each G5is hydrogen or acyl group (-(C=O)alkyl).

[0092] Clause 10: The RENTAC ligand of clause 9, wherein each G5is hydrogen or acetyl.

[0093] Clause 11: The RENTAC ligand of clause 10 in which the CM moiety is a group of the formula .The RENTAC ligand of any one of clauses 3 to 6, in which the CM moiety is a group of the formula I-Cre R3and ach occurrence from hydrogen, halogen, hydroxyl, amino, cyano, C1-C2alkyl, C1-C2alkoxy, mono- or di-C1-C2alkylamino, C1-C2haloalkyl, C1- C2haloalkoxy or R3and R4are taken together to form an oxo group.

[0095] Clause 13: The RENTAC ligand of clause 12, in which R3and R4are both hydrogen at all occurrences.

[0096] Clause 14: The RENTAC ligand of clause 13, in which the CM moiety is a group of the formula O H N O .of clause 13, in which the CM moiety is a group of the formula

[0098] Clause 16: The RENTAC ligand of clause 13, in which the CM moiety is a group of the formula . ligand of any one of clauses 3 to 6, wherein m3 is 3, X3is NR2and G5is H at all occurrences.

[0100] Clause 18: The RENTAC ligand of any one of clauses 3 to 6, in which the CM moiety is a group of formula I-D . ligand of clauses 3 to 6, in which the CM moiety is agroup of formula I-E, whereoccurrence from hydrogen, halogen, hydroxyl, amino, cyano, C1-C2alkyl, C1-C2alkoxy, mono- or di-C1-C2alkylamino, C1-C2haloalkyl, C1- C2haloalkoxy or R3and R4are taken together to form an oxo group.

[0102] Clause 20: The RENTAC ligand of clause 19, in which the CM moiety is a group of the formulaO O H .the CM moiety is a group of the formula .the CM moiety is a group of the formula .1 to 22, wherein the Linker group, L, comprisesa straight or branched C1-C20alkylene optionally containing one or more double or triple bonds in which one or more CH2 groups is replaced by NR6, CR7R8, S, or O, and which C1-C20alkylene is optionally substituted by one or more groups independently chosen from halo, hydroxyl, oxo, and cyano; where R6is H or C1-C4alkyl where R7and R8are joined to form a 3- to 7-membered cycloalkyl group or 3- to 7- membered heterocycloalkyl group containing 1 or 2 heteroatoms independently chosen from N, O, and S; and which straight or branched C1-C20alkylene optionally comprises one or more 3- to 7- membered carbocylic rings and one or more 3- to 7-membered heterocyclic rings containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, which carbocyclic and heterocyclic rings are optionally substituted with halogen, hydroxyl, cyano, amino, C1- C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy.

[0106] Clause 24: The RENTAC of clause 23 wherein the Linker group L is a straight or branched C1-C16alkylene optionally containing one or more double or triple bonds in which one or more CH2 groups is replaced by NR6, CR7R8, S, or O, and which C1-C16 alkylene is optionally substituted by one or more groups independently chosen from halo, hydroxyl, oxo, and cyano and which has an amino group (NR6) at bound to the first and final carbon of the C1-C16alkylene.

[0107] Clause 25: The RENTAC of clause 23, wherein the Linker group comprises a polyethylene glycol, a polypropylene glycol, or a polyethylene-propylene glycol of 2 to 12 repeating units.

[0108] Clause 26: The RENTAC ligand of clause 23, wherein the Linker group is where p is an integer from 0 to 20 and in which any CH2 group is substituted with oxo or replaced by NR6, S, SO, or SO2.

[0109] Clause 27: The RENTAC ligand of clause 23, wherein the Linker group is .ligand of clause 23, wherein the Linker comprises 2 to 8 polyethylene groupswhere C1 and C2 are connector groups chosen from ester, amide, -CO-, -S-, -SO-, -SO2- NR6, and O.

[0111] Clause 29: The RENTAC ligand having the structure O H H2NNON. H2N NH ..

[0117] Clause 35: The RENTAC ligand of any of the preceding clauses, covalently bound to one or more molecules of a Pharmaceutical Agent (PA) to provide a Pharmaceutical Agent / RENTAC ligand conjugate, a RENTAC conjugate of Formula IV (PA)x-L-CM (IV) where x is 1-10.

[0118] Clause 36: An RENTAC conjugate of the Formula V, (PA)x-L-CM (IV) where, PA is a Pharmaceutical Agent providing a therapeutically active moiety; L is a bond or a linker; CM is a carbohydrate moiety comprising 1 to 16 carbohydrate residues derived from a monosaccharide, a disaccharide, a trisaccharide, or a tetrasaccharide; and x is 1-10.

