Compounds containing one or more diboronates and related insulin analogs

Abstract

This disclosure relates to novel compounds comprising one or more aromatic boron-containing groups including diboronate, and to methods for producing the disclosed compounds. This disclosure further relates to pharmaceutical compositions comprising the disclosed compounds, and to their use in the prevention and treatment of diseases and disorders such as hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, metabolic syndrome X, or dyslipidemia, gestational diabetes, prediabetes, Alzheimer's disease, MODY 1, MODY 2, or MODY 3 diabetes, mood disorders, and mental disorders.

Description

[Technical Field]

[0001] This disclosure relates to novel compounds comprising one or more aromatic boron-containing groups, including diboronates. This disclosure relates to the use of novel compounds for binding to glucose. This disclosure further relates to the use of kits and compounds and / or pharmaceutical compositions comprising the disclosed compounds for the treatment of disorders characterized by elevated glucose levels, such as hyperglycemia, prediabetes and diabetes (e.g., type 1 diabetes, type 2 diabetes, gestational diabetes, MODY 1, MODY 2, or MODY 3 diabetes), impaired glucose tolerance, obesity, metabolic syndrome, dyslipidemia, neurological disorders, mood disorders, and psychiatric disorders.

[0002] Sequence List This application is filed together with an electronic sequence listing. The sequence listing is provided as a file titled "30583M_WO_SL.xml," created on April 10, 2024, and is 30,688,753 bytes in size. The electronic information of the sequence listing is incorporated herein by reference in its entirety. [Background technology]

[0003] Boronic acids are generally considered Lewis acids, and because they can form complexes with Lewis bases such as hydroxide anions, they are thought to have a tendency to bind to hydroxyls. Therefore, molecules containing boronic acid or boronic acid salts have a general tendency to bind to hydroxyl groups. This binding tendency can be used to detect hydroxyl-containing groups with boron-oxidized labeling reagents, where the boronic acid group binds to the hydroxyl, and depending on the solvent and buffer conditions, the boronic acid salt can form a hydrolyzable boronic acid ester bond to the hydroxyl group of a hydroxyl-containing molecule, such as the hydroxyl group present in a diol (e.g., glucose). While boron-containing compounds can bind to diol-containing molecules, achieving selectivity using boron-containing compounds has been difficult due to their ability to bind to various diols, including cis-diols, to varying degrees. Improved binding affinity of boron-containing compounds to a specific adjacent diol of interest may be achieved, but this may result in a loss of selectivity.

[0004] Glucose is the body's primary fuel, and blood glucose levels in healthy individuals are tightly controlled. For example, between meals, blood glucose levels are around 5 mmol / L (mM), and after a meal, when blood glucose levels rise, insulin quickly returns them to 5 mM. The hormone insulin is secreted from beta cells in the pancreas, and when insulin binds to insulin receptors in the body's cells (e.g., muscle and fat), the cells are stimulated to absorb glucose through translocation of glucose transporters (GLUT4) from storage vesicles to the cell surface (see, for example, Huang, SH et al. Cell Metabolism, 5:237-252 (2007)).

[0005] Diabetic patients may lose the ability to produce insulin due to autoimmunity against beta cells (Type 1), or they may have reduced insulin sensitivity in combination with impaired insulin secretion (Type 2). For example, individuals with Type 1 diabetes can control their glucose levels by relying on multiple daily insulin injections, typically once daily and with meals (bolus), for basic use (see, e.g., Polonsky, K. Set al. The Journal of Clinical Investigation 81:442-448 (1988)). Complete daily insulin administration is extremely difficult because glucose levels can fluctuate unpredictably. In fact, despite many technological advances in diabetes treatment, researchers are now observing a deterioration in long-term glucose control and / or overall metabolic health, partly due to lifestyle issues.

[0006] Glucose sensors and glucose-sensing insulin analogs are known in the art. See, for example, International Publication Nos. 2016 / 179568(A1) and 2021 / 202802(A1). However, there is a need in the art to develop glucose sensors and glucose-sensing insulins that have improved properties, such as binding to insulin receptors, respond proportionally to different glucose concentrations, and provide a stepwise and reversible response to changes in glucose levels under physiological conditions.

[0007] Therefore, there is an unmet medical need for novel compounds, such as those that can control blood glucose levels, bind to glucose, and can be used in glucose-responsive insulin analogs / conjugates.

[0008] According to certain embodiments, the inventors disclose glucose sensors and glucose-sensing insulin analogs having improved properties, such as an extended terminal half-life and / or reduced clearance, improved affinity for the insulin receptor, and / or improved activation of the insulin receptor. [Overview of the project] [Means for solving the problem]

[0009] In the first embodiment, a compound comprising one or more diboronates of the following formula, or a stereoisomer thereof or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

[0010] [ka]

[0011] Each Z1b is independently a linker moiety. Each n' is 0, 1, 2, 3, 4, or 5. At least one n' is 1, 2, 3, 4, or 5. X1 may contain a drug substance or polypeptide. Each Z1c is covalently bonded to the amine of X1, either directly or via one or more Z1b. At least one Z1c is independently selected from diboronates, which are independently selected from formulas FF12A, FF12B, FF12C, FF12D, FF116A, FF116B, FF116C, FF116D, FF225, and FF227. Each additional Z1c is optionally and independently selected from diboronates, sugar moieties, diol-containing moieties, and polyol-containing moieties, and the diboronates are independently selected from formulas FF12A, FF12B, FF12C, FF12D, FF116A, FF116B, FF116C, FF116D, FF225, and FF227. Each q' is 1, 2, 3, 4, or 5, and if q' is 2 or greater, the corresponding Z1c and Z1b are independently selected and may be the same or different. Formulas FF12A, FF12B, FF12C, FF12D, FF116A, FF116B, FF116C, FF116D, FF225, and FF227 are,

[0012] [ka] That is the case.

[0013] In the above formulas, X represents the covalent bond site of Z1b to the amine, or, if n' is 0, the covalent bond site of X1 to the amine. Each i can be 1, 2, 3, 4, 5, 6, or 7. The B1 and B2 groups in the above formulas may be the same or different, and each independently represents an aromatic boron-containing group. If each Z1c is selected from formulas FF225 and FF227, then at least one of B1 and B2 is formula F7, which is given by:

[0014] [ka]

[0015] One R1 of F7 is (C=O)--- * This represents, --- * represents the bond point to the rest of Z1c. Each of the remaining R1s independently represents H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Y10 can be selected from CH3 and OCF3, where m is 1, 2, 3, 4, 5, 6, or 7. Y8 can be O or NR, where R is a C1-C6 alkyl group or H. Each Y10 is independently selected from H, CH3, F, and CF3, and for at least one F7, at least one Y10 is not H.

[0016] In a second embodiment, the compound is selected from the group consisting of polypeptides comprising an A chain and a B chain, wherein the A chain contains a sequence selected from 1, 24051, and 24052. The B chain may contain a sequence selected from SEQ ID NOs: 24063, 25228, 25229, 25232, 25305, 25308, 25312, 25236, 25095, and 25380-25397.

[0017] In the third embodiment, the pharmaceutical composition comprises at least one compound or a pharmaceutically acceptable salt thereof according to any one of the embodiments of the first and second embodiments.

[0018] In a fourth aspect, the disclosure includes compounds of the following formulas, or stereoisomers or mixtures of stereoisomers thereof, or pharmaceutically acceptable salts thereof. Z1c Linker The Z1c linker is

[0019] [ka]

[0020] [ka]

[0021] [ka]

[0022] [ka]

[0023] [ka] You can choose from these options.

[0024] The group X in the above formula can be selected from a leaving group, NH2, and H. The B1 and B2 groups may be the same or different, and each independently represents an aromatic boron-containing group.

[0025] In a fifth aspect, the disclosure includes a polypeptide comprising an A chain and a B chain, wherein the A chain comprises a sequence selected from 1, 24051, and 24052. The B chain may comprise a sequence selected from 25000 to 25397.

[0026] In a sixth aspect, the disclosure includes a compound having agonist activity on an insulin receptor, or a pharmaceutically acceptable salt thereof, comprising at least one aromatic boron-containing group having agonist activity on an insulin receptor. The compound may have a first EC50 activity that activates the insulin receptor at a first glucose concentration, and a second EC50 activity that activates the insulin receptor at a second glucose concentration. When the first glucose concentration is 5.6 mM and the second glucose concentration is 16.7 mM, the compound has an insulin receptor agonist potency ratio of about 1.2 to about 20, for example, about 1.5 to about 15, about 2 to about 14, about 2.5 to about 13, about 2.5 to about 12, about 2.5 to about 11, about 2.5 to about 10, about 2.5 to about 9, about 2.5 to about 8, about 2.5 to about 7, about 2.5 to about 6, about 2.5 to about 5, or about 2.5 to about 4.5 for the first EC50 to the second EC50.

[0027] In a seventh aspect, the disclosure includes compounds having agonist activity to glucose, or pharmaceutically acceptable salts thereof, comprising at least one aromatic boron-containing group having binding affinity to glucose. When administered at a dose of 30 nmol / kg to a first group of rats having a first glucose infusion rate to provide a blood glucose concentration of 100 mg / dL, and to a second group of rats having a second glucose infusion rate to provide a blood glucose concentration of 200 mg / dL, the compound provides relative glucose infusion rate differences (mg / kg / min.min) of about 1 to about 2500, about 1 to about 2000, about 1 to about 1500, about 100 to about 1500, and about 1000 to about 1500, as well as relative glucose infusion rate ratios of about 0.1 to about 5, about 0.2 to about 4.5, about 0.5 to about 4, about 0.5 to about 3.5, about 1 to about 3.5, about 1.5 to about 3.5, or about 2 to about 3.

[0028] In the eighth aspect, the disclosure includes compounds according to any one of the embodiments in the preceding aspects, or pharmaceutically acceptable salts thereof, for use as pharmaceuticals.

[0029] In the ninth aspect, the disclosure includes a method for treating or preventing diabetes mellitus, impaired glucose tolerance, hyperglycemia, or metabolic syndrome. This method includes administering a compound of any one embodiment of the first, second, or fifth to eighth aspects described above, or a pharmaceutical composition according to the third aspect, to a subject in need.

[0030] In the tenth aspect, the disclosure includes a compound, a use of the compound, a method of administering the compound, or a device or formulation containing the compound, according to any one embodiment of the first, second, or fifth to eighth aspects described above, or a pharmaceutical composition according to the third aspect. The disclosure includes a use or method in the treatment or prevention of diabetes, impaired glucose tolerance, hyperglycemia, or metabolic syndrome. The disclosure includes the manufacture of a pharmaceutical product containing such a compound. The disclosure includes the use of such a compound as a therapeutic agent for the treatment of diabetes or obesity, for the control of blood glucose levels, or for the control of drug release. The disclosure includes a method of administering the compound to a subject as a therapeutic or prophylactic agent. The disclosure includes the use of a compound according to any one embodiment of the fourth aspect as an active pharmaceutical ingredient or as an intermediate in the synthesis of a therapeutic or prophylactic compound.

[0031] In the eleventh aspect, the disclosure includes a compound comprising at least one diboronate, the diboronate comprising at least two aromatic boron-containing groups, at least one aromatic boron-containing group being covalently bonded to the compound and selected from F3 to F11, and the other aromatic boron-containing groups being covalently bonded to the compound and selected from F1 to F11 or a boronic acid.

[0032] [ka] Selected arbitrarily from the above.

[0033] In each of F1 to F11, at least one R1 is covalently bonded to the compound. Each of the remaining R1 or R2 is independently H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, m is 1, 2, 3, 4, 5, 6, or 7. For equations F3 to F4, R w is O or S. For formula F6, if Y8 is O, then i is 1, 2, 3, 4, or 5, or i is 2, 3, 4, or 5 and 0, 1, or 2 R1 represent F, Cl, CF2, CF3, SF5, OCF3, SO2CH3, and / or SO2CF3, or if Y8 is NR, then R is an alkyl group or H and i is 1, 2, 3, 4, or 5. For formulas F5 and F7-F10, if Y8 is O, i is 1, 2, 3, 4, or 5; if Y8 is NR, R is an alkyl group or H, i is 1, 2, 3, 4, or 5; Y9 is CH3, F, CF3, CHF2, or OCH3; and each Y10 is independently selected from H, CH3, CH2CH3, CH2CH2OH, F, CF3, CHF2, and OCH3, provided that at least one Y10 is not H.

[0034] In the twelfth aspect, the disclosure includes tautomers, stereoisomers, or mixtures of stereoisomers of the compounds according to the eleventh aspect, or pharmaceutically acceptable salts, hydrates, or isotopic derivatives thereof.

[0035] In the 13th aspect, the disclosure includes compounds comprising X1 and one or more Z1c, or tautomers, stereoisomers or mixtures thereof, or pharmaceutically acceptable salts or hydrates or isotopic derivatives thereof, wherein X1 is (i) NH2 or OH, (ii) Active pharmaceutical ingredients containing amines, (iii) Active pharmaceutical ingredients covalently bonded to an amine-containing linker, (iv) an amine configured to be covalently bonded to the active pharmaceutical ingredient, Each Z1c is directly or indirectly covalently bonded to the amine of X1, or to the OH group if X1 is OH, and each Z1c is independently, a) Formulas FF1~FF48 (Formulas FF1~FF48 are,

[0036] [ka]

[0037] [ka]

[0038] [ka] And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, 5, 6, or 7. j is 1, 2, 3, 4, 5, 6, or 7. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group. b) Models FF49~FF88 (Models FF49~FF88 are,

[0039] [ka]

[0040] [ka] And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, 5, 6, or 7. j is 1, 2, 3, 4, 5, 6, or 7. R1a is selected from COOH, CH3, H, and OH. R2, R3, R4, and R5 are each independently selected from CH3, H, OH, and COOH, and at least one of R2, R3, R4, and R5 is CH3 or OH. B1 and B2 may be the same or different, and each is independently an aromatic boron-containing group. c) Formulas FF89~FF112 (Forms FF89~FF112 are,

[0041] [ka] And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, 5, 6, or 7. B1, B2, and B3 may be the same or different, and each is independently an aromatic boron-containing group, a carboxylic acid derivative, or H, and in each FF89-FF112 structure containing B1, B2, and B3 groups, at least two of B1, B2, and B3 groups are independently aromatic boron-containing groups. d) Formulas FF113~FF136 (Formulas FF113~FF136 are,

[0042] [ka] And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, 5, 6, or 7. j is 1, 2, 3, 4, 5, 6, or 7. k is 1, 2, 3, 4, 5, 6, or 7. m is 1, 2, 3, 4, 5, 6, or 7. Each R1 is independently selected from H, alkyl groups, acyl groups, cycloalkyl groups, haloalkyl groups, aryl groups, and heteroaryl groups, and each R1 optionally contains one or more alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyls, alkyls, or aryl groups. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group. e) Formulas FF137~FF160 (Formulas FF137~FF160 are,

[0043] [ka] And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, 5, 6, or 7. j is 1, 2, 3, 4, 5, 6, or 7. k is 1, 2, 3, 4, 5, 6, or 7. m is 1, 2, 3, 4, 5, 6, or 7. Each R1 is independently selected from H, alkyl groups, acyl groups, cycloalkyl groups, haloalkyl groups, aryl groups, and heteroaryl groups, and each R1 optionally contains one or more alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyls, alkyls, or aryl groups. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group. f) Formulas FF161~FF164 (Formulas FF161~FF164 are,

[0044] [Chemical formula] and wherein X represents any covalent bond point directly to the amine of X1, or to the amine directly or indirectly covalently bonded to X1, or to OH when X1 is OH, i is 1, 2, 3, 4, or 5, j is 1, 2, 3, 4, or 5, each R6, R7, R8, and R9 for different values of j are independently selected from H, CF3, CH3, CHF2, and (CH2) m CH3, m is 1, 2, 3, 4, or 5, Y3, Y4, Y5, Y6 and Y7 are each independently selected from H, CH2-X4, and Formulas IV-1 to IV-135, X4 is selected from -COOH, -(CH2) m COOH, alkyl group, acyl group, cycloalkyl group, haloalkyl group, aryl group, and heteroaryl group, each X4 optionally contains one or more halogenated alkyl, halide, sulfhydryl, aldehyde, amine, acid, hydroxyl, alkyl, or aryl groups, wherein m is 1, 2, 3, 4, or 5, at least one of Y5, Y6 and Y7 in Formulas FF162 and FF163 is not H, and at least one of Y7, R8 and R9 in FF164 is not H, Formulas IV-1 to IV-135 are

[0045] [Chemical formula] ​​​​​​​​​​​​​​​​​In the formula, Xa represents CH=O, CHF2, CF3, CH2SH, COOH, CH2OH, CH2NO2, CH2NH2, CH3, C(CH3)3, CH(CH3)2, CH((CH2)3-CH3)2, or CH(CH2-CH3)2. Xb represents O, NH, CH2, or S. Xc represents CH or N, Each R 10 These are independently H, F, Cl, Br, CH3, CF3, CH=O, OH, COOH, and (CH2) n Selected from CH3, m is 1, 2, 3, 4, or 5, and n is 1, 2, 3, 4, or 5. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group. Formulas IV-1 to IV-135 * (This represents the connection point to the corresponding equations FF161~164), g) Formulas FF165~FF166 (Forms FF165~FF166 are,

[0048] [ka] And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. m is 1, 2, 3, 4, 5, 6, or 7. n is 1, 2, 3, 4, 5, 6, or 7. X5 is S, O, or NH. Each R1 independently contains H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, where m is 1, 2, 3, 4, 5, 6, or 7), h) Formulas FF167~FF192 (Forms FF167~FF192 are,

[0049] [ka] And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group. i) Formulas FF193~FF209 (Forms FF193~FF209 are,

[0050] [ka] And, In the formulas, R in FF208 and FF209 is an alkyl, aryl, or halide covalently bonded to the amino group of the side chain of FF208 or FF209 via at least one CH2 group. R1 and R2 are independently selected from H, CH3, alkyl, and formulas IV-1 to IV-135. i is 1, 2, 3, 4, or 5. j is 1, 2, 3, 4, or 5. X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group. j) Formula FF210~FF224 (Formula FF210~FF224 is,

[0051] [ka] And, In the formulas, R11 in FF210 to FF212 is selected from formulas IV-1 to IV-135, and R12 is selected from amine, hydroxyl, alkyl, and halide groups. Each R13 is independently selected from H, CH3, alkyl, aryl and formulas IV-1 to IV-135, and R14 is selected from H, CH3, alkyl, aryl and heteroaryl. In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. X'' represents a covalent bond to the amine--N of the compound, and -- represents a monocovalent bond to the CH2 or CH group of the compound. i is 1, 2, 3, 4, or 5. j is 1, 2, 3, 4, or 5. B1, B2, B3, B4, B5, and B6 each independently represent an aromatic boron-containing group, and in each FF structure containing B1, B2, and B3 groups, at least two of B1, B2, and B3 groups are independently aromatic boron-containing groups), and k) Model FF225~FF231 (Model FF225~FF231 is,

[0052] [ka] In this formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, 5, 6, or 7. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group, and B1 and B2 in formulas FF225 to FF231 are not boronic acids or F2 or F6 aromatic boron-containing groups. Formulas F2 and F6 are,

[0053] [ka] And, R1 in the 4th or 5th position is (C=O)--- * This represents, --- * This represents the connection point to the rest of Z1c, 0, 1, or 2 R1 represent F, Cl, CF2, CF3, SF5, OCF3, SO2CH3, and / or SO2CF3, and each of the remaining R1 represents H. Y8 is O, i is 1, At least one primary or secondary amine from FF1-FF223 and FF225-231 is selected (optionally covalently bonded to B6).

[0054] In a 14th aspect, the Disclosure includes a composition or mixture comprising at least one compound described in any one of the embodiments of the 11th, 12th, or 13th aspect for use as a pharmaceutical for the treatment of diabetes, for the control of blood glucose levels, or for controlling the release of a drug based on physiological levels of low molecular weight or sugar-containing diols. The Disclosure includes a method for administering such a compound to a human subject as a therapeutic or prophylactic agent. The Disclosure includes a method for producing such a compound, the method comprising at least one alkylation and / or amidation step. The Disclosure includes a method for treating a subject by administering a device or formulation comprising such a compound. The Disclosure includes a method for treating or prophylactically treating diabetes, impaired glucose tolerance, hyperglycemia, or metabolic syndrome, the method comprising administering a therapeutically effective amount of such a compound to a subject in need thereof.

[0055] In the 15th aspect, the disclosure includes compounds selected from formulas FF1 to FF231, where formulas FF1 to FF48 are:

[0056] [ka]

[0057] [ka]

[0058] [ka] And, In the formula, X is selected from maleimide, amine, OH, and halogen. i is 1, 2, 3, 4, 5, 6, or 7. j is 1, 2, 3, 4, 5, 6, or 7. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group. Formulas FF49~FF88 are,

[0059] [ka]

[0060] [ka] And, In the formula, X is selected from maleimide, amine, OH, and halogen. i is 1, 2, 3, 4, 5, 6, or 7. j is 1, 2, 3, 4, 5, 6, or 7. R1a is selected from COOH, CH3, H, and OH. R2, R3, R4, and R5 are each independently selected from CH3, H, OH, and COOH, and at least one of R2, R3, R4, and R5 is CH3 or OH. B1 and B2 may be the same or different, and each is independently an aromatic boron-containing group. Formulas FF89~FF112 are,

[0061] [ka] And, In the formula, X is selected from maleimide, amine, OH, and halogen. i is 1, 2, 3, 4, 5, 6, or 7. B1, B2, and B3 may be the same or different, and each independently represents an aromatic boron-containing group, a carboxylic acid derivative, or H, and at least two of B1, B2, and B3 in each FF structure are independently aromatic boron-containing groups. Formulas FF113~FF136 are,

[0062] [ka] And, In the formula, X is selected from maleimide, amine, OH, and halogen. i is 1, 2, 3, 4, 5, 6, or 7. j is 1, 2, 3, 4, 5, 6, or 7. k is 1, 2, 3, 4, 5, 6, or 7. m is 1, 2, 3, 4, 5, 6, or 7. Each R1 is independently selected from H, alkyl groups, acyl groups, cycloalkyl groups, haloalkyl groups, aryl groups, and heteroaryl groups, and each R1 optionally contains one or more alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyls, alkyls, or aryl groups. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group. Formulas FF137~FF160 are,

[0063] [ka] And, In the formula, X is selected from maleimide, amine, OH, and halogen. i is 1, 2, 3, 4, 5, 6, or 7. j is 1, 2, 3, 4, 5, 6, or 7. k is 1, 2, 3, 4, 5, 6, or 7. m is 1, 2, 3, 4, 5, 6, or 7. Each R1 is independently selected from H, alkyl groups, acyl groups, cycloalkyl groups, haloalkyl groups, aryl groups, and heteroaryl groups, and each R1 optionally contains one or more alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyls, alkyls, or aryl groups. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group. Formulas FF161~FF164 are,

[0064] [ka] And, In the formula, X is selected from maleimide, amine, OH, and halogen. i is 1, 2, 3, 4, or 5. j is 1, 2, 3, 4, or 5. For different values ​​of j, each R6, R7, R8, and R9 independently corresponds to H, CF3, CH3, CHF2, and (CH2). m Selected from CH3, where m is 1, 2, 3, 4, or 5. Y3, Y4, Y5, Y6, and Y7 are each independently selected from H, CH2-X4, and formulas IV-1 to IV-135. X4 is -COOH, -(CH2) m Selected from COOH, alkyl groups, acyl groups, cycloalkyl groups, haloalkyl groups, aryl groups, and heteroaryl groups, each optionally containing one or more alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyls, alkyls, or aryl groups, where m is 1, 2, 3, 4, or 5. At least one of Y5, Y6, and Y7 in formulas FF162 and FF163 is not H, and at least one of Y7, R8, and R9 in FF164 is not H. Equations IV-1 to IV-135 are,

[0065] [ka]

[0066] [ka]

[0067] [ka] And, During the ceremony, Xa represents CH=O, CHF2, CF3, CH2F, COOH, CH2OH, CH2NO2, CH2NH2, CH3, C(CH3)3, CH(CH3)2, CH((CH2)3CH3)2, or CH(CH2CH3)2. Xb represents O, NH, CH2, or S. Xc represents CH or N, Each R 10 These are independently H, F, Cl, Br, CH3, CF3, CH=O, OH, COOH, and (CH2) n Selected from CH3, m is 1, 2, 3, 4, or 5, and n is 1, 2, 3, 4, or 5. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group. Formulas IV-1 to IV-135 * (This represents the connection point to the corresponding equations FF161~164), Formulas FF165~FF166 are,

[0068] [ka] And, In the formula, X is selected from maleimide, amine, OH, and halogen. m is 1, 2, 3, 4, 5, 6, or 7. n is 1, 2, 3, 4, 5, 6, or 7. X5 is S, O, or NH. Each R1 independently contains H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, where m is 1, 2, 3, 4, 5, 6, or 7), Formulas FF167~FF192 are,

[0069] [ka] And, In the formula, X is selected from maleimide, amine, OH, and halogen. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group. Formulas FF193~FF209 are,

[0070] [ka] And, In the formulas, R in FF208 and FF209 is an alkyl, aryl, or halide covalently bonded to the amino group of the side chain of FF208 or FF209 via at least one CH2 group. R1 and R2 are independently selected from H, CH3, alkyl, and formulas IV-1 to IV-135. i is 1, 2, 3, 4, or 5. j is 1, 2, 3, 4, or 5. In the formula, X is selected from maleimide, amine, OH, and halogen. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group. Formulas FF210~FF224 are,

[0071] [ka] And, In the formulas, R11 in FF210 to FF212 is independently selected from formulas IV-1 to IV-135, and R12 is selected from amine, hydroxyl, alkyl, and halide groups. Each R13 is independently selected from H, CH3, alkyl, aryl, and formulas IV-1 to IV-135, and R14 is selected from H, CH3, alkyl, aryl, and heteroaryl. In the formula, X is independently selected from maleimide, amine, OH, and halogen. X'' is an amine, i is 1, 2, 3, 4, or 5. j is 1, 2, 3, 4, or 5. and B1, B2, B3, B4, B5, and B6 each independently represent an aromatic boron-containing group, and in each FF structure containing B1, B2, and B3 groups, at least two of B1, B2, and B3 groups are independently aromatic boron-containing groups. Formulas FF225~FF231 are,

[0072] [ka] And, In the formula, X is selected from maleimide, amine, OH, and halogen. i is 1, 2, 3, 4, 5, 6, or 7. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group, and B1 and B2 in formulas FF225 to FF231 are not boronic acids or F2 or F6 aromatic boron-containing groups. Formulas F2 and F6 are,

[0073] [ka] And, R1 in 5th place is (C=O)--- * This represents, --- * This represents the connection point to the remaining part of FF225~FF231, 0, 1, or 2 R1 represent F, Cl, CF2, CF3, SF5, OCF3, SO2CH3, and / or SO2CF3, and each of the remaining R1 represents H. Y8 is O, i is 1, Each of the remaining R1s is H, Y8 is O, i is 1, At least one primary or secondary amine from FF1-FF223 and FF225-FF231 is optionally covalently bonded to B6. If X is an amine in any one of the formulas FF1-FF223 and FF225-FF231, then X is optionally acetylated or alkylated.

[0074] In a sixteenth aspect, the disclosure includes a human insulin analog comprising an A chain and a B chain, wherein the sequence of the A chain is X aa’ X bb’ X cc’ X dd’ X ee’ X ff’ X gg’ VEQCCX hh’ X ii’ ICSLYQLENYCNX jj’ X kk’ X ll’ X mm’ X nn’ X oo’ X pp’ (Sequence ID 24015) is included, and the sequence of the B strand is, (i)X aa X bb X cc X dd KX ee X ff X gg X hh X ii X jj KX kk X ll X mm X nn QHLCGSHLVEALYLVCX oo X pp X qq GFFYTX rr X ss X tt Xuu X vv X ww (SEQ ID NO: 24016) (X aa’ 、X bb’ 、X cc’ 、X dd’ 、X ee’ 、X ff’ 、X gg’ 、X hh’ 、X ii’ 、X jj’ 、X kk’ 、X ll’ 、X mm’ 、X nn’ 、X oo’ 、X pp’ 、X aa 、X bb 、X cc 、X dd 、X ee 、X ff 、X gg 、X hh 、X ii 、X jj 、X kk 、X ll 、X mm 、X nn 、X oo 、X pp 、X qq 、X rr 、X ss 、X tt 、X uu 、X vv 、and X ww is each independently either absent or selected from the amino acid residues A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, Y, and W), (ii)X aa X bb X cc X dd KPX ee X ff X gg X hh X ii X jj X kk X ll X mm X nn QHLCGSHLVEALYLVCX oo X pp X qqGFFYTX rr X ss X tt X uu X vv X ww (Sequence ID 24017) (X aa’ , X bb’ , X cc’ , X dd’ , X ee’ , X ff’ , X gg’ , X hh’ , X ii’ , X jj’ , X kk’ , X ll’ , X mm’ , X nn’ , X oo’ , X pp’ , X aa , X bb , X cc , X dd , X ff , X gg , X hh , X ii , X jj , X kk , X ll , X mm , X nn , X oo , X pp , X qq , X rr , X ss , X tt , X uu , X vv , and X ww Each of these is either absent or selected from amino acid residues A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, Y, and W, and X ee (Selected from amino acid residues A, E, F, H, I, K, L, N, P, Q, R, S, T, V, Y and W), (iii)X aa X bb X cc X dd KX ee X ff X gg X hh X ii X jj KX kk Xll X mm X nn QHLCGSHLVEALYLVCX oo X pp X qq GFFYTX rr X ss X tt X uu X vv X ww (Sequence ID 24018) (X aa’ , X bb’ , X cc’ , X dd’ , X ee’ , X ff’ , X gg’ , X hh’ , X ii’ , X jj’ , X kk’ , X ll’ , X mm’ , X nn’ , X oo’ , X pp’ , X aa , X bb , X cc , X dd , X ee , X ff , X gg , X hh , X ii , X jj , X kk , X ll , X mm , X nn , X oo , X pp , X qq , X rr , X ss , X tt , X uu , X vv , and X ww Each of these is either absent or selected from amino acid residues A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, Y, W, and X ee , X ff , X gg , X hh , X ii , X jj At least one of the following exists, X ee , Xff , X gg , X hh , X ii , X jj At least one of them is G), (iv)X aa X bb X cc X dd KX ee X ff X gg X hh X ii X jj KX kk X ll X mm X nn QHLCGSHLVEALYLVCX oo X pp X qq GFFYTX rr X ss X tt X uu X vv X ww (Sequence ID 24019) (X aa’ , X bb’ , X cc’ , X dd’ , X ee’ , X ff’ , X gg’ , X hh’ , X ii’ , X jj’ , X kk’ , X ll’ , X mm’ , X nn’ , X oo’ , X pp’ , X aa , X bb , X cc , X dd , X ee , X ff , X gg , X hh , X ii , X jj , X kk , X ll , X mm , X nn , X oo , X pp , X qq , X rr , X ss, X tt , X uu , X vv , and X ww Each of these is either absent or selected from amino acid residues A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, Y, W, and X ee , X ff , X gg , X hh , X ii , X jj At least one of the following exists, X ee , X ff , X gg , X hh , X ii , X jj At least one of them is S), or (v)X aa X bb X cc X dd KX ee X ff X gg X hh X ii X jj KX kk X ll X mm X nn QHLCGSHLVEALYLVCX oo X pp X qq GFFYTX rr X ss X tt X uu X vv X ww (Sequence ID 24020) (X aa’ , X bb’ , X cc’ , X dd’ , X ee’ , X ff’ , X gg’ , X hh’ , X ii’ , X jj’ , X kk’ , X ll’ , X mm’ , X nn’ , X oo’ , X pp’ , X aa , Xbb , X cc , X dd , X ee , X ff , X gg , X hh , X ii , X jj , X kk , X ll , X mm , X nn , X oo , X pp , X qq , X rr , X ss , X tt , X uu , X vv , and X ww Each of these is either absent or selected from amino acid residues A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, Y, W, and X ee , X ff , X gg , X hh , X ii , X jj At least two of these exist, X ee , X ff , X gg , X hh , X ii , X jj (At least one of them is S, and the other is G), including. [Modes for carrying out the invention]

[0075] While aromatic boron-containing compounds (e.g., 3A) can bind to diol-containing molecules, achieving selectivity using aromatic boron-containing compounds (which can function as molecular sensors) is difficult due to their ability to bind to various diols, including cis-diols, to varying degrees. Improved binding affinity of aromatic boron-containing compounds (which can function as sensors) to a specific adjacent diol of interest may result in a loss of selectivity.