[0119] Clause 37: The RENTAC conjugate of clause 36, wherein at least one carbohydrate residue comprises at least one acylated hydroxy group.

[0120] Clause 38: The RENTAC conjugate of clauses 36 or 37, wherein all carbohydrate residues comprise acylated hydroxy groups.

[0121] Clause 39: The RENTAC conjugate of clauses 36, 37, or 38, wherein at least one carbohydrate residue is a group an acylated lactobionic acid, an acylated galactose, or a acylated cellobionic acid of the formula Owhere Ac is H or an acyl group (-(C=O)alkyl) having 2 to 10 carbon atoms, provided that not all Ac are H.

[0122] Clause 40: The RENTAC conjugate of any one of clauses 35 to 39, wherein the PA is a large molecule (MW > 500 D) such as a recombinant protein or monoclonal antibody or a small molecule (MW < 500 K).

[0123] Clause 41: The RENTAC conjugate of any one of clauses 35 to 40, wherein the PA is class I (high solubility, high permeability) pharmaceutical agent, a class I (Low solubility, high permeability) pharmaceutical agent, a class III (high solubility, low permeability)pharmaceutical agent, a class IV (low solubility, low permeability) pharmaceutical agent, or any combinations thereof.

[0124] Clause 42: The RENTAC conjugate of any one of clauses 35 to 41, wherein the CM specifically binds to a kidney cell surface factor.

[0125] Clause 43: The RENTAC conjugate of any one of clauses 35 to 42, wherein the CM specifically binds to a kidney cell surface factor chosen from megalin or cubilin, and is directly or indirectly conjugated with PA.

[0126] Clause 44: The RENTAC conjugate of any one of clauses 35 to 43, wherein the CM and PA are indirectly conjugated by way of a linker.

[0127] Clause 45: The RENTAC conjugate of any one of clauses 35 to 44, wherein the CM and PA are directly conjugated by way of a bond.

[0128] Clause 46: The RENTAC conjugate of clause 42, wherein the kidney cell surface factor is internalized when bound by the CM.

[0129] Clause 47: The RENTAC conjugate of any one of clauses 35 to 46, wherein the PA is sunitinib, gemcitabine, cabozantinib, temsirolimus, interferon, avelumab, axitinib, belzutifan, bevacizumab, everolimus, ipilimumab, Lenvatinib mesylate, nivolumab, pazopanib HCl, or pembrolizumab, pirfenidone, lademirsen, nintedanib, PRM-151, epigallocatedchin gallate, ziritaxestat, pentoxifylline, berberine, betulinic acid, celastrol, curcumin, salidroside, polydatin, resveratrol, finerenone, empagliflozin, nedosiran, budesonide, difelikefalin, TAMRA, kielin, tolvaptan, nintedanib, paclitaxel, bleomycin, cyclosporin, cisplatin, romidepsin, doxorubicin, docetaxel, danunorubicin, vincristine, methotrexate, cyclophosphamide, venetoclax, hydroxyurea, mercaptopurine, prednisolone, cytarabine, pirfenidone, or any combinations thereof.

[0130] Clause 48: The RENTAC conjugate of any one of clauses 35 to 47, wherein the PA is 5-carboxytetramethylrhodamine (TAMRA) a fluorescent molecule if the formula:

[0131] Clause 49: The RENTAC conjugate of any one of clauses 35 to 48, wherein the RENTAC conjugate is O .Terminology

[0132] The following terms are used to describe the invention of the present disclosure. In instances where a term is not specifically defined herein, that term is given an art-recognized meaning by those of ordinary skill applying that term in context to its use in describing the present disclosure.

[0133] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For example, any nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization described herein are well known and commonly used in the art. In case of conflict, the present disclosure, including definitions, will control. Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the embodiments and aspects described herein.

[0134] Compounds and materials are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. The following terms are used to describe the invention of the present disclosure. In instances where a term is not specifically defined herein, that term is given an art-recognized meaning by those of ordinary skill applying that term in context to its use in describing the present disclosure.

[0135] The use of the terms “a” and “an” and “the” and similar referents (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. By way of example, "an element" means one element or more than one element.

[0136] As used herein, the term “substantially” means to a great or significant extent, but not completely.

[0137] It should also be understood that, in certain methods described herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited unless the context indicates otherwise. Furthermore, the terms first, second, etc., as used herein are not meant to denote any particular ordering, but simply for convenience to denote a plurality of, for example, layers.