[0076] A framework in which the boron functional groups (e.g., sensors) of an aromatic boron-containing compound are arranged in a specific or specific shape can enhance selectivity for a particular vicinal diol while maintaining affinity for the diol of interest. According to some embodiments, the aromatic boron-containing compounds disclosed herein have different pendant groups on an aromatic boron-based framework, along with specific framework shapes that affect binding to hydroxyl-containing molecules.

[0077] According to some embodiments, the compounds of the present disclosure include aromatic boron-containing compounds having boron functional groups oriented in three-dimensional space, the boron-containing compounds being spatially oriented to bond with hexoses containing adjacent diols, the boron groups being able to appropriately bond with hydroxyl groups of adjacent diol molecules, and providing enhanced selectivity. In some embodiments, the aromatic boron-containing compounds are modified with specific functional groups on an aromatic ring, together with a suitable or preferred backbone, which can provide higher selectivity and / or affinity for bonding toward the adjacent diol of interest and away from other diols in the body.

[0078] In some embodiments, the aromatic boron-containing compound is conjugated to the active pharmaceutical ingredient (e.g., a small molecule, polypeptide), and the aromatic boron-containing compound provides intramolecular and / or intermolecular interactions with the active pharmaceutical ingredient and / or proteins in the body, such as albumin and / or globulins, which are circulating proteins in blood and / or plasma. In some embodiments, the aromatic boron-containing compound exhibits reversible binding to glycated proteins in the body, such as glycated albumin, and this binding is reversibly influenced by the level of blood glucose or plasma glucose molecules. In some embodiments, selective binding of the sensor to specific adjacent diols alters the degree of their intramolecular and / or intermolecular binding, thereby regulating the pharmacokinetics and overall activity of the active pharmaceutical ingredient in the body. This effect can be controlled by the level of adjacent diols present.

[0079] In some embodiments, the active pharmaceutical ingredient (API) is a peptide hormone. In some embodiments, the human peptide hormone, e.g., the peptide hormone, is insulin or an insulin analog, glucagon, or another incretin hormone. In some embodiments, the sensor is selective for adjacent diols in glucose, and this selectivity is enhanced while maintaining affinity for glucose and simultaneously reducing affinity for other sugars in the blood. In some embodiments, pendant groups on the backbone and the aromatic core of the boron-containing compound (e.g., in combination) allow for control of the overall activity and / or pharmacokinetics of the conjugated API based on the levels of glucose and / or other adjacent diols in the blood.

[0080] In some embodiments, the aromatic boron-containing compound comprises a specific skeletal molecule (e.g., FF structure, FFL-1 to FFL-68, DSL-1 to DSL-172) having conjugated boron functional groups (e.g., F1 to F11), the skeletal structure being used to orient the boron functional groups in a three-dimensional shape such that the boron functional groups are oriented close to each other and within a distance that helps them engage with a specific hydroxyl orientation of a selected hexose such as glucose. In some embodiments, the boron functional group is selected from F1 to F11. In some embodiments, the boron functional group is selected from F2, F6, and F7. In some embodiments, the boron functional group is selected from F2 and F7. In some embodiments, the boron functional group is F2. In some embodiments, the boron functional group is F7.

[0081] While not bound by theory, the aromatic boron-containing compounds (e.g., molecules) disclosed herein are thought to improve selectivity by at least one of the following three mechanisms: (1) The FF skeleton promotes the alignment of the orientation of the hydroxyl and / or alkoxy groups on the boron group in the aromatic boron-containing compound with the hydroxyl group in the adjacent diol molecule, thereby improving selectivity. (2) Further increases in selectivity can be obtained by identifying specific functional groups attached to or near the aromatic core of the boron-containing compound that influence the electronic structure of the aromatic boron-containing compound, thereby favoring reversible bonding to the adjacent diol at physiological pH. (3) Functional groups attached to the aromatic boron-containing compound (e.g., sensor skeleton) help provide steric hindrance to reduce bonding to undesirable hexoses while maintaining bonding to a desired sugar such as glucose. In some embodiments, the FF skeleton provides glucose bonding. In some embodiments, the combination of the FF skeleton and indirect and / or direct linkers provides affinity to plasma proteins, e.g., glycated proteins, though not limited to those mentioned above, and the combination of the FF skeleton and indirect and / or direct linkers (e.g., Z1b) provides reversible interactions with plasma proteins controlled by the binding of sugar molecules to the FF skeleton under physiological conditions. These effects combined in this disclosure (e.g., compounds of formulas I, III) provide desired or preferred selectivity of binding toward the adjacent diol-containing molecule of interest and away from other diols in the body.

[0082] In some embodiments, an aromatic boron-containing compound is conjugated to a drug substance (API) that provides intramolecular and / or intermolecular interactions between the aromatic boron-containing compound and proteins in the body. Such proteins may include circulating proteins in blood and / or human plasma, such as albumin, glycosylated proteins, and / or glycated proteins including immunoglobulins and glycated plasma proteins such as glycated albumin. In some embodiments, selective binding of the sensor to a specific adjacent diol in the molecule of interest alters the degree of intramolecular and intermolecular binding, thereby modulating the pharmacokinetics and overall activity of the API in the body. In some embodiments, the API is a peptide hormone, and in certain embodiments, the peptide hormone is an incretin hormone such as insulin, and the adjacent diol-containing molecule is glucose, but the disclosure is not limited thereto.

[0083] definition Unless otherwise defined, all terms used herein (including technical and scientific terms) have the same meaning as those generally understood by those skilled in the art to the extent of this disclosure. Terms such as those defined in commonly used dictionaries should be construed to have meanings consistent with their meanings in the relevant art and / or context of this specification, and should not be construed in an idealized or overly formal sense unless expressly defined herein.

[0084] Unless otherwise specifically described herein, the functional groups, functional moieties, and reactions referred to herein are, for example, from *Organic Chemistry*, Thomas Sorrell, University Science Books, Sausalito, 1999; *Larock*, *Comprehensive Organic Transformations*, VCH Publishers, Inc., New York, 1989; and *Carruthers*, *Some Modern Methods of Organic Synthesis*, 3 rdEdition,Cambridge University Press,Cambridge,1987;Smith and March,March's Advanced Organic Chemistry,5 th It is understood that this has meaning consistent with standard descriptions and / or general principles of organic chemistry, as described in Edition, John Wiley & Sons, Inc., New York, 2001. Common functional groups (such as alkyl, aryl, and acetyl) encompass specific examples or species that fall under the category of functional groups as commonly defined in the field of organic chemistry, and those skilled in the art can identify specific exemplary embodiments of functional groups.

[0085] Unless otherwise specified herein, all chemical terms, functional groups, and general terms used throughout this specification are defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75. th Ed. is identified according to the inside of the cover. In certain embodiments, the terms “a,” “an,” and “the,” as well as similar referents used herein, should be interpreted as covering both singular and plural forms unless otherwise indicated by the context. The term “CAS#,” as used herein and also referred to as CASRN or CAS number, is a unique numerical identifier assigned by the Chemical Abstracts Service (CAS) to every chemical substance listed in published scientific literature.

[0086] Where used herein, the nomenclature of compounds, including organic compounds, may be given using the common nomenclature, IUPAC, IUBMB, or CAS recommendations. Those skilled in the art can readily verify the structure of a compound once a name has been given, either by systematic reduction of the compound structure using the nomenclature rules, or by using commercially available software such as CHEMDRAW® (Cambridgesoft Corporation, USA).

[0087] The terms used herein are for illustrative purposes only and are not intended to limit the disclosure. Where used herein, the terms “comprises,” “comprising,” “includes,” and “including” identify the presence of a described feature, integer, action, operation, element, and / or component, but do not exclude the presence or addition of one or more other features, integers, actions, operations, elements, components, and / or their bases. Where used herein, the term “and / or” includes any and all combinations of one or more of the related enumerated items. Where preceding a list of elements, expressions such as “at least one of ~” qualify the entire list of elements and not the individual elements of the list.

[0088] Where used herein, the terms “substantially,” “about,” and similar terms are used as approximations, not as terms of degree, and are intended to describe inherent deviations in measured or calculated values ​​that would be recognized by those skilled in the art. Where used throughout, the term “about” is used to describe and explain small variations. For example, “about” may mean that a number may change by only ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%, or ±0.05%. A number changed by the term “about” includes a specific identifier. For example, “about 5.0” includes 5.0.

[0089] Furthermore, the use of “may” when describing embodiments of the Disclosure refers to “one or more embodiments of the Disclosure.” As used herein, the terms “use,” “using,” and “used” may be considered synonymous with “utilize,” “utilizing,” and “utilized,” respectively. Also, the term “exemplary” is intended to refer to an example or description.

[0090] Any numerical range listed herein is intended to include all subranges of the same numerical precision that are contained within the listed range. For example, the range "1 to 10" is intended to include all subranges between (and including) the listed minimum value of 1 and the listed maximum value of 10, i.e., all subranges having a minimum value of 1 or more and a maximum value of 10 or less, such as 2 to 7. Any maximum numerical limit listed herein is intended to include all lower numerical limits contained within it, and any minimum numerical limit listed herein is intended to include all upper numerical limits contained within it. Accordingly, the applicant reserves the right to modify this specification, including the claims, to explicitly list any subranges contained within the ranges explicitly listed herein.

[0091] As used herein, “aromatic boron-containing group” refers to a compound having at least one boron atom covalently bonded to an aromatic group, and / or a compound having at least one boron atom covalently incorporated within an aromatic group. As used herein, the term “aromatic” may include “heterocyclic,” “heterocyclyl,” or “heterocyclic formula.” As used herein, the terms “heterocyclic,” “heterocyclyl,” or “heterocyclic formula” each refer to an unsaturated 3- to 18-membered ring containing 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the term “aromatic” may include “aryl.” As used herein, the term “aryl” refers to a monocyclic, bicyclic, or other polycarbonate aromatic ring system having 5- to 14 ring atoms. The aryl group may optionally be condensed to one or more rings selected from aryl, cycloalkyl, heteroaryl, and heterocyclyl. Examples of aryl groups include, but are not limited to, monocyclic aromatic ring systems containing six carbon atoms in the ring.

[0092] As used herein, the term “heteroaryl” refers to a monocyclic, bicyclic, or polycyclic aromatic ring system containing one or more heteroatoms, such as nitrogen, oxygen, and sulfur, e.g., 1 to 3 heteroatoms. Heteroaryls can be substituted with one or more substituents. Heteroaryls can also be condensed with non-aromatic rings. Exemplary heteroaryl groups include, but are not limited to, monocyclic aromatic rings, the rings containing 2 to 5 carbon atoms and 1 to 3 heteroatoms. In some embodiments, aromatic boron-containing groups may include, but are not limited to, aryl and heteroarylboronic acids, aryl and heteroarylboronic acid esters, and / or boroxol. Examples of aromatic boron-containing groups useful according to certain embodiments include, for example, those described herein as FF1-FF231, F1-F11, and FFL-1-FFL-68, and further, for example, those disclosed in patent application PCT / US2021 / 025261 (filed March 31, 2021) as compounds F1-F9, F12-F43, and F500-F520, and those disclosed in PCT / US2021 / 059802 (filed November 18, 2021) as compounds FF1-FF224 and F1-F10. These disclosures are expressly incorporated herein by reference in their entirety.

[0093] As used herein, the term “small molecule linker” refers to a chemical group (e.g., a skeleton, a moiety) having a first bond to X1 and a second bond to Z1b, Z1a, or Z1c. In some embodiments, the first bond is to X1 and the second bond is to Z1c. In some embodiments, the first bond is to X1 and the second bond is to Z1a. In some embodiments, the small molecule linker is a moiety / chemical group selected from formulas IIa-IIai and IIIa-IIIai. In some embodiments, the small molecule linker is an L- or D-amino acid comprising a moiety / chemical group selected from formulas FL1-FL19, FL5A, FL5B, FL65A, FL65B, FL69, FL69A, FL69B, FL70, FL70A, and FL70B, and at least one amine group directly conjugated to Z1c, wherein the acidic functional group of the amino acid is conjugated to X1 of formula I or formula IB.

[0094] As used herein, the term “indirect linker” refers to a chemical group (e.g., a skeleton, a moiety) having a first bond to X1 and a second bond to Z1b, Z1a, or Z1c. In some embodiments, the first bond is to X1 and the second bond is to Z1c. In some embodiments, the first bond is to Z1a and the second bond is to Z1c. In some embodiments, the indirect linker is an L- or D-amino acid comprising a moiety / chemical group selected from formulas FL1-FL19, FL5A, FL5B, FL65A, FL65B, FL69, FL69A, FL69B, FL70, FL70A, and FL70B, and at least one amine group directly conjugated to Z1c, wherein the acid functional group of the amino acid is independently conjugated to Z1a or X1 of formula I or formula IB.

[0095] As used herein, the term “part” refers to a chemical group (e.g., Z1c) that includes at least one bond site to another group, such as a skeleton (e.g., X1, Z1b1, Z1b2). For example, a linker part is a chemical group having two bond sites. For example, in formula IE, Z1b is a linker part having a first bond site to the amine of X1 and a second bond site to Z1c. In some embodiments, the first bond site (i.e., a covalent bond) is to X1, and the second bond site (i.e., a covalent bond) is to Z1c. In some embodiments, each Z1b is independently a linker part. In some embodiments, Z1b is selected from formulas FL3, FL5, FL5A, FL5B, FL65A, FL65B, FL69, FL69A, FL69B, FL70, FL70A, and FL70B. In some embodiments, at least one Z1c is covalently bonded to the amine of X1 via one or more Z1b, each Z1b independently selected from the formulas FL(IA), FL(IB), FL3, FL5, FL5A, FL5B, FL65A, FL65B, FL69, FL69A, FL69B, FL70, FL70A, and FL70B.

[0096] As used herein, “diol-containing moiety” is a diol-containing group comprising at least two hydroxyl groups. In some embodiments, the diol is not a sugar. In some embodiments, the diol-containing moiety may have a carbon length of 3 to 26. In addition, or instead, the molecular weight of the diol-containing moiety may be 90 to 570. Examples of such non-sugar diol-containing moieties may be provided by organic acids (such as gluconic acid, threonic acid, glyceric acid, galactonic acid, and dihydroxycinnamic acid), thiol-containing compounds (such as 1-thioglycerol and 1,2,3-butanetriol-4-mercapto), and amino compounds (such as (±)-3-amino-1,2-propanediol, (±)-3-amino-1,2-propanediol, and glucosamine).

[0097] As used herein, “polyol-containing portion” is an alcohol having one or more hydroxyl groups. In some embodiments, the polyol may be, for example, sorbitol (produced from glucose), xylitol (from xylose), erythritol (from erythrose), lactitol (from lactose), maltitol (from maltose), mannitol (from mannose), polyglycitol (from starch hydrolysate), isomalt, glycerol, propylene glycol, polyethylene glycol (PEG), polypropylene glycol, polyoxyethylated polyol (e.g., polyoxyethylated polyol, POG), polyoxyethylated sorbitol, or polyoxyethylated glucose.

[0098] As used herein, “near the C-terminus of the B chain” includes 10 or fewer amino acids from the C-terminus of the B chain (e.g., 9 amino acids, 8 amino acids, 7 amino acids, 6 amino acids, 5 amino acids). In some embodiments, the amine to which the diboronate is covalently bonded is located at or near the C-terminus of the B chain, preferably the B29 lysine or B21 lysine amine. As used herein, the numbering (e.g., B29, B21) refers to the wild-type sequence number used in human insulin chain B, where the B chain is an amino acid sequence.

[0099] [Table 1] It has the following characteristics. For example, B29 is K in the wild-type sequence, and B21 is E in the wild-type sequence.

[0100] As used herein, the “near the N-terminus” of the A chain or B chain includes 10 or fewer amino acids from the N-terminus of the A chain or B chain (for example, 9 amino acids, 8 amino acids, 7 amino acids, 6 amino acids, or 5 amino acids).

[0101] As used herein, “amino acids” include protein-constitutive (or natural) amino acids (among the 20 standard amino acids) and non-protein-constitutive (or non-natural) amino acids. Protein-constitutive amino acids are those that are naturally incorporated into proteins. Standard amino acids are those encoded by the genetic code. Non-protein-constitutive amino acids are those not found in proteins or not produced by standard cellular mechanisms (e.g., they may be post-translationally modified). In general, amino acid residues (peptides / protein sequences) can be identified by their full names, their one-letter codes, and / or their three-letter codes. These three methods are fully equivalent. Hereafter, each amino acid of a compound in this disclosure for which optical isomers are not described should be understood to mean the L-isomer (unless otherwise specified). An amino acid is a molecule containing an amino group, a carboxylic acid group, and optionally, one or more further groups often referred to as side chains.

[0102] As used herein, the term “amino residue” formally refers to an amino acid from which a hydroxyl group has been removed from a carboxyl group and / or, formally, an amino acid from which a hydrogen atom has been removed from an amino group. As will be apparent from the following examples, amino acid residues may be identified by their full name, their one-letter code, and / or their three-letter code. These three methods are fully equivalent and interchangeable.

[0103] As used in this invention, the term "alkyl" is defined herein as C 1~30 Alkyl groups refer to saturated linear or branched hydrocarbons, such as linear or branched groups, consisting of 1 to 30 carbon atoms. In some embodiments, alkyl groups are C1-C 22 It is an alkyl group. In some embodiments, the alkyl group is C1-C 20 It is an alkyl group. In some embodiments, the alkyl group is C1-C 18 It is an alkyl group. In some embodiments, the alkyl group is C1-C 16 It is an alkyl group. In some embodiments, the alkyl group is C1-C 14It is an alkyl group. In some embodiments, the alkyl group is C1-C 12 It is an alkyl group. In some embodiments, the alkyl group is C1-C 10 It is an alkyl group. In some embodiments, the alkyl group is a C1-C8 alkyl group. In some embodiments, the alkyl group is a C1-C6 alkyl group. In some embodiments, the alkyl group is a C1-C4 alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. In some embodiments, "alkyl" is a linear hydrocarbon. In some embodiments, "alkyl" is a branched-chain hydrocarbon.

[0104] As used herein, the term “cycloalkyl” refers to a saturated or unsaturated cyclic, bicyclic, or bridging bicyclic hydrocarbon group of 3 to 16 or 3 to 8 carbon atoms, referred herein as “(C3-C8) cycloalkyl” derived from cycloalkanes. Examples of cycloalkyl groups include, but are not limited to, cyclohexane, cyclohexene, cyclopentane, and cyclopentene. Cycloalkyl groups can be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Cycloalkyl groups can condense with other cycloalkyl (saturated or partially unsaturated), aryl, or heterocyclyl groups to form bicyclic, tetracyclic, and so on. The term "cycloalkyl" also includes crosslinked and spirocondensed cyclic structures, which may or may not contain heteroatoms. In some embodiments, the cycloalkyl group is (C3-C6)cycloalkyl.

[0105] As used herein, the term “acyl” refers to RC(O)- groups such as (alkyl)-C(O)-, (alkenyl)-C(O)-, (alkynyl)-C(O)-, (aryl)-C(O)-, (cycloalkyl)-C(O)-, (heteroaryl)-C(O)-, and (heterocyclyl)-C(O)-, where the group is bonded to the parent molecular structure via a carbonyl functional group. In some embodiments, it refers to, for example, the total number of chain or ring atoms of the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heteroaryl moiety plus the carbonyl carbon of the acyl. 1-10 It is an acyl radical. For example, C4-acyl has a carbonyl group in addition to the other three ring or chain atoms. In some embodiments, it is C1-C 22 It is an acyl group. In some embodiments, it is C1-C 20It is an acyl group. In some embodiments, it is C1-C 18 It is an acyl group. In some embodiments, it is C1-C 16 It is an acyl group. In some embodiments, it is C1-C 14 It is an acyl group. In some embodiments, it is C1-C 12 It is an acyl group. In some embodiments, it is C1-C 10 It is an acyl group. In some embodiments, it is a C1-C8 acyl group.

[0106] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trichloromethyl. In some embodiments, it is C1-C 22 It is a haloalkyl group. In some embodiments, it is C1-C 20 It is a haloalkyl group. In some embodiments, it is C1-C 18 It is a haloalkyl group. In some embodiments, it is C1-C 16 It is a haloalkyl group. In some embodiments, it is C1-C 14 It is a haloalkyl group. In some embodiments, it is C1-C 12 It is a haloalkyl group. In some embodiments, it is C1-C 10 It is a haloalkyl group. In some embodiments, it is a C1-C8 haloalkyl group. In some embodiments, it is a C1-C6 haloalkyl group.

[0107] As used herein, the term “aryl” refers to a monocyclic, bicyclic, or other polycarbonate aromatic ring system having 5 to 14 ring atoms. The aryl group may optionally be condensed to one or more rings selected from aryl, cycloalkyl, heteroaryl, and heterocyclyl groups. The aryl groups of this disclosure may be substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azlenyl, and naphthyl, as well as benzo-condensed carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Examples of aryl groups include, but are not limited to, monocyclic aromatic ring systems containing six carbon atoms in the ring.

[0108] As used herein, “leaving group” is an atom (or group of atoms) that can be substituted as a stable species having bonding electrons. For example, a leaving group is an anion (e.g., Cl - The leaving group may be a halogen or a neutral molecule (e.g., H2O). In some embodiments, the leaving group is a halogen, an N-hydroxysuccinimide (NHS) group, a 2,3,5,6-tetrafluorophenol (TFP) group, a pentafluorophenol (Pfp) group, or a sulfonic acid ester.

[0109] "Isomers" refer to compounds that have the same number and types of atoms, and therefore the same molecular weight, but differ in terms of the arrangement or configuration of atoms in space.

[0110] "Stereoisomer" or "optical isomer" means a stable isomer having at least one chiral atom or having restricted rotations that produce a perpendicular asymmetric plane (e.g., certain biphenyl, allene, and spiro compounds) and that can rotate plane-polarized light. Because the compounds of this disclosure have chiral centers and other chemical structures that can produce stereoisomers, this disclosure intends to describe stereoisomers and mixtures thereof. Because the compounds of this disclosure and their salts contain chiral carbon atoms, they can exist as single stereoisomers, racemates, and mixtures of enantiomers and diastereomers. In some embodiments, such compounds are prepared as racemic mixtures. In some embodiments, such compounds can be prepared or isolated as pure stereoisomers, for example, as individual enantiomers or diastereomers, or as stereoisomer-rich mixtures. As will be discussed in more detail below, individual stereoisomers of a compound can be prepared by synthesis from optically active starting materials containing the desired chiral center, or by separation or resolution such as the preparation of a mixture of enantiomer products followed by conversion to a mixture of diastereomers and subsequent separation or recrystallization, chromatographic techniques, the use of chiral resolving agents, or direct separation of enantiomers in a chiral chromatography column. Starting compounds for specific stereochemistrys are either commercially available or prepared by the methods described below, and are solvable by arts well known in the art.

[0111] As used herein, “fatty acid” is a carboxylic acid having an aliphatic chain. Saturated fatty acids have a saturated aliphatic chain, while unsaturated fatty acids have an unsaturated aliphatic chain. In some embodiments, fatty acids are C3-C3 26 It is a fatty acid. In some embodiments, the fatty acid is C4-C 20These are fatty acids. In some embodiments, the fatty acids are CH3CH2COOH, CH3(CH2)2COOH, CH3(CH2)3COOH, CH3(CH2)4COOH, CH3(CH2)5COOH, CH3(CH2)6COOH, CH3(CH2)7COOH, CH3(CH2)8COOH, CH3(CH2)9COOH, CH3(CH2) 10 COOH, CH3(CH2) 11 COOH and CH3(CH2) 12 COOH, CH3(CH2) 13 COOH, CH3(CH2) 14 COOH, CH3(CH2) 15 COOH, CH3(CH2) 16 COOH, CH3(CH2) 17 COOH and CH3(CH2) 18 The fatty acid is a saturated fatty acid selected from COOH. In some embodiments, the fatty acid is an unsaturated fatty acid selected from α-linoleic acid, stearidonic acid, eicosapentanoic acid, ceruvonic acid, linoleic acid, linoleradicic acid, γ-linolenic acid, oleic acid, elaidic acid, and gondounic acid.

[0112] The term "pharmaceutically acceptable salt" refers to a salt of an acidic or basic group that may be present in the compounds used in this composition.

[0113] As used herein, “API” refers to small molecule compounds and / or polypeptide-containing compounds. According to some embodiments, APIs suitable for use in the compounds and methods described herein are therapeutically, prophylactically, and / or diagnostically active APIs.

[0114] The terms “first,” “second,” and “third” may be used herein to describe various elements (such as molecules, components, groups, and / or parts), but it will be understood that these elements should not be limited by these terms. These terms are used only to distinguish one element from another. Thus, the first element described below may be called the second element without departing from the spirit and scope of this disclosure. When an element or group is referred to as “connected to,” “conjugated with,” “linked,” or “coupled to” another element or group, it will be understood that the two elements may be directly connected or may have one or more intervening elements. The combinations and combinations described herein have the option of being direct conjugations or direct connections unless expressly excluded or excluded by the context.

[0115] As used herein, the terms “directly covalently conjugated” or “covalently conjugated directly” may be used interchangeably to indicate that the first group is “directly” or “directly covalently conjugated” or “covalently conjugated directly” to the second group, meaning that the first and second groups are covalently bonded together without any additional intervening groups.

[0116] As used herein, the terms “indirectly covalently conjugated” or “covalently conjugated indirectly” can be used interchangeably to indicate that a first group is “indirectly” or “indirectly covalently conjugated” or “covalently conjugated indirectly” to a second group, meaning that the first and second groups are covalently bonded together by at least one additional intervening group (e.g., a small molecule, a linker moiety, a spacer, a linear sequence of amino acids, and / or a nonlinear sequence of amino acids).

[0117] In some embodiments, one or more groups (e.g., X1a, Z1a, Z1c) are covalently bonded to each other directly or indirectly (e.g., via one or more linkers such as Z1b, Z1b1, Z1b2). For example, according to a particular embodiment, Z1c is covalently bonded directly or indirectly (e.g., via one or more Z1b linkers) to an amine of X1, or to an OH group if X1 is an OH group. As an example, according to a particular embodiment, one or more drug substance or polypeptides (X1) are covalently bonded to one or more Z1b groups. As another example, according to a particular embodiment, one or more drug substance (X1) are covalently bonded to one or more amine-containing linkers. In some embodiments, X represents a covalent bond site either directly to an amine of X1, or to an amine directly covalently bonded to X1, or to X1 via one or more Z1b groups. In some embodiments, X represents a covalent bond site that is directly to the amine of X1, or to an amine directly or indirectly covalently bonded to X1, or to an OH group if X1 is an OH group. In some embodiments, each Z1c is independently covalently bonded directly or indirectly to the amine of Z1a, the amine of Z1b, or to X1. In some embodiments, each Z1c is independently covalently bonded directly or via one or more Z1b to the amine of X1. In some embodiments, at least one Z1c is covalently bonded to the amine of X1 via one or more Z1b.

[0118] In the context of efficacy against insulin receptors, the terms “insulin receptor agonist,” “compound having agonist efficacy,” and “agonist efficacy” in the context of compounds having agonist efficacy against insulin receptors refer to compounds that bind and / or activate insulin receptors (e.g., compounds of formula I or formula IB, proteins, e.g., the fusion protein described in U.S. Patent Application Publication No. 2016 / 0324932).

[0119] The terms "short-acting insulin receptor agonist" and "short-acting insulin" refer to insulin receptor agonists marketed under the trade name Humulin® that have an onset of activity equivalent to or faster than that of human insulin isophane and human insulin. For example, short-acting insulin may have an onset of action occurring within 10 minutes of injection. As another example, short-acting insulin may have an onset of action occurring within 20 minutes of injection. In some embodiments, short-acting insulin may have maximum efficacy (peak) within 1 to 4 hours after injection. In some embodiments, short-acting insulin can be administered before, during, and / or immediately after a meal.

[0120] The terms "long-acting insulin receptor agonist" and "long-acting insulin" refer to insulin receptor agonists that have a later onset of action than Humulin®. For example, long-acting insulin may have an onset of action 1 to 2 hours or later. In certain embodiments, long-acting insulin may have maximum efficacy (peak) within 6 to 20 hours or have a long-lasting effect. In some embodiments, long-acting insulin may be administered once daily or, for example, once weekly.

[0121] When used herein in relation to insulin receptor agonists, the term “suitable for meal administration” refers to a short-acting insulin receptor agonist suitable for controlling blood glucose levels during and / or immediately after a meal.