[0138] The terms “comprising”, “having”, “including”, and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to”) unless otherwise noted. Wherever open-ended transitional terms are used, embodiments claimed using the intermediate “consisting essentially of" or closed-ended “consisting of” language are also included as alternatives.

[0139] The terms “about” or “approximately,” as used herein, is inclusive of the stated value and means within an acceptable range of deviation for the particular value as determined by one of ordinary skill in the art, considering the measurement in question and the error associated with measurement of the particular quantity (i.e., the limitations of the measurement system). For example, “about” can mean within one or more standard deviations, or within ± 10% or 5% of the stated value. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All ranges disclosed herein include both end points as discrete values as well as all integers and fractions specified within the range. For example, a range of 0.1-2.0 includes 0.1, 0.2, 0.3, 0.4...2.0. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention as used herein.

[0140] The phrase "and / or," as used herein in the specification and in the claims, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with "and / or" should be construed in the same fashion, i.e., "one or more" of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the "and / or" clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to "A and / or B", when used in conjunction with open-ended language such as "comprising" can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0141] As used herein in the specification and in the claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or "exactly one of," or, when used in the claims, "consisting of," will refer to the inclusion of exactly one element of a number or list of elements. In general, the term "or" as used herein shall only be interpreted as indicating exclusive alternatives (i.e., "one or the other but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of."

[0142] As used herein in the specification and in the claims, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified. Thus, as a nonlimiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently "at least one of A and / or B") can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one,optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0143] The phrase "one or more," as used herein, means at least one, and thus includes individual components as well as mixtures / combinations of the listed components in any combination.

[0144] Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients and / or reaction conditions are to be understood as being modified in all instances by the term "about," meaning within 10% of the indicated number (e.g., "about 10%" means 9%-11% and "about 2%" means 1.8%-2.2%).

[0145] All percentages and ratios are calculated by weight unless otherwise indicated. All percentages are calculated based on the total composition unless otherwise indicated. Generally, unless otherwise expressly stated herein, "weight" or "amount" as used herein with respect to the percent amount of an ingredient refers to the amount of the raw material comprising the ingredient, wherein the raw material may be described herein to comprise less than and up to 100% activity of the ingredient. Therefore, weight percent of an active in a composition is represented as the amount of raw material containing the active that is used and may or may not reflect the final percentage of the active, wherein the final percentage of the active is dependent on the weight percent of active in the raw material.

[0146] All ranges and amounts given herein are intended to include subranges and amounts using any disclosed point as an end point. Thus, a range of "1% to 10%, such as 2% to 8%, such as 3% to 5%," is intended to encompass ranges of "1% to 8%," "1% to 5%," "2% to 10%," and so on. All numbers, amounts, ranges, etc., are intended to be modified by the term "about," whether or not so expressly stated. Similarly, a range given of "about 1% to 10%" is intended to have the term "about" modifying both the 1% and the 10% endpoints. Further, it is understood that when an amount of a component is given, it is intended to signify the amount of the active material unless otherwise specifically stated.

[0147] As used herein, the term “administering” means the actual physical introduction of a composition into or onto (as appropriate) a subject, a host, or cell. Any and all methods of introducing the composition into the subject, host or cell are contemplated according to the invention; the method is not dependent on any particular means of introduction and is not to be so construed. Means of introduction are well-known to those skilled in the art, and also are exemplified herein. “Providing” means giving, administering, selling, distributing, transferring (for profit or not), manufacturing, compounding, or dispensing.

[0148] As used herein, “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0149] The term “subject” or “patient” is used herein to refer to an animal, such as a mammal, including a primate (such as a human, a non-human primate, e.g., a monkey, and a chimpanzee), a non-primate (such as a cow, a pig, a camel, a llama, a horse, a goat, a rabbit, a sheep, a hamster, a guinea pig, a cat, a dog, a rat, a mouse, and a whale), a bird (e.g., a duck or a goose), and a shark. In an embodiment, the subject or patient is a human subject or a human patient, such as a human being treated or assessed for a disease, disorder or condition, a human at risk for a disease, disorder or condition, a human having a disease, disorder or condition, and / or human being treated for a disease, disorder or condition as described herein. In one embodiment, the subject is about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years of age. In another embodiment, the subject is about 5-10, 10-15, 15-20, 20-25, 25-30, 30-35, 35-40, 40-45, 45- 50, 50-55, 55-60, 60-65, 65-70, 70-75, 75-80, 80-85, 85-90, 90-95, 95-100 years of age. Values and ranges intermediate to the above recited ranges are also intended to be part of this invention. In addition, ranges of values using a combination of any of the above-recited values as upper and / or lower limits are intended to be included. As used herein, a subject is “in need of treatment” if such subject would benefit biologically, medically, or in quality of life from such treatment. A subject in need of treatment does not necessarily present symptoms, particular in the case of preventative or prophylaxis treatments.

[0150] All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention as used herein. Unless defined otherwise, technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art of this disclosure.

[0151] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presentedas lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group.

[0152] All compounds are understood to include all possible isotopes of atoms occurring in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers and encompass heavy isotopes and radioactive isotopes. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include11C,13C, and14C. Accordingly, the compounds disclosed herein may include heavy or radioactive isotopes in the structure of the compounds or as substituents attached thereto. Examples of useful heavy or radioactive isotopes include18F,15N,18O,76Br,125I and131I.

[0153] A significant change is any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student’s t-test, where p < 0.05.

[0154] All statements herein reciting principles, aspects, and embodiments of the disclosure, as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents as well as equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure.

[0155] Various other components may be included and called upon for providing for aspects of the teachings herein. For example, additional materials, combinations of materials and / or omission of materials may be used to provide for added embodiments that are within the scope of the teachings herein. Adequacy of any particular element for practice of the teachings herein is to be judged from the perspective of a designer, manufacturer, seller, user, system operator or other similarly interested party, and such limitations are to be perceived according to the standards of the interested party.

[0156] In the disclosure hereof any element expressed as a means for performing a specified function is intended to encompass any way of performing that function including, for example, a) a combination of circuit elements and associated hardware which perform that function or b) software in any form, including, therefore, firmware, microcode or the like as set forth herein, combined with appropriate circuitry for executing that software to perform the function. Applicants thus regard any means which can provide those functionalities as equivalent to those shown herein. No functional language used in claims appended herein is to be construed as invoking 35 U.S.C. §112(f) interpretations as “means-plus-function” language unless specifically expressed as such by use of the words “means for” or “steps for” within the respective claim.

[0157] When introducing elements of the present invention or the embodiment(s) thereof, the articles “a,” “an,” and “the” are intended to mean that there are one or more of the elements. Similarly, the adjective “another,” when used to introduce an element, is intended to mean one or more elements. The terms “including” and “having” are intended to be inclusive such that there may be additional elements other than the listed elements. The term “exemplary” is not intended to be construed as a superlative example but merely one of many possible examples.

[0158] Certain compounds are described herein using a general formula that includes variables, e.g. AC, G, X, n, m, R1, R2, R3, R4, R5, R6, R7, and R8. Unless otherwise specified, each variable within such a formula is defined independently of other variables. Thus, if a group is said to be substituted, e.g. with 0-2 R*, then said group may be substituted with up to two R* groups and R* at each occurrence is selected independently from the definition of R*. When a group is substituted by an “oxo” substituent a carbonyl bond replaces two hydrogen atoms on a carbon. An “oxo” substituent on an aromatic group or heteroaromatic group destroys the aromatic character of that group, e.g. a pyridyl substituted with oxo is a pyridone.

[0159] Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation into an effective therapeutic agent.

[0160] The term “substituted” means that any one or more hydrogen atoms bound to the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded. When the substituent is oxo (i.e., =O), then 2 hydrogens on the atom are replaced. When aromatic moieties are substituted by an oxo group, the aromatic ring is replaced by the corresponding partially unsaturated ring. For example, a pyridyl group substituted by oxo is a pyridone. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation into an effective therapeutic agent. Unless otherwise specified substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent the point of attachment of this substituent to the core structure is in the alkyl portion.

[0161] Substituents are named into the ring unless otherwise indicated. A dash ("-") or a double bond (“=”) that is not between two letters or symbols indicates the point of attachment for a substituent. For example, -CONH2is attached through the carbon atom.

[0162] An “active agent” means a compound (including a compound disclosed herein), element, or mixture that when administered to a patient, alone or in combination with another compound,element, or mixture, confers, directly or indirectly, a physiological effect on the subject. The indirect physiological effect may occur via a metabolite or other indirect mechanism. The “active agent” may also potentiate, or make more active another active agent. For example, the compounds of Formula I potentiate the activity of other active agents when given in combination with another active agent, for example by lowering the effective dose of the other active agent.

[0163] “Alkyl” includes both branched and straight-chain saturated aliphatic hydrocarbon groups, having the specified number of carbon atoms. Thus, the term C1- C6alkyl includes alkyl groups having from 1 to about 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, and sec-pentyl. C1- C4alkyl includes alkyl groups having 1, 2, 3, or 4 carbon atoms.