[0122] As used herein in relation to insulin receptor agonists, the term “suitable for once-weekly administration” refers to an insulin receptor agonist having a pharmacokinetic and pharmacodynamic profile long enough to control blood glucose levels throughout the day when administered at a frequency of once a week or less. Examples of such molecules include the fusion protein described in US2016 / 0324932, which includes BIF. BIF, also known as insulin efcitra alfa, comprises a dimer of an insulin receptor agonist fused to a human IgG Fc region, the insulin receptor agonist comprising an insulin B chain analog fused to an insulin A chain analog by the use of a first peptide linker, the C-terminal residue of the insulin A chain analog directly fused to the N-terminal residue of a second peptide linker, and the C-terminal residue of the second peptide linker directly fused to the N-terminal residue of a human IgG Fc region. BIF is identified by CAS registry number 2131038-11-2 and has the following chemical names: (1) Immunoglobulin G2 (human Fc fragment), insulin [47-threonine, 51-aspartic acid, 58-glycine] (human A chain) fusion protein with a dimerized peptide (synthetic 20-amino acid linker) fusion protein, insulin [16-glutamic acid, 25-histidine, 27-glycine, 28-glycine, 29-glycine, 30-glycine] (human B chain) fusion protein with a peptide (synthetic 7-amino acid linker); and (2) Tris(tetraglycylglutaminyl)pentaglysyl(59-78) homosapiens immunoglobulin heavy chain constant γ2{del-CH1, hinge-(7-12), CH2, CH3[K 107 >del(300)]}(79-299), Homo sapiens insulin B chain [Y16>Y(16), F25>H(25), TPKT27-30>GGGG(27-30)](1-30) fusion protein having diglycylceryltetraglycyl(31-37) insulin A chain [I10>T(47), Y14>D(51), N21>G(58)](38-58) fusion protein having dimer (80-80':83-83')-bisdisulfide.

[0123] As used herein, “glucose-sensing insulin” refers to an insulin receptor agonist having a blood glucose-dependent onset of activity and / or level of activity. Examples of such molecules include compounds of formula I or formula Ib disclosed herein, such as in Examples 1A to 82A.

[0124] The term "incretin-based therapy" includes any treatment that involves, or enhances, enables, enhances, and / or stimulates, the administration of metabolic hormones known as incretins, including but not limited to GLP-1, gastric inhibitory peptide (GIP), and glucagon. Currently available incretin-based therapies include GLP-1R agonists.

[0125] DPP-4 inhibitors are compounds that interfere with the DPP-4 enzyme, which is involved in the breakdown of incretins. Currently available DPP-4 inhibitors include sitagliptin (Januvia®) and linagliptin (Tradjenta®).

[0126] "GLP-1R agonists" and "glucagon receptor agonists" are defined as compounds containing the amino acid sequence of natural human GLP-1 (SEQ ID NO: 25) or human glucagon, as well as GLP-1 analogs, GLP-1 derivatives, or GLP-1 fusion proteins, which maintain complete or partial activity at the GLP-1 receptor. GLP-1R activity may be measured by methods known in the art, including in vivo experiments and in vitro assays measuring GLP-1 receptor binding activity or receptor activation, such as assays using islet cells or insulinoma cells, as described in European Patent No. 619,322 and U.S. Patent No. 5,120,712, respectively. GLP-1 analogs are molecules having modifications, including one or more amino acid substitutions, deletions, inversions, or additions, when compared to the amino acid sequence of natural human GLP-1 (SEQ ID NO: 25). GLP-1 derivatives are molecules that have the amino acid sequence of natural human GLP-1 (SEQ ID NO: 25) or a GLP-1 analog, but further have at least one chemical modification of one or more of the following: an amino acid side group, an α-carbon atom, a terminal amino group, or a terminal carboxylic acid group. GLP-1 fusion proteins are heterologous proteins comprising GLP-1, a GLP-1 analog, or a GLP-1 derivative moiety, and a second polypeptide. Currently available GLP-1R agonists include (Byetta® and Bydureon®), liraglutide (Victoza®), albiglutide (Tanzeum®), and dulaglutide (Trulicity®), the structures of which are known in the art. See, for example, U.S. Patent No. 5,424,286 (exenatide); U.S. Patent No. 6,268,343 (liraglutide); U.S. Patent Application Publication No. 20140447 I 7 (albiglutide); and U.S. Patent No. 7,452,966 (zulaglutide).

[0127] The term “excipient” means any substance added to a composition other than the fusion protein or any other additional active ingredient. Examples of such excipients that may be used in the compositions of this disclosure include buffers, surfactants, isotonic agents, and preservatives. “Pharmacologically acceptable excipient” means an excipient that is compatible with the other components of the composition and suitable for contact with any tissue, organ, or body part it may encounter, and that does not carry the risk of toxicity, irritation, allergic reaction, immunogenicity, or any other complications that disproportionately outweigh its therapeutic benefits. In some embodiments, excipients may be used to stabilize an agonist while in solution or to increase its initiation and maximum efficacy. Examples of such excipients include mannitol, sorbitol, m-cresol, EDTA, and citrate.

[0128] A “buffer” is a substance that resists changes in pH through the action of its acid-base conjugate components. In certain embodiments, the compositions of the present disclosure have a pH of about 5.5 to about 9.0, preferably about 7.0 to about 8.0, and more preferably about 7.2 to about 7.8. Suitable buffers for controlling the pH of the compositions of the present disclosure within a desired range include, but are not limited to, phosphates, acetates, citrates, or these acids, arginine, TRIS, HEPES, and histidine buffers, and combinations thereof. “TRIS” refers to 2-amino-2-hydroxymethyl-1,3,-propanediol and any pharmaceutically acceptable salt thereof. The free base and hydrochloride forms (i.e., TRIS-HCl) are two common forms of TRIS. TRIS is also known in the art as trimethylolaminomethane, tromethamine, and tris(hydroxymethyl)aminomethane. Preferred buffering agents in the compositions of this disclosure are citrates or citric acid, phosphates, and TRIS.

[0129] The compounds disclosed herein may comprise one or more protein components (for example, if X1 comprises one or more protein components). In some embodiments, the compounds disclosed herein comprise two or more fusion protein components or two or more conjugate protein components. As used herein, the term “fusion protein” refers to a combination of two or more distinct proteins linked together directly via a peptide bond between the C-terminus of one protein and the N-terminus of another protein, or indirectly via a linker that connects the C-terminus, N-terminus, or side chain of one protein to the C-terminus, N-terminus, or side chain of another protein (i.e., via a chemical linker such as a biofunctionalized PEG linker), or via a continuous amino acid chain. As used herein, the term “conjugate protein” refers to a combination of two or more distinct proteins linked together chemically, either directly by chemical bonds or indirectly via a chemical linker. In some cases, two or more proteins may act on the same or similar receptors (i.e., a fusion of two insulin agonist peptides), or on distinct and different receptors (i.e., one protein is an insulin receptor agonist and the other is a glucagon receptor agonist). In some cases, the fusion protein may contain only one agonist protein, while the other protein may be a human IgG Fc region or a single-domain antibody (nanobody) or a variable heavy chain sequence (V H H) is the answer.

[0130] The phrase "composition containing a fusion protein" encompasses compositions containing monomers, homodimers, heterodimers, or polymers of a fusion protein. In certain embodiments, the pharmaceutical compositions of this disclosure are compositions containing a fusion protein at a concentration of at least 1 mg / mL, at least 2 mg / mL, at least 5 mg / mL, at least 10 mg / mL, at least 20 mg / mL, at least 25 mg / mL, at least 30 mg / mL, at least 35 mg / mL, at least 50 mg / mL, at least 55 mg / mL, at least 50 mg / mL, at least 65 mg / mL, at least 75 mg / mL, at least 100 mg / mL, or higher. In some embodiments, the fusion protein is present at a concentration of 10 to 100 mg / mL. In some embodiments, the fusion protein is present at a concentration of 15 to 75 mg / mL, and in some embodiments, the fusion protein is present at a concentration of 20 to 65 mg / mL.

[0131] The pharmaceutical compositions of this disclosure may also contain a “surfactant,” meaning a substance that reduces the surface tension of a liquid. Examples of surfactants used in pharmaceutical compositions and which may be used in certain compositions of this disclosure include polysorbate 20, polysorbate 80, polyethylene glycol (e.g., PEG 400, PEG 3000, TRITON X-100), polyethylene glycol alkyl ether (e.g., BRIJ), polypropylene glycol, block copolymer (e.g., poloxamer, PLURONIC F68; poloxamer 407, PLURONIC F127; TETRONICS), sorbitan alkyl ester (e.g., SPAN), polyethoxylated castor oil (e.g., KOLLIPHOR, CREMOPHOR), and trehalose.

[0132] The pharmaceutical compositions of this disclosure may also contain preservatives. The term “preservative” refers to a compound added to a pharmaceutical formulation to act as an antimicrobial agent. Preservatives known in the art as effective and acceptable in parenteral formulations include, among others, benzalkonium chloride, benzethonium, chlorohexidine, phenol, m-cresol, benzyl alcohol, methyl- or propyl-paraben, chlorobutanol, o-cresol, p-cresol, chlorocresol, phenylmercury nitrate, thimerosal, benzoic acid, and various mixtures thereof. Examples of phenolic preservatives include the compounds phenol, m-cresol, o-cresol, p-cresol, chlorocresol, methylparaben, benzyl alcohol, and mixtures thereof. If a preservative is required, the preservatives used in the compositions of this disclosure are preferably phenolic preservatives, preferably m-cresol, phenol, and / or benzyl alcohol. Certain phenolic preservatives, such as phenol and m-cresol, are known to stabilize conformational changes by binding to insulin and insulin hexamers, thereby increasing either physical stability, chemical stability, or both. However, in compositions containing other proteins, such preservatives may contribute to the formation of protein aggregates or high molecular weight polymers (HMWPs). See, for example, Maa YF and Hsu CC, Int J Pharm 140:155-168 (1996), Fransson J, et al., Pharm. Res., 14:606-612 (1997); Lam XM, et al., Pharm. Res., 14:725-729 (1997); Remmele RL Jr, et al., Pharm Res 15:200-208 (1998), and Thirumangalathu R, et al., J Pharm Sci 95:1480-1497 (2006). In some cases, such protein assemblies in therapeutic formulations can be undesirable due to their tendency to induce an immune response.

[0133] As used herein, the term “lipophilic” means the ability to dissolve in lipids and / or to penetrate, interact with, and / or traverse biological membranes; the term “lipophilic moiety” or “lipophilic substance” means a lipophilic moiety and / or a moiety that, when bonded to another chemical moiety, increases the lipophilicity of such chemical moiety. Examples of lipophilic moieties include, but are not limited to, alkyls, fatty acids, fatty acid esters, cholesteryls, and adamantyls. In some embodiments, the lipophilic moiety has at least 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, the lipophilic portion has carbon atoms between the lower limit of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 and the upper limit of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In some embodiments, the lipophilic portion has carbon atoms between the lower limit of 2, 3, 4, 5, 6, 7, 8, 9, or 10 and the upper limit of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22. In some embodiments, the lipophilic moiety has carbon atoms between a lower limit of 3, 4, 5, 6, 7, 8, or 9 and an upper limit of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14. In some embodiments, the lipophilic moiety has carbon atoms between a lower limit of 3, 4, 5, 6, or 7 and an upper limit of 6, 7, 8, 9, or 10. In some embodiments, the lipophilic moiety is selected from the group consisting of saturated or unsaturated linear or branched alkyl moieties, saturated or unsaturated linear or branched fatty acid moieties, cholesterol, and adamantane.Examples of alkyl moieties include saturated linear alkyl moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, octadecyl, nonadecyl, and eicosyl; saturated branched alkyl moieties such as isopropyl, sec-butyl, tert-butyl, 2-methylbutyl, tert-pentyl, 2-methyl-pentyl, 3-methylpentyl, 2-ethylhexyl, and 2-propylpentyl; and unsaturated alkyl moieties derived from the above saturated alkyl moieties, including but not limited to vinyl, allyl, 1-butenyl, 2-butenyl, ethynyl, 1-propynyl, and 2-propynyl. Examples of fatty acid portions include, but are not limited to, unsaturated fatty acid portions such as lauroylates, myristoleates, palmitoleates, oleates, eloidates, erucic acids, linoleates, linolenic acids, arachidonic acids, eicosapentaenoates, and docosahexaenoates, as well as saturated fatty acid portions such as acetates, caproates, caprylates, caprinates, laurates, myristicates, palmitates, stearates, arachidinates, behenates, lignoserates, and serotinates.

[0134] As used herein, “combination therapy” or administration “in combination with” one or more additional therapeutic agents includes the administration of two or more active agents (e.g., two or more pharmacological agents) intended to treat a given indication and / or a related condition. The administration may be simultaneous (parallel) or sequential (sequential) in any order. The two or more agents of “combination therapy” may be formulated as separate compositions (e.g., formulations) or as a single composition (formulation). “Combination therapy” includes the administration of agents having different mechanisms of action or targeting different indications and / or conditions, as well as agents having similar mechanisms of action or targeting similar indications and / or conditions. For example, because patients with type 1 diabetes produce little to no insulin, effective insulin therapy for type 1 diabetes may involve the use of two types of extracorporeal insulin: rapid-acting mealtime insulin delivered by bolus injection, and long-acting basal insulin administered once or twice daily between meals to control blood glucose levels. Treatment for patients with type 2 diabetes typically begins with prescribed weight loss, exercise, and a diabetic diet. However, if these measures fail to control elevated blood glucose levels, oral medications and incretin therapy may be required, such as glucagon-like peptide-1 (GLP-1) receptor agonists and / or dipeptidyl peptidase 4 (DPP-4) inhibitors that increase incretin levels. If these medications remain insufficient, insulin therapy may be considered. Patients with type 2 diabetes whose disease has progressed to the point of requiring insulin therapy may generally begin with once-daily injections of long-acting basal insulin, but in some cases, rapid-acting insulin injections with meals may be appropriately included. In some embodiments, this disclosure provides combination therapies comprising administering rapid-acting insulin and basal insulin and / or a fusion protein comprising, for example, one or more diboronate sensors disclosed herein.

[0135] The terms “administer,” “give administration,” or “dosage” include any method or act of delivering a pharmacological agent (e.g., a medicine) to an intended subject (e.g., a patient). The pharmacological agent may be any suitable therapeutic agent, such as a biological agent, such as an antibody or its antigen-binding fragment (e.g., a pharmaceutical composition containing such an antibody or antigen-binding fragment), a peptide agent (e.g., a hormone or a modified analog thereof), or a low molecular weight agent (e.g., a structurally defined small molecule or chemical substance). Administration of a pharmacological agent may be systemic or topical. In some embodiments, administration may include one or more pharmacological agents that can be administered in parallel, simultaneously, or sequentially.

[0136] The terms “simultaneous” and “parallel” are used interchangeably and, as herein, are used to refer to the administration of two or more therapeutic agents in which at least a portion of the administrations overlaps in time, or the administration of the second therapeutic agent occurs within a period shorter than the time required to initiate the subsequent administration after the administration of the first therapeutic agent. For example, simultaneous administration includes administering a second drug after a first drug without adding any delay beyond the time required to complete the first administration and initiate the second administration.

[0137] The terms “sequentially” and “continuously” are used interchangeably and herein to refer to the administration of two or more therapeutic agents with a grace period between the administration of one therapeutic agent and the administration of another. For example, continuous administration includes the administration of two or more therapeutic agents administered at time intervals of more than about 15 minutes, for example, about 20, 30, 40, 50, or 60 minutes, one day, two days, three days, one week, two weeks, three weeks, or one month or longer.