[0164] “Alkylene” when used, refers to a –(CH2)n- group (n is an integer generally from 0- 6), which may be optionally substituted. When substituted, the alkylene group preferably is substituted on one or more of the methylene groups with a C1-C6 alkyl group (including a cyclopropyl group or a t-butyl group), but may also be substituted with one or more halo groups, preferably from 1 to 3 halo groups or one or two hydroxyl groups, O-(C1-C6 alkyl) groups or amino acid sidechains as otherwise disclosed herein.

[0165] “Alkoxy” is an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3- methylpentoxy. Similarly, an “alkylamino” or “mono-alkylamino” is an alkyl group as defined above with the indicated number of carbon atoms attached through an NH bridge and a di-alkylamino is two independently chosen alkyl groups, as described above, attached through a nitrogen bridge.

[0166] "Aryl" indicates aromatic groups containing only carbon in the aromatic ring or rings. Typical aryl groups contain 1 to 3 separate, fused, or pendant rings and from 6 to about 18 ring atoms, without heteroatoms as ring members. When indicated, such aryl groups may be further substituted with carbon or non-carbon atoms or groups. Aryl groups include, for example, phenyl, naphthyl, including 1- naphthyl, 2-naphthyl, and bi-phenyl.

[0167] A “carbocyclic group” is a monocyclic or bicyclic saturated, partially unsaturated, or aromatic ring system in which all ring atoms are carbon. Rings may be fused (e.g. naphthyl), pendant (e.g., biphenyl), bridged, or spiro. Bicyclic carbocyclic groups can be fused, pendant, spiro, or bridged. Usually, each ring of the carbocycle contains from 3-6 ring atoms and a bicyclic carbocycle contains from 6 to 10 ring atoms, but some other number of ring atoms may be specified. Unless otherwise indicated, the carbocycle may be attached tothe group it substitutes at any carbon atom that results in a stable structure. When indicated the carbocyclic rings described herein may be substituted at any carbon atom if the resulting compound is stable. Examples of carbocycles include phenyl, naphthyl, biphenyl, tetrahydronaphthyl, cyclopropyl, cyclohexyl, and cyclohexenyl.

[0168] “Cycloalkyl” is a saturated hydrocarbon ring groups, having the specified number of carbon atoms, usually from 3 to 7 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl as well as bridged or caged saturated ring groups such as norborane or adamantane. In the term “(cycloalkyl)alkyl,” cycloalkyl and alkyl are as defined above, and the point of attachment in on the alkyl group.

[0169] “Halo” or “halogen” as used herein includes fluoro, chloro, bromo, and iodo.

[0170] “Haloalkyl” includes both branched and straight-chain saturated aliphatic hydrocarbon groups, having the specified number of carbon atoms, substituted with 1 or more halogen atoms, generally up to the maximum allowable number of halogen atoms. Thus, the term C1- C6haloalkyl includes haloalkyl groups having from 1 to about 6 carbon atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2- fluoroethyl, chloromethyl, chloroethyl, and penta-fluoroethyl. C1-C2alkyl includes alkyl groups having 1or 2 carbon atoms, substituted with 1 or more halogen atoms, generally up to the maximum allowable number of halogen atoms.

[0171] “Haloalkoxy” is an haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of haloalkoxy include, but are not limited to, chloromethoxy, chloroethoxy, bromo-n-propoxy, bromo-i-propoxy, iodo-n- butoxy, iodo-2-butoxy, or chloro-n-pentoxy.

[0172] A “heterocyclic group” is a monocyclic saturated, partially unsaturated, or aromatic ring containing from 1 to 4 heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon, or a bicyclic saturated, partially unsaturated, or aromatic heterocycle containing at least 1 heteroatom chosen from N, O, and S in one of the two rings of the two ring system and containing up to about 4 heteroatoms independently chosen from N, O, and S in each ring of the two ring system. The rings of a bicyclic heterocyclic group can be in fused, bridged, pendant, or spiro orientation. Usually, each ring of the heterocycle contains from 4-6 ring atoms but some other number of ring atoms may be specified. Unless otherwise indicated, the heterocycle may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. When indicated the heterocycles described herein may be substituted on carbon, sulfur, or nitrogen atom if the resulting compound is stable. It is preferred that the total number of heteroatoms in a heterocycle is not more than 4 and that thetotal number of S and O atoms in a heterocycle is not more than 2, more preferably not more than 1. Examples of heterocycles include, pyridyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benz[b]thiophenyl, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, dihydroisoindolyl, 5,6,7,8-tetrahydroisoquinoline, pyrazolyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl. In certain embodiments a heterocycle is chosen from pyridinyl, pyrimidinyl, furanyl, thienyl, and pyrrolyl.

[0173] “Heteroaryl” is a stable monocyclic aromatic ring having the indicated number of ring atoms which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5- to 7-membered aromatic ring which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon. Monocyclic heteroaryl groups typically have from 5 to 7 ring atoms. In some embodiments bicyclic heteroaryl groups are 9- to 10-membered heteroaryl groups, that is, groups containing 9 or 10 ring atoms in which one 5- to 7-member aromatic ring is fused to a second aromatic or non-aromatic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heteroaryl group is not more than 2. It is particularly preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include, but are not limited to, oxazolyl, pyranyl, pyrazinyl, pyrazolyl, pyridizinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl, pyrazolyl, thiophenyl, triazolyl, benzo[d]oxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxadiazolyl, dihydrobenzodioxynyl, furanyl, imidazolyl, indolyl, and isoxazolyl.

[0174] “Heterocycloalkyl” is a stable monocyclic ring having the indicated number of ring atoms which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5- to 7-membered cyclic ring which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon. Monocyclic heterocycloalkyl groups typically have from 5 to 7 ring atoms. The stable monocyclic heterocycloalkyl may have 3-10 ring atoms which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon. In some embodiments bicyclic heterocycloalkyl groups are 9- to 10-membered heterocycloalkyl groups, that is, groups containing 9 or 10 ring atomsin which one 5- to 7-member cyclic ring is fused to a second aromatic or non-aromatic ring. It is preferred that the total number of S and O atoms in the heteroaryl group is not more than 2. Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl.

[0175] “Pharmaceutical compositions” are compositions comprising at least one active agent, such as a compound or salt of Formula I and at least one other excipient. “Carriers” are any inactive materials, including excipients and diluents, which may be added to the pharmaceutical compositions including carriers and diluents. Pharmaceutical compositions meet the U.S. FDA’s GMP (good manufacturing practice) standards for human or non-human drugs.

[0176] “Pharmaceutically acceptable salt” includes derivatives of the disclosed compounds wherein the parent compound is modified by making non-toxic acid or base salts thereof, and further refers to pharmaceutically acceptable hydrates or solvates of such compounds and such salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxylmaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)n-COOH where n is 0-4, and the like. Lists of additional suitable salts may be found, e.g., in G. Steffen Paulekuhn, et al., Journal of Medicinal Chemistry 2007, 50, 6665 and Handbook of Pharmaceutically Acceptable Salts: Properties, Selection and Use, P. Heinrich Stahl and Camille G. Wermuth Editors, Wiley- VCH, 2002.

[0177] The term “carrier” applied to pharmaceutical compositions / combinations of the invention refers to a diluent, excipient, or vehicle with which an active compound is provided. A “pharmaceutically acceptable carrier” means a substance, e.g., excipient, diluent, or vehicle, that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceuticallyacceptable carrier” includes both one and more than one such carrier.

[0178] While the invention has been described with reference to an exemplary embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims. Any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context. Other Embodiments

[0179] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

CLAIMS What is claimed is:

1. A Renal Tubule Targeting Carbohydrate (RENTAC) ligand of Formula I, where L-CM (I) L is one or more linker group(s) covalently bound to a CM; and CM is a carbohydrate moiety comprising 1 to 16 carbohydrate residues derived from a monosaccharide, a disaccharide, a trisaccharide, or a tetrasaccharide; where at least one carbohydrate residue is a group an acylated lactobionic acid, an acylated galactose, or a acylated cellobionic acid of the formula O Oan acyl group (-(C=O)alkyl) having 2 to 10 carbon atoms, provided that not all Ac are H.

2. The RENTAC ligand of claim 1, wherein the CM is a carbohydrate moiety of Formula (I-A), where A)or branched C1-C16alkylene optionally containing one or more double or triple bonds in which one or more CH2 groups is replaced by NR1, S, or O where R1is H or C1-C4alkyl and which C1-C16 alkylene is optionally substituted by one or more groups independently chosen from halo, hydroxyl, oxo, and cyano; G5is hydrogen or a straight or branched C1-C10alkyl optionally containing one or more double or triple bonds in which one or more CH2 groups is replaced by NR1, S, or Owhere R1is H or C1-C4alkyl and which C1-C10alkyl is optionally substituted by one or more groups independently chosen from halo, hydroxyl, oxo, and cyano; X1, X2, X3and X4, are independently chosen at each occurrence from NR2, CR2R3, OR2, or SR2where R3is hydrogen or C1-C4 alkyl; and R2is AcOor X2is group of the formulam1, m3, and m4 are each integers independently chosen from 1 to 4; m2 is an integer chosen from 0 to 4; and n1 and n4 are integers independently chosen from 0 – 10; such that up to 4 X groups may be present at any position on the G group bearing the same number (up to 4 X1groups may be bound to G1, up to 4 X2groups may be bound to G2, up to 4 X3groups may be bound to G3, and up to 4 X4groups may be bound to G4).