[0138] As used herein, the term “basal insulin” may refer to several types of basal insulin, such as long-acting insulin. For example, insulin glargine, marketed under the trade name LANTUS®, contains a modified insulin structure in which asparagine at position 21 in the insulin A chain is replaced with glycine, and two arginines are added to the C-terminus of the B chain. In another example, insulin glargine-algr, marketed under the trade name LANTUS®, contains a modified insulin structure in which asparagine at position 21 in the insulin A chain is replaced with glycine, and two arginines are added to the C-terminus of the B chain. In yet another example, insulin detemir, marketed under the trade name LEVEMIR®, contains a modified insulin structure in which threonine at position 30 in the B chain is deleted, and lysine at position 29 in the B chain is derivatized through a covalent bond between a 14-carbon myristoyl fatty acid and the amine group of lysine at position B29. Insulin degludec, available in Europe and Japan under the trade name TRESIBA®, contains a modified insulin structure in which threonine at position 30 of the B chain is deleted and the ε-amino group of lysine at position 29 of the B chain is covalently derivatized with hexadecanedioic acid via a γ-L-glutamic acid linker. All of these insulins are suitable for once-daily administration. In some embodiments, the Disclosure provides the use of one or more compounds (e.g., fusion proteins of formula I or formula IB) in the manufacture of pharmaceuticals for the treatment of diseases (e.g., diabetes mellitus, obesity, dyslipidemia, or metabolic syndrome), and the pharmaceuticals are administered simultaneously, separately, or sequentially in combination with other active ingredients. The compounds and combinations disclosed herein (e.g., compounds of formula I or formula IB, fusion proteins) are effective in treating diseases and / or conditions in subjects requiring them by administering a therapeutically effective amount of the compounds and / or compositions of the Disclosure to patients requiring them.

[0139] As used herein, the terms “therapeutic dose” and “preventive dose” refer to the amount that provides therapeutic benefit in treating, preventing, or managing a disease or its apparent symptoms. A therapeutic dose may treat a disease or condition, its symptoms, or its predisposition to disease for the purpose of treating, curing, reducing, alleviating, modifying, correcting, improving, or influencing the disease, its symptoms, or predisposition to disease. A therapeutically effective set or specific amount can be readily determined by a typical healthcare professional and may vary depending on factors known in the art, such as the type of disease, the patient’s medical history and age, the stage of the disease, and the administration of other therapeutic agents. In some embodiments, the term “therapeutic dose” refers to the amount of a combination of the compounds and / or pharmaceutical compositions and / or active substances disclosed herein that is sufficient to regulate a patient’s blood glucose without causing unacceptable side effects. The therapeutic dose of a combination of the compounds and / or pharmaceutical compositions and / or active substances disclosed herein administered to a subject depends on the type and severity of the disease and the subject’s characteristics, such as general health, age, sex, weight, and tolerance to the drug. Those skilled in the art will be able to determine an appropriate dose depending on these and other factors. For example, the therapeutically effective dose of the fusion protein of this disclosure when administered once a week is in the range of about 0.01 nmol / kg to about 100 nmol / kg. In some embodiments, the therapeutically effective dose of the fusion protein of this disclosure when administered once a week is in the range of about 1 nmol / kg to about 50 nmol / kg. In some embodiments, the therapeutically effective dose of the fusion protein of this disclosure when administered once a week is in the range of about 16 nmol / kg to about 25 nmol / kg. In certain embodiments, the therapeutically effective dose of the fusion protein of this disclosure when administered once a week is in the range of about 1 mg to about 200 mg. In some embodiments, the therapeutically effective dose of the fusion protein of this disclosure when administered once a week is in the range of about 25 mg to about 175 mg. In some embodiments, the therapeutically effective dose of the fusion protein of this disclosure when administered once a week is in the range of about 100 mg to about 160 mg.

[0140] The terms “subject” and “patient” are used interchangeably herein and refer to the person receiving therapy or treatment. In some embodiments, “subject” and “patient” are human beings.

[0141] The terms "blood glucose level" and "blood glucose" are used interchangeably herein and refer to the concentration of sugar present in the blood. The amount of sugar in a blood sample can be measured using a blood glucose meter or glucometer. Blood glucose levels are generally measured as mg of sugar per dL of blood (mg / dL). Blood glucose levels can refer to any level of sugar disclosed herein. For example, blood glucose levels include the concentration of glucose in the blood, also known as blood glucose / concentration.

[0142] As used herein, the term “steady state” refers to a constant / fixed state in which there is no increase or decrease in the variable of interest, or the fluctuation is minimal (i.e., less than 10%). In some embodiments, an insulin receptor agonist is infused intravenously (IV) in a fixed-dose bolus, and blood glucose is maintained at a predetermined “steady state” level (e.g., 100 mg / dL for normal blood glucose, 200 mg / dL for hyperglycemia) by continuous infusion of glucose at a variable rate (mg / kg / min). The amount of glucose infused to maintain the “steady state” blood glucose level is equal to the systemic glucose uptake and utilization.

[0143] The term "hyperglycemia" is used herein to refer to physiologically high blood glucose levels. Hyperglycemia refers to a state of physiologically high blood glucose levels. The blood glucose levels considered hyperglycemic vary depending on the species. For example, in rats, hyperglycemia refers to blood glucose levels of 200 mg / dL or higher. In humans, hyperglycemia refers to blood glucose levels greater than 180 mg / dL.

[0144] The term "normal blood glucose" is used herein to refer to physiologically normal blood glucose levels. Normal blood glucose refers to a state of normal blood glucose levels. Blood glucose levels considered normal vary depending on the species. For example, in rats, normal blood glucose refers to blood glucose levels below 200 mg / dL. In humans, normal blood glucose refers to blood glucose levels between 70 and 180 mg / dL.

[0145] The term "glucose infusion rate" is used herein to refer to the rate at which glucose is injected into a subject. The glucose infusion rate (GIR) is calculated in mg / kg / min as follows: (infusion rate (mL / hour) × glucose concentration (g / dL) × 1000 (mg / g)) / weight (kg) × 60 (min / hour) × 100 (mL / dL), where "infusion rate" refers to the rate at which glucose is injected into the subject, "glucose concentration" refers to the concentration of glucose being injected, and "weight" refers to the body weight of the subject. In some embodiments, the GIR corresponds to the glucose infusion rate required to maintain a specific blood glucose level.

[0146] As used herein, the term “relative glucose infusion rate difference” refers to the difference in the amount of glucose infused between two different conditions, experiments, or measurements. In some embodiments, it may be measured by taking the difference between (a) the area under the curve (AUC) for one recorded GIR to maintain a particular blood glucose concentration and (b) the AUC for another recorded GIR to maintain a different blood glucose concentration. Generally, the AUC for the GIR to maintain a lower blood glucose concentration is subtracted from the AUC for the GIR to maintain a higher blood glucose concentration. For example, if the AUC for a first GIR (providing a blood glucose concentration of 100 mg / dL) is 600 mg / kg / min and the AUC for a second GIR (providing a blood glucose concentration of 200 mg / dL) is 800 mg / kg / min, then subtracting the AUC of the first GIR from the AUC of the second GIR gives a relative glucose infusion rate difference of 200 mg / kg / min.

[0147] As used herein, the term “relative glucose infusion rate ratio” refers to the ratio of the amount of glucose injected between two different conditions, experiments, or measurements. In some embodiments, it may be measured by taking the ratio of (a) the area under the curve (AUC) for one recorded GIR to maintain a blood glucose concentration and (b) the AUC for another recorded GIR to maintain a different glucose concentration. Generally, the AUC for the GIR to maintain a higher blood glucose concentration is divided by the AUC for the GIR to maintain a lower blood glucose concentration. For example, if the AUC of a first GIR (providing a blood glucose concentration of 100 mg / dL) is 600 mg / kg / min and the AUC of a second GIR (providing a blood glucose concentration of 200 mg / dL) is 800 mg / kg / min, then dividing the AUC of the second GIR by the AUC of the first GIR gives a relative glucose infusion rate ratio of 1.33.

[0148] As used herein, the term “Area under curve” refers to the area bounded by a curve, an axis, and two boundary points, whether plotted or mathematically represented. In some embodiments, the curve used to calculate the Area under curve (AUC) is a measure of GIR as a function of time, with the X-axis corresponding to time and the Y-axis corresponding to GIR, and the origin at 0 on the Y-axis (i.e., the X-axis and Y-axis intersect at 0 on the Y-axis). For example, the curve may be a GIR recorded over a period of time, and the boundary points are the GIR at the start and end of injection in the experiment. The AUC is then calculated for the area between the plotted curve and the X-axis between the start boundary point and the end boundary point. Mathematically, the AUC can be calculated according to methods known to those skilled in the art, e.g., the method in Tai MM (1994) Diabetes Care, 17(2):152-154 (the contents of which are incorporated herein by reference in their entirety). In some embodiments, the area under the curve (AUC) is calculated using the trapezoidal rule and applying baseline correction. In some embodiments, the AUC is calculated using GraphPad Prism v9. For baseline correction, the average GIR value from 30 minutes before injection (x=-30 min) to the time of injection (x=0) can be subtracted from each GIR value from time 0 (x=0) to the last measured point in time (x=300). The trapezoidal calculation is as follows:

[0149]

number

[0150]

number

[0151] As used herein, the term "EC50" refers to the maximum half-value effective concentration of a compound in a dose-response assay. EC50 is a measure of the concentration of a compound required to produce half of the maximum possible effect as a result of exposure to the compound. EC50 can be calculated using methods known in the art. In some embodiments, EC50 is given by the following formula: Y = bottom + (X^hill slope) * EC50 can be calculated using a four-parameter logistic regression curve with the formula (top-bottom) / (X^hill slope + EC50^hill slope), where Hill slope refers to the slope of the sigmoid curve between the upper and lower plateaus of the dose-response curve. In some embodiments, EC50 can be calculated using GraphPad Prism v7, 8, or 9. If a compound has its EC50 measured at two or more concentrations of sugar (e.g., glucose), then (a) the term “first sugar concentration” refers to a first, lower sugar concentration, for example, if the concentration is about 3 mM or about 5.6 mM, and (b) “second sugar concentration” refers to a second, higher sugar concentration, for example, if the concentration is about 10 mM, about 16.7 mM, about 20 mM, or about 30 mM. In some embodiments, for example, the fold change in insulin receptor phosphorylation (IR phosphorylation) activity of exemplary compounds of formula I or formula IB from low glucose concentration (e.g., about 5.6 mM) to high glucose concentration (e.g., about 16.7 mM) was evaluated by comparing the EC50 of the dose-response curves. This fold change in activity was determined by dividing the EC50 of the compound (e.g., a compound of formula I or formula IB) at a "low" glucose concentration (e.g., about 5.6 mM) by the EC50 of the same compound at a "high" glucose concentration (e.g., about 16.7 mM), while keeping all other conditions constant. See the example titled "In vitro demonstration of the activity of compounds of formula IB".

[0152] As used herein, the term "Kd" refers to the dissociation constant, reflecting the binding affinity between a ligand (e.g., a diboronate sensor as described herein) and its target (e.g., a sugar, e.g., glucose). For example, in the context of the diboronate sensors described herein, "glucose Kd" and "average glucose Kd" refer to the affinity of the diboronate sensor to glucose, in which case Kd is measured before the diboronate sensor is conjugated to an insulin molecule to produce the compounds described herein. The binding of the diboronate sensors described herein to glucose can be measured by an Alizarin red S (ARS) substitution assay, which is recorded before the diboronate sensor is conjugated (e.g., covalently bonded) to an insulin molecule (e.g., a compound of formula I or formula IB). The ARS substitution assay is known in the art, for example, in Springsteen and Wang (2001) Chem. 1608-1609, which is incorporated herein by reference in its entirety. In the ARS substitution assay, the diboronate sensor disclosed herein is incubated with ARS, and the fluorescence emission is recorded. The diboronate sensor and ARS compositions described herein are then titrated against serial dilutions of sugar (e.g., glucose), and the fluorescence emission after incubation is measured to determine the substitution of the ARS when the diboronate sensor binds to the sugar. The change in intensity (fluorescence emission with and without sugar) can be plotted against the sugar concentration to generate an association constant for sugar binding. If the diboronate sensor has a higher binding constant for the sugar, Kd increases. Furthermore, the diboronate sensors described herein include those with selective affinity / binding to sugars. For example, the diboronate sensors described herein may include sensors with increased affinity (binding ability) to glucose, but without increased affinity to other sugars such as lactate and / or fructose. See the example titled "Procedure for Measuring Glucose, Fructose, and Lactate Binding (Kd) Using an ARS Substitution Assay."

[0153] As used herein, the terms “clamp,” “clamp assay,” and “clamped” refer to the hyperglycemic / euglycemic clamp (glucose clamp), which is recognized as the “gold standard” method for detecting insulin activity via glucose utilization in experimental animals and humans. In a hyperglycemic / euglycemic clamp, in certain embodiments, plasma (blood) insulin concentration rises rapidly and is maintained by continuous insulin infusion, while plasma glucose concentration is kept constant at a predetermined hyperglycemic or euglycemic level by a variable glucose infusion rate (GIR). Once a steady-state blood glucose level is achieved, the glucose infusion rate is equal to insulin receptor-stimulated glucose uptake by all tissues in the body and is therefore a measure of insulin activity at a particular blood glucose level. For example, in some embodiments, glucose is continuously infused into the subject throughout the course of the study, and the glucose infusion rate is adjusted to maintain a constant blood glucose level in response to the administration of a compound (e.g., a compound of formula I or formula IB). Changes in the glucose infusion rate in response to the administration of a compound at a specific dose level or concentration are recorded and used to determine the glucose infusion rate. In some embodiments, the sugar is glucose. See, for example, Lautt WW, et al. (1998) Canadian Journal of Physiology and Pharmacology. 76 (12):1080-1086 (the entire content of which is incorporated herein by reference). The clamp techniques / assays mentioned and used herein are known in the art and are modifications of disclosed techniques. See the example titled "In vivo demonstration of the activity of compounds of formula IB".

[0154] As used herein, terms such as "[bond point to]", "[bond to]", and "[covalent bond to]" indicate that the indicated atom, bond, or linkage is closer to the indicated group than other bond points or covalent bonding variables in the structural formula. In some embodiments, the bond point or covalent bond may be directly adjacent to the indicated group, and in some embodiments, other atoms or groups may be present between them.

[0155] As used herein, the term “homology percentage” refers to the percentage of sequence identity between two sequences after optimal alignment. Identical sequences have a homology percentage of 100%. Optimal alignment may be performed by homology alignment algorithms, such as those described by Pearson and Lipman’s Similarity Search Method, Proc. Natl. Acad. Sci. USA 85:2444 (1988), or by general methods described in Neddleman and Wunsch’s Similarity Search, J. Mol. Biol. 48:443 (1970), including the execution of these algorithms or visual comparisons. As used herein, “insulin A chain” refers to the insulin chain with the highest homology percentage to the A chain of wild-type human insulin. As used herein, “insulin B chain” refers to the insulin chain with the highest homology percentage to the B chain of wild-type human insulin.

[0156] In some embodiments, the terms “covalently connected,” “covalently conjugated,” or “via covalent bonds” may be used interchangeably to indicate that two or more atoms, groups, or chemical moieties are bonded or connected via chemical bonds. In some embodiments, a chemical bond (which may be called a covalent bond in some embodiments) may be one or more shared electron pairs between two atoms, groups, or chemical moieties (e.g., in a single, double, or triple bond). In some embodiments, a chemical (covalent) bond may further include one or more atoms or functional groups, which may be referred to using the corresponding names of those functional groups in the art. For example, a covalent bond containing an -SS- group may be called a disulfide bond, a covalent bond containing an -(C=O)- group may be called a carbonyl bond, a covalent bond containing an -(CF2)- group may be called a difluoromethylene bond, and so on. The type of bond or functional group within a covalent bond is not limited unless explicitly stated, for example, if it is stated that it contains or is selected from certain groups. The preferred type or kind of covalent bond will be understood from the description and / or context.

[0157] In some embodiments, insulin receptor agonists may bind to or associate with human serum albumin (HSA) before binding to the insulin receptor. For example, an insulin receptor agonist containing any one of DSL-1 to DSL-172 may associate with or bind to HSA via hydrogen bonding, ion association, or hydrolyzable boron ester bonding. These interactions may occur along the surface of HSA, e.g., salt crosslinks to lysine residues, cleavable boron ester bonds formed by serine, threonine and / or tyrosine hydroxyl groups, and / or at specific locations on HSA, e.g., site I or site II small molecule drug binding sites, or one or more of the seven fatty acid binding sites (Yamasaki, K. et. al. (2013) Biochimica et Biophysica Acta 12:5435-5443).

[0158] In some embodiments, the side chains of amino acids may be covalently bonded (e.g., linked or crosslinked) via any number of chemical bonds (e.g., bonding sites) as commonly described in Bioconjugate Techniques (Third edition), edited by Greg T. Hermanson, Academic Press, Boston, 2013. For example, the side chains may be covalently bonded via amides, esters, ethers, thioethers, isoureas, imines, triazoles, or any suitable covalent chemistry available in the art for covalently bonding one peptide, protein, or synthetic polymer to a second peptide, protein, or synthetic polymer. The term polymer includes polypeptides. The term "covalent chemistry" may refer to one or more functional groups contained in the bonding site and / or the chemical reactions used to form the bonding site.

[0159] The term "adjacent diol" refers to a group of molecules in which two hydroxyl groups occupy adjacent positions, that is, are bonded to adjacent atoms. Such molecules may include, but are not limited to, sugars such as hexoses, glucose, mannose, and fructose.

[0160] In some embodiments, the term “albumin” means human serum albumin or a protein having at least 60% homology to human serum albumin protein. In some embodiments, it should be understood that albumin may be further chemically modified for binding purposes. In some embodiments, such modifications may include one or more covalently linked linkers. In some embodiments, the term “albumin” means human serum albumin or a protein having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology percentages to human serum albumin protein. In some embodiments, the term “albumin” means human serum albumin or a protein having at least 90% homology percentages to human serum albumin protein. In some embodiments, the term “albumin” means human serum albumin or a protein having at least 95% homology percentages to human serum albumin protein. In some embodiments, the term “albumin” means human serum albumin, or a protein having at least 99% homology to human serum albumin protein. In some embodiments, albumin is unmodified human serum albumin.

[0161] The term “treatment” means both the prevention and minimization of the disease, disorder, or condition mentioned (i.e., “treatment” means both the prophylactic and therapeutic administration of the compounds of the Disclosure or compositions containing the compounds of the Disclosure, unless otherwise indicated or unless the context clearly contradicts it). The route of administration may be any route that effectively delivers the compounds of the Disclosure to a desired or appropriate location in the body, such as parenteral, e.g., subcutaneous, intramuscular, oral, or intravenous. In the case of parenteral administration, the compounds of the Disclosure are formulated in the same manner as known insulin preparations. Furthermore, in the case of parenteral administration, the compounds of the Disclosure are administered in the same manner as known insulin administrations, and physicians are familiar with this procedure. The amount of the compounds of the Disclosure to be administered, the frequency of administration of the compounds of the Disclosure, and the selection of one or more compounds of the Disclosure to be administered optionally together with another antidiabetic compound should be determined in consultation with a practicing physician familiar with the treatment of the condition being treated (e.g., diabetes).

[0162] In some embodiments, “therapeutic composition” and “pharmaceutical composition” as used herein mean compositions intended to have therapeutic effects, such as pharmaceutical compositions, genetic material, biologics, and other substances. Pharmaceutical compositions can be configured to function in the body with therapeutic quality. Concentrations may be changed, for example, to reduce the frequency of supplementation. In some embodiments, “therapeutic effective dose” and “preventive effective dose” refer to amounts that provide therapeutic benefit in the treatment, prevention, or management of a disease or its apparent symptoms. A therapeutic effective dose may treat a disease or condition, symptoms of a disease, or predisposition to a disease for the purpose of treating, curing, reducing, alleviating, modifying, correcting, improving, or influencing the disease, symptoms of a disease, or predisposition to a disease. A therapeutically effective set or specific amount can be readily determined by a typical healthcare professional and may vary depending on factors known in the art, such as the type of disease, the patient’s medical history and age, the stage of the disease, and the administration of other therapeutic agents. In some embodiments, the modified insulin described herein may be delivered to the body by injection or inhalation or by other routes and may reversibly bind to soluble glucose in a non-depot form. In some embodiments, the modified insulin described herein is released over a long period of time from a local depot in the body or from a form bound to a serum protein such as albumin. In some embodiments, the release of modified insulin is accelerated as glucose levels rise, and such release rates may depend on blood glucose levels or levels of other small molecules in the blood, including diol-containing molecules. In some embodiments, the release, bioavailability, and / or solubility of the modified insulin described herein are controlled as a function of blood or serum glucose concentration or the concentration of other small molecules in the body.

[0163] Unless otherwise specified, the structures described herein also mean that they may contain different compounds by the presence of only one or more isotopically enriched atoms. For example, deuterium ( 2 H) or tritium ( 3 Replacement of hydrogen by H), or 13 C- or 14Compounds having the current structure, except for carbon substitution by a 1C carbon atom, are within the scope of this disclosure. Such compounds may be useful, for example, as analytical tools, probes in biological assays, or therapeutic agents.

[0164] In some embodiments, functional groups can be covalently bonded or linked via any suitable covalent chemistry (linker) that can be used to covalently bond one functional group or amino acid side chain to another functional group, non-limiting examples of which include amides, esters, ethers, thioethers, isoureas, imines, and triazole linkers. In some embodiments, functional groups are covalently bonded by click chemistry reactions as defined in the art. These include, but are not limited to, cycloaddition reactions, 3+2 cycloaddition, strain-enhanced alkyne-nitrone cycloaddition, strain alkenes, alkenes, and tetrazine reverse demand Diels-Alder reactions, copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), thiol-maleimide addition, strain-enhanced azide-alkyne cycloaddition, Staudinger ligation, nucleophilic ring-opening reactions, and addition to carbon-carbon multiple bonds. Some of these reactions are described, for example, by H. Kolb, M. Finn and K. Sharpless (2001); Click Chemistry: Diverse Chemical Function from a Few Good Reactions, Angewandte Chemie International Edition 40(11):2004-2021; Kolb and Sharpless, Drug Discovery Today 8:1128-1137, 2003; Huisgen, R. Angew. Chem. Int. Ed. Engl. 1963, 2, 565; Agard, N.J.; Baskin, J.M.; Prescher, JA; Lo, A.; Bertozzi, CRACS Chem. Biol. 2006, 1, 644. Those skilled in the art can select buffers, pH, and reaction conditions suitable for such click reactions. In some embodiments, covalent bonding is the result of a “biorthogonal reaction” as defined in the art.Such reactions are described, for example, by Sletten, Ellen M.; Bertozzi, Carolyn R. (2009). Bioorthogonal Chemistry: Fishing for Selectivity in a Sea of ​​Functionality, Angewandte Chemie International Edition 48(38):6974-98.; Presser, Jennifer A; Bertozzi, Carolyn R (2005). Chemistry in living systems, Nature Chemical Biology 1(1):13-21.

[0165] In some embodiments, functional groups may be bonded using natural chemical ligation, for example, as described by Dawson, PE; Muir, TW; Clark-Lewis, I.; Kent, SB (1994) Synthesis of proteins by native chemical ligation, Science 266(5186):776-778. Where used herein, terms such as “linking” and “covalent bond” may, in some embodiments, refer to any of the chemistry described above. The terms “amine,” “amino group,” and / or “amine group” may be used interchangeably to indicate the amino group or amine group to which the described element is covalently bonded when used to describe a covalent bond or part of the connectivity. In some embodiments, the amino group or amine group may be a primary amine, a secondary amine, or

[0166]

number

[0167] In some embodiments, the amino or amine group may be an NH2 group at the N-terminus of a peptide or peptide chain, or an NH2 group on a lysine side chain, but embodiments of the present disclosure are not limited thereto. In some embodiments, the linkage of a first group to a second group is described by reference to an amine or amino group derived from the second group, which is part of the covalent bond between the first and second groups. For example, an amine on a lysine side chain on X1 may be referred to as an amine, and may further be described as being conjugated via an amide bond to specify the structure and linkage of the functional group constituting the covalent bond. When the covalent bond is via an amine bond or amine linkage, it is referred to as an amine linkage. It should be understood that a carbonyl group linked to an amine (e.g., a (C=O)-NH moiety) constitutes an amide bond, and therefore, by definition, an amine bond is not directly linked to a carbonyl group. In other words, the terms “amide bond” and / or “amide linkage” can be used interchangeably to indicate a carbonyl (e.g., (C=O)-NH moiety) connected to an amine when used to describe a covalent bond or connectivity.

[0168] In some embodiments, further modifications include the addition of chemical entities (e.g., partial or functional groups) such as carbohydrate groups, one or more cis-diol-containing groups, one or more phosphate groups, one or more catechol groups, farnesyl groups, isofarnesyl groups, fatty acid groups, or linker linking for conjugation, functionalization, or other modifications intended to affect the pharmacokinetics, pharmacodynamics, and / or biophysical solution properties of insulin.

[0169] In some embodiments, the compound comprises a human peptide hormone (e.g., as X1). In some embodiments, the peptide hormone is a polypeptide hormone from the human pancreas. In some embodiments, X1 in formula I is NH2. In some embodiments, the compound, such as the compound of formula I, comprises human insulin or a human insulin analog. In some embodiments, two different amine groups in insulin are covalently bonded as described by formula I or formula IB.

[0170] It will be understood that “human peptide hormone,” “human pancreatic polypeptide hormone,” “insulin,” “human insulin,” “modified insulin,” and “human insulin analog” may be used interchangeably in some of the embodiments described. That is, for example, in a particular embodiment, “human insulin analog” may be used instead in embodiments described as using human insulin. In some embodiments, a compound such as the compound of formula I comprises human insulin or a human insulin analog. In some embodiments, the compound comprises human insulin or a human insulin analog as described by formula I or formula IB for p'=1, and a single amino group in insulin is conjugated as described by formula I or formula IB. In some embodiments, the amino group is the N-terminus of the B chain of insulin or the amino group of the lysine side chain. In some embodiments, two different amine groups in insulin are each independently covalently bonded as described by formula I or formula IB. In some embodiments, at least one amine group is the N-terminus of the B chain of insulin. In some embodiments, the amino group comprises the amino group of the lysine residue side chain of insulin.

[0171] Various suitable modifications of peptide hormones known to those skilled in the art (e.g., human polypeptide hormones, e.g., insulin) are included within the scope of this disclosure. In some embodiments, the polypeptide optionally extended at the N-terminus of the B chain or the C-terminus of the A chain of insulin may contain sequences having up to 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence homology to the human polypeptide sequence. In some embodiments, the polypeptide of Z1a, or the polypeptide optionally extended at the N-terminus of the B chain or the C-terminus of the A chain of insulin, contains sequences having up to 70% sequence homology to the human polypeptide sequence. In some embodiments, the polypeptide of Z1a, or the polypeptide optionally extended at the N-terminus of the B chain or the C-terminus of the A chain of insulin, optionally contains one or more lysine residues adjacent to a proline residue, where proline is the C-terminus of lysine. In some embodiments, the amino groups of the lysine residues are each independently conjugated as described by formula I or formula IB.

[0172] In some embodiments, insulin is further modified by conjugation to sugars, diol-containing molecules, and / or polyol-containing molecules. In some embodiments, the human polypeptide hormone is a bi- or tri-hybrid peptide comprising sequences of two or more human peptide hormones and can act via multiple receptors; for example, glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonists or GLP-1 / GIP / glucagon tri-agonists. In some embodiments, the human polypeptide hormone is an intestinal hormone. In some embodiments, human polypeptide hormones include c-peptide, adrenocorticotropic hormone (ACTH), amyrin, angiotensin, atrial natriuretic peptide (ANP), calcitonin, cholecystokinin (CCK), gastrin, ghrelin, glucagon, growth hormone, follicle-stimulating hormone (FSH), insulin, leptin, melanocyte-stimulating hormone (MSH), oxytocin, parathyroid hormone (PTH), prolactin, renin, somatostatin, thyroid-stimulating hormone (TSH), and thyrotropin-releasing hormone. The compounds are selected from hormones (TRH), vasopressin, vasoactive intestinal peptides, neuropeptides, peptide hormones that affect cardiovascular health or appetite, hybrids of one or more of these peptides, and analogs of one of these peptides. In some embodiments, the compounds include human polypeptide hormones further modified by, for example, polymers, XTEN protein sequences, or covalent bonding to aliphatic chains. In some embodiments, polymer-modified compounds have a longer circulating time in the blood. In some embodiments, polymer-modified compounds have a circulating time suitable for once-daily, once-weekly, or once-monthly injections.In some embodiments, polymer-modified compounds, such as long-acting variants, require injections once daily, once weekly, or once monthly. In some embodiments, human polypeptide hormones or analogues comprise one or more L- or D-amino acids, each independently being one of 20 standard or non-standard amino acids.

[0173] In some embodiments, the insulin receptor agonist is an insulin analog comprising an A chain and a B chain, wherein the A chain comprises a sequence selected from SEQ ID NOs: 1, 25, 24051, and 24052, and optionally, the B chain comprises a sequence selected from SEQ ID NOs: 24060, 24061, 24062, 24063, 24064, and 25000-25397. In some embodiments, the insulin analog comprises an A chain comprising a sequence selected from SEQ ID NOs: 1, 24051, and 24052, and a B chain comprising a sequence selected from SEQ ID NOs: 24063, 25095, 25228, 25229, 25232, 25236, 25305, 25308, 25312, and 25380-25397. In some embodiments, the insulin analog comprises human insulin having an A chain and a B chain, with up to six residues mutated, deleted, or additionally inserted into each of the A chain and / or B chain. In some forms, the insulin analog comprises insulin containing an A chain and a B chain having a linkage peptide that connects the C-terminus of the B chain to the N-terminus of the A chain, the linkage peptide comprising the natural proinsulin C peptide and shorter versions of C peptides known in the art, the shorter versions of C peptides enabling the single-chain insulin to retain biological activity and / or potency.

[0174] The terms analog and analogue are alternative notations of the same word and are used interchangeably herein and have the same meaning. In the context of human hormones, endocrine hormones, insulin, human insulin, glucagon, amylin, relaxin, GLP-1, oxytomodulin, somatostatin, gastric inhibitory polypeptides, glucose-dependent insulin-secreting polypeptides, and hybrid peptides comprising sequences derived from two or more human polypeptide hormones, an analog means any related sequence resulting from a parent sequence, including up to eight amino acid mutations, deletions or insertions and / or additional chemical modifications. In some embodiments, as is known in the Art, such analogues may enhance biological activity, pharmacokinetics, pharmacodynamics, potency, stability and / or chemical and physical properties.

[0175] In some embodiments, the human hormone analog comprises one or more residues that are 2-aminoisobutyric acid and / or other artificial (i.e., non-natural) amino acids.

[0176] In some embodiments, the C-terminus of the B-chain of insulin is covalently bonded to the N-terminus of the A-chain in the insulin analog. In some embodiments, the C-terminus of the B-chain of insulin is covalently bonded to the N-terminus of the A-chain, and the binding peptide is a C-peptide, further comprising any intermediate compound containing a conjugate of formula I or formula IB.