3. The RENTAC ligand of claim 1 or 2, wherein Ac is an acetyl group (- (C=O)CH3) at all occurrences.

4. The RENTAC ligand of claims 1, 2, or 3, where all Ac are non-hydrogen.

5. The RENTAC ligand of any one of claim 1 to 4 wherein the CM comprises a Lactobionic acid group.

6. The RENTAC ligand of any one of claims 2 to 5, wherein the CM is a carbohydrate moiety in which m1, m2, and n1 are all 0 and G2is a bond, i.e. a group of the Formula I-B .

7. The RENTAC ligand of any one of claim 2 or 6, wherein the CM is a carbohydrate moiety in which each X3and X4are NR1.

8. The RENTAC ligand of any one of claims 2 to 7, wherein the CM is a moiety in which each G5is hydrogen or acyl group (-(C=O)alkyl).

9. The RENTAC ligand of claim 8, wherein each G5is hydrogen or acetyl.

10. The RENTAC ligand of claim 9 in which the CM moiety is a group of the formula11. The RENTAC ligand of any one of claims 2 to 5, in which the CM moiety is a group of the formula I-C at each occurrence from hydrogen, halogen,C2alkoxy, mono- or di-C1-C2alkylamino, C1- C2haloalkyl, C1-C2haloalkoxy or R3and R4are taken together to form an oxo group.

12. The RENTAC ligand of claim 11, in which R3and R4are both hydrogen at all occurrences.

13. The RENTAC ligand of claim 12, in which the CM moiety is a group of the formula .

14. The RENTAC ligand of claim 12, in which the CM moiety is a group of the formula.

15. The RENTAC ligand of claim 12, in which the CM moiety is a group of the formula .

16. The RENTAC ligand of any one of claims 2 to 5, wherein m3 is 3, X3is NR2and G5is H at all occurrences.

17. The RENTAC ligand of any one of claims 2 to 5, in which the CM moiety is a group of formula I-D .

18. The RENTAC ligand of claims 2 to 5, in which the CM moiety is a group of formula I-E, where) at each occurrence from hydrogen, halogen, hydroxyl, amino, cyano, C1-C2alkyl, C1-C2alkoxy, mono- or di-C1-C2alkylamino, C1- C2haloalkyl, C1-C2haloalkoxy or R3and R4are taken together to form an oxo group.

19. The RENTAC ligand of claim 18, in which the CM moiety is a group of the formula O O .

20. The RENTAC of ligand claim 18, in which the CM moiety is a group of the formula .

21. The RENTAC of ligand claim 18, in which the CM moiety is a group of the formula .

22. The RENTAC ligand of any one of claims 1 to 21 wherein the Linker group, L, comprises a straight or branched C1-C20alkylene optionally containing one or more double or triple bonds in which one or more CH2 groups is replaced by NR6, CR7R8, S, or O, and which C1-C20alkylene is optionally substituted by one or more groups independently chosen from halo, hydroxyl, oxo, and cyano; where R6is H or C1-C4alkyl where R7and R8are joined to form a 3- to 7-membered cycloalkyl group or 3- to 7- membered heterocycloalkyl group containing 1 or 2 heteroatoms independently chosen from N, O, and S; and which straight or branched C1-C20alkylene optionally comprises one or more 3- to 7- membered carbocylic rings and one or more 3- to 7-membered heterocyclic rings containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, which carbocyclic and heterocyclic rings are optionally substituted with halogen, hydroxyl, cyano, amino, C1- C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy.

23. The RENTAC ligand of claim 22 wherein the Linker group L is a straight or branched C1-C16alkylene optionally containing one or more double or triple bonds in which one or more CH2 groups is replaced by NR6, CR7R8, S, or O, and which C1-C16 alkylene is optionally substituted by one or more groups independently chosen from halo, hydroxyl, oxo, and cyano and which has an amino group (NR6) at bound to the first and final carbon of the C1-C16alkylene.

24. The RENTAC of ligand claim 22, wherein the Linker group comprises a polyethylene glycol, a polypropylene glycol, or a polyethylene-propylene glycol of 2 to 12 repeating units.

25. The RENTAC of ligand claim 22, wherein the Linker group is where p is an integer from 0 to 20 and in which any CH2group is by NR6, S, SO, or SO2.of claim 22, wherein the Linker group is . of claim 22, wherein the Linker comprises 2 to 8polyethylene groupsgroups chosen from ester, amide, -CO-, -S-, -SO-, - SO2- NR6, and O.

28. The RENTAC ligand of claim 11, having the structure29. The RENTAC ligand of claim 11, having the structure.

30. The RENTAC ligand of claim 11, having the structure: O H H2N N .

31. The RENTAC ligand of claim 18, having the structure .

32. The RENTAC ligand of claim 18, having the structureH2N NH O O .is a group of the formula .

34. The RENTAC ligand of any of the preceding claims, covalently bound to one or more molecules of a Pharmaceutical Agent (PA) to provide a Pharmaceutical Agent / RENTAC ligand conjugate, a RENTAC conjugate of Formula IV (PA)x-L-CM (IV) where x is 1-10.

35. A RENTAC conjugate of Formula (V) (PA)x-L-CM (V), where PA is a Pharmaceutical Agent; L is a bond or a linker; CM is a carbohydrate moiety comprising 1 to 16 carbohydrate residues derived from a monosaccharide, a disaccharide, a trisaccharide, or a tetrasaccharide; and x is 1-10. wherein the least one carbohydrate residue comprises at least one acylated hydroxy group; andat least one carbohydrate residue is a group an acylated lactobionic acid, an acylated galactose, or a acylated cellobionic acid of the formula O O AcOor an group atoms, provided that not all Ac are H.

36. The RENTAC conjugate of claim 35, wherein all carbohydrate residues comprise acylated hydroxy groups.

37. The RENTAC conjugate of any one of clauses 34 to 36, wherein the PA is a large molecule (MW > 500 D) such as a recombinant protein or monoclonal antibody or a small molecule (MW < 500 K).

38. The RENTAC conjugate of any one of claims 34 to 36, wherein the PA is class I (high solubility, high permeability) pharmaceutical agent, a class I (Low solubility, high permeability) pharmaceutical agent, a class III (high solubility, low permeability) pharmaceutical agent, a class IV (low solubility, low permeability) pharmaceutical agent, or any combinations thereof.

39. The RENTAC conjugate of any one of claims 34 to 38, wherein the CM specifically binds to a kidney cell surface factor.

40. The RENTAC conjugate of any one of claims 34 to 39, wherein the CM specifically binds to a kidney cell surface factor chosen from megalin or cubilin, and is directly or indirectly conjugated with PA.

41. The RENTAC conjugate of any one of claims 34 to 39, wherein the RENTAC ligand specifically binds to a kidney cell surface factor chosen from megalin or cubilin, and is directly or indirectly conjugated with PA.

42. The RENTAC conjugate of any one of claims 34 to 39, wherein the CM and PA are indirectly conjugated by way of a linker.

43. The RENTAC conjugate of any one of clauses 34 to 39, wherein the CM and PA are directly conjugated by way of a bond.

44. The RENTAC conjugate of any one of claims 34 to 43, wherein the PA is sunitinib, gemcitabine, cabozantinib, temsirolimus, interferon, avelumab, axitinib, belzutifan, bevacizumab, everolimus, ipilimumab, Lenvatinib mesylate, nivolumab, pazopanib HCl, or pembrolizumab, pirfenidone, lademirsen, nintedanib, PRM-151, epigallocatedchin gallate, ziritaxestat, pentoxifylline, berberine, betulinic acid, celastrol, curcumin, salidroside, polydatin, resveratrol, finerenone, empagliflozin, nedosiran, budesonide, difelikefalin, TAMRA, kielin, tolvaptan, nintedanib, paclitaxel, bleomycin, cyclosporin, cisplatin, romidepsin, doxorubicin, docetaxel, danunorubicin, vincristine, methotrexate, cyclophosphamide, venetoclax, hydroxyurea, mercaptopurine, prednisolone, cytarabine, pirfenidone, or any combinations thereof.

45. The RENTAC conjugate of any one of claims 35 to 42, wherein the PA is 5-carboxytetramethylrhodamine (TAMRA) a fluorescent molecule if the formula:

46. The RENTAC conjugate of any one of claims 34 to 42, wherein the RENTAC conjugate is O H .

Images