[0177] In some embodiments, the insulin analog includes insulin lispro, or glargine-type modifications, or any suitable modifications to human insulin that affect the pharmacokinetics or half-life of insulin in the body (e.g., blood). In some embodiments, the insulin repro used to prepare the PEGylated insulin repro compounds of this disclosure may be prepared by any of a variety of recognized peptide synthesis techniques, including solution-phase, solid-phase, semi-synthetic, and recombinant DNA methods. For example, U.S. Patent No. 5,700,662 (Chance, et al.) and European Patent No. 214,826 (Brange, et al.) disclose the preparation of various insulin analogs. The A and B chains of insulin lispro can also be prepared via proinsulin-like precursor molecules using recombinant DNA technology. In some embodiments, a proinsulin-like precursor is used to prepare the insulin lispro used to prepare the PEGylated insulin lispro compounds of this disclosure.

[0178] In some embodiments, the insulin portion of the compounds of the present invention may be prepared by the production of precursor protein molecules using recombinant DNA technology. The DNA, including cDNA and synthetic DNA, may be double-stranded or single-stranded. The coding sequences encoding the precursor protein molecules described herein may be altered as a result of genetic coding duplication or degeneracy. To produce the precursor proteins of this disclosure, DNA can be introduced into host cells. Suitable host cells are transiently or stably transfected or transformed in an expression system for producing the precursor proteins. Host cells may be bacterial cells such as strains K12 or B of Escherichia coli, fungal cells such as yeast cells, or mammalian cells such as Chinese hamster ovary ("CHO") cells. Expression vectors are typically replicable in the host organism, either as episomes or as an integrated portion of host chromosomal DNA. Generally, expression vectors include selection markers, e.g., tetracycline, neomycin, and dihydrofolate reductase, to allow selection of those cells transformed with the desired DNA sequence.

[0179] In some embodiments, the polypeptide hormone is glucagon. In some embodiments, glucagon has additional mutations and modifications known to affect the solubility and solution stability of glucagon. In some embodiments, the compound, for example, the compound of formula I or formula IB, comprises a conjugation of a diboronate, diol-containing moiety, or polyol to the N-terminus of the B chain of insulin via a peptide bond, and at least one additional conjugation to insulin as described by formula I or formula I. In some embodiments, the compound comprises a conjugation of Z1a to the N-terminus of the B chain of insulin via a peptide bond, and at least one additional conjugation to insulin as described by formula I. In some embodiments, the additional conjugation is to a lysine residue of insulin. In some embodiments, at least one such lysine is a residue between position 15 and the C-terminus of the B chain of insulin. In some embodiments, the lysine residue is optionally adjacent to proline, glycine, arginine, threonine, or serine. In some embodiments, one or more amino acids of formula I or formula IB are D-amino acids. In some embodiments, any secondary or primary amine in a compound, such as a compound represented by formula I or formula IB, is optionally acetylated independently. In some embodiments, the compound of formula I or formula IB has a polypeptide hormone X1 further conjugated with a drug molecule, contrast agent, chelating agent, contrast agent, radioisotope, or molecule involved in immune cells.

[0180] In some embodiments, X1 is a polypeptide hormone comprising a peptide ligand that binds to an extracellular protein receptor. In some embodiments, X1 comprises a polypeptide analog of a human polypeptide hormone having at least 50% homology to a native human polypeptide hormone. In some embodiments, X1 comprises a polypeptide analog of a human polypeptide hormone having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology to a native human polypeptide hormone. In some embodiments, X1 comprises a polypeptide analog of a human polypeptide hormone having at least 90% homology to a native human polypeptide hormone. In some embodiments, X1 comprises a polypeptide analog of a human polypeptide hormone having at least 95% homology to a native human polypeptide hormone. In some embodiments, X1 comprises a polypeptide analog of a human polypeptide hormone having at least 99% homology to a native human polypeptide hormone. In some embodiments, X1 is a human insulin analog having up to 10 additional residues added to the A or B chain of insulin.

[0181] In some embodiments, the term “glucose responsiveness” refers to the change in activity in the presence and absence of glucose, or in the difference between low and high levels of glucose (e.g., 5.6 mM glucose vs. 16.7 mM glucose, 3 mM glucose vs. 20 mM glucose). In some embodiments, the activity of conjugate insulin is evaluated by the concentration of insulin (in nanomolar units (nM) of insulin) required to induce a semi-maximal response (EC50) in a cell-based assay. Conjugate insulin at low EC50 concentrations is more active than insulin at higher EC50 concentrations (e.g., insulin with an EC50 of 3 nM is more active than insulin with an EC50 of 50 nM). “Glucose response” is observed when insulin changes from a lower EC50 (higher nM) to a higher EC50 (lower nM), respectively, in the presence and absence of glucose, or in the difference between lower and higher levels of glucose.

[0182] In some embodiments, the compound of formula I or formula IB comprises one or more L- or D-artificial amino acids that are not one of the 20 natural amino acids. In some embodiments, the side chains of such artificial amino acids can be covalently bonded by several reactions, including bioorthogonal reactions, as described, for example, by Rostovtsev, VV, Green, LG, Fokin, VV & Sharpless, KBA: stepwise huisgen cycloaddition process: copper(I)-catalyzed regioselective "ligation" of azides and terminal alkynes. Angew. Chem. Int. Ed. 41, 2596-2599 (2002), or by: Liang, Y., Mackey, JL, Lopez, SA, Liu, F. & Houk, KN: Control and design of mutual orthogonality in bioorthogonal cycloadditions. J. Am. Chem. Soc. 134, 17904-17907 (2012). In some embodiments, the compound of formula I or formula IB may contain one or more L- or D-artificial amino acids that are not one of the 20 natural amino acids. In some embodiments, Z1a contains one or more L- or D-artificial amino acids that are not one of the 20 natural amino acids. In some embodiments, the side chains of two amino acids in formula I or formula IB may be covalently bonded together via a triazole bond.

[0183] Insulin is an important regulator of blood glucose (sugar) levels. In healthy individuals, insulin is present and, when released from the pancreas, acts to lower blood glucose levels by, for example, binding to and activating insulin receptors, thereby inducing glucose absorption by liver, fat, and skeletal muscle cells. Diabetes mellitus (DM), commonly referred to as diabetes, is a group of metabolic diseases characterized by persistently high blood glucose levels over a long period.

[0184] As used herein, “insulin” encompasses both wild-type and modified forms of insulin that can bind to and be activated by insulin receptors or that can cause a measurable decrease in blood glucose when administered in vivo, and also encompasses both wild-type and modified forms of human insulin that can bind to and be activated by human insulin receptors or that can cause a measurable decrease in blood glucose when administered in vivo to humans.

[0185] In some embodiments, insulin includes insulin of any species, whether in purified, synthetic, or recombinant form, and includes human insulin, porcine insulin, bovine insulin, sheep insulin, and rabbit insulin. In some embodiments, insulin has two chains, a B chain and an A chain. In some embodiments, the chains are linked together via a peptide, such as a c-peptide known in the art, or a shortened version thereof, and in other embodiments, insulin may be provided as proinsulin (insulin precursor) which can be further processed into mature insulin. Various modified forms of insulin are known in the art and can be chemically modified, such as by the addition of chemical moieties such as PEG groups or fatty acyl chains. Modified insulin may be mutated, including by the addition, deletion, or substitution of amino acids. In some embodiments, the term "desB30" refers to insulin lacking the B30 amino acid residue.

[0186] As used herein, the term “insulin analog” means modified human insulin having insulin receptor agonist activity, wherein 1 to 10 amino acid residues are modified compared to human insulin (e.g., substitution, deletion, addition (i.e., elongation), insertion, and any combination thereof). In this context, the insertion or addition of one or more amino acids is considered a single modification. For example, an insulin analog may have 1 to 9 modified amino acid residues. As yet another example, an insulin analog may have 1 to 8 modified amino acid residues. As yet another example, an insulin analog may have 1 to 7 modified amino acid residues. As yet another example, an insulin analog may have 1 to 6 modified amino acid residues. As yet another example, an insulin analog may have 1 to 5 modified amino acid residues. As yet another example, an insulin analog may have 1 to 4 modified amino acid residues. As yet another example, an insulin analog may have 1 to 3 modified amino acid residues. As yet another example, an insulin analog may have 1 to 2 modified amino acid residues. In some embodiments, the insulin analog may have 2, 3, 4, 5, 6, 7, 8, or 9 modified amino acid residues.

[0187] Modifications in the insulin molecule are indicated by the chain (A or B), position, and the one- or three-letter code of the amino acid residue substituting the native amino acid residue. In this specification, terms such as "A1," "A2," and "A3" refer to the amino acids at positions 1, 2, and 3 of the A chain (counting from the N-terminus), respectively. Similarly, terms such as "B1," "B2," and "B3" refer to the amino acids at positions 1, 2, and 3 of the B chain (counting from the N-terminus), respectively. Using one-letter amino acid codes, terms such as A21A, A21G, and A21Q indicate that the amino acid at position A21 is A, G, and Q, respectively. Using three-letter amino acid codes, the corresponding expressions are A21Ala, A21Gly, and A21Gln, respectively.

[0188] Therefore, for example, an insulin analog having four modifications comprises an A chain and a B chain, the A chain containing the sequence GIVEQCCTSICSLYQLENYCN (SEQ ID NO: 1), the B chain containing the sequence GKGSHKFVNQHLCGSHLVEALYLVCGKRGFFYTPR (SEQ ID NO: 25228), the A chain having the wild-type sequence of human insulin's A chain (e.g., no mutations, deletions, or additions), the B chain being extended at the N-terminus with GKGSHK (i.e., 6 amino acids added / appended to the N-terminus), the amino acid at position 21 of the B chain (i.e., E) being substituted with K, the amino acid at position 29 of the B chain (i.e., K) being substituted with R, and the amino acid at position 30 of the B chain (i.e., Thr) being deleted (as shown below).

[0189] [ka]

[0190] As yet another example, an insulin analog with seven modifications comprises an A chain and a B chain, the A chain contains the sequence GIVEQCCTSICSLYQLENYCGK (SEQ ID NO: 25), the B chain contains the sequence KGSHKFVDQHLCGSHLVEALYLVCGKRGFFYTPR (SEQ ID NO: 25393), the A chain has the amino acid at position 21 (i.e., N) replaced with G, and the A chain is extended with K at the C-terminus (i.e., one amino acid is added to the C-terminus). The B chain is extended at the N-terminus with KGSHK (i.e., 5 amino acids are added / appended to the N-terminus), the amino acid at position 3 (i.e., N) in the B chain is replaced with D, the amino acid at position 21 (i.e., E) in the B chain is replaced with K, the amino acid at position 29 (i.e., K) in the B chain is replaced with R, and the amino acid at position 30 (i.e., T) in the B chain is deleted (as shown below).

[0191] [ka]

[0192] As yet another example, an insulin analog with two modifications comprises an A chain and a B chain, where the A chain contains the sequence GIVEQCCTSICSLYQLENYCN (SEQ ID NO: 1), and the B chain contains the sequence KFVNQHLCGSHLVEALYLVCGKRGFFYTPKT (SEQ ID NO: 24060), where the A chain has the wild-type sequence of human insulin chain A (e.g., no mutations, deletions, or additions), and the B chain is extended at the N-terminus with K (i.e., one amino acid is added / appended to the N-terminus), and the amino acid at position 21 of the B chain (i.e., E) is substituted with K (as shown below).

[0193] [ka]

[0194] As yet another example, an insulin analog with six modifications comprises an A chain and a B chain, the A chain contains the sequence GIVEQCCTSICSLYQLENYCGK (SEQ ID NO: 25), the B chain contains the sequence KGSHKFVNQHLCGSHLVEALYLVCGKRGFFYTPR (SEQ ID NO: 25313), the A chain has the amino acid at position 21 (i.e., N) replaced with G, the A chain is extended with K at the C-terminus (i.e., one amino acid is added / appended to the C-terminus), the B chain is extended with KGSHK at the N-terminus (i.e., five amino acids are added / appended to the N-terminus), the B chain has the amino acid at position 21 (i.e., E) replaced with K, the B chain has the amino acid at position 29 (i.e., K) replaced with R, and the B chain has the amino acid at position 30 (i.e., T) deleted (as shown below).

[0195] [ka]

[0196] As yet another example, an insulin analog with four modifications comprises an A chain and a B chain, the A chain containing the sequence GIVEQCCTSICSLYQLENYCN (SEQ ID NO: 1), the B chain containing the sequence KGSHFVNQHLCGSHLVEALYLVCGKRGFFYTPR (SEQ ID NO: 24061), the A chain having the wild-type sequence of human insulin's A chain (e.g., no mutations, deletions, or additions), the B chain being extended with KGSH at the N-terminus (i.e., four amino acids added / appended to the N-terminus), the amino acid at position 21 of the B chain (i.e., E) being substituted with K, the amino acid at position 29 of the B chain (i.e., K) being substituted with R, and the amino acid at position 30 of the B chain (i.e., Thr) being deleted (as shown below).

[0197] [ka]

[0198] As yet another example, an insulin analog with five modifications comprises an A chain and a B chain, the A chain contains the sequence GIVEQCCTSICSLYQLENYCN (SEQ ID NO: 1), and the B chain contains the sequence KGSHQHLCGSHLVEALYLVCGKRGFFYTPR (SEQ ID NO: 24062). The A chain has the wild-type sequence of human insulin's A chain (e.g., no mutations, deletions, or additions), the B chain is extended with KGSH at the N-terminus (i.e., 4 amino acids added / appended to the N-terminus), the first three residues (FVN) are deleted, the amino acid at position 21 of the B chain (i.e., E) is substituted with K, the amino acid at position 29 of the B chain (i.e., K) is substituted with R, and the amino acid at position 30 of the B chain (i.e., Thr) is deleted (as shown below).

[0199] [ka]

[0200] As yet another example, an insulin analog with five modifications comprises an A chain and a B chain, the A chain contains the sequence GIVEQCCTSICSLYQLENYCN (SEQ ID NO: 1), and the B chain contains the sequence KGSHKQHLCGSHLVEALYLVCGKRGFFYTPR (SEQ ID NO: 24063). The A chain has the wild-type sequence of human insulin's A chain (e.g., no mutations, deletions, or additions), the B chain is extended with KGSHK at the N-terminus (i.e., 5 amino acids added / appended to the N-terminus), the first three residues (FVN) are deleted, the amino acid at position 21 of the B chain (i.e., E) is substituted with K, the amino acid at position 29 of the B chain (i.e., K) is substituted with R, and the amino acid at position 30 of the B chain (i.e., Thr) is deleted (as shown below).

[0201] [ka]

[0202] As yet another example, an insulin analog with two modifications comprises an A chain and a B chain, where the A chain contains the sequence GIVEQCCTSICSLYQLENYCN (SEQ ID NO: 1), and the B chain contains the sequence GKGGGGSGGGGSGGGGSFVNQHLCGSHLVEALYLVCGERGFFYTPK (SEQ ID NO: 25397), where the A chain has the wild-type sequence of human insulin chain A (e.g., no mutations, deletions, or additions), and the B chain is elongated at the N-terminus with GKGGGGSGGGGSGGGGS (i.e., 17 amino acids added / appended to the N-terminus), and the amino acid at position 30 of the B chain (i.e., Thr) is deleted (as shown below).

[0203] [ka]

[0204] In some embodiments, insulin analogs include, but are not limited to, insulin that has been chemically modified compared to wild-type human insulin, such as by the addition of a chemical moiety, such as a PEG group or a fatty acyl chain. In some embodiments, the modified insulin / insulin analog / analog used interchangeably herein may have mutations including the addition, deletion, or substitution of amino acids. Different protomers of insulin may arise from these changes and be incorporated into some embodiments. In some embodiments, the active form of insulin has fewer than 11 such modifications (e.g., 1-4, 1-3, 1-9, 1-8, 1-7, 1-6, 2-6, 2-5, 2-4, 1-5, 1-2, 2-9, 2-8, 2-7, 2-3, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-9, 4-8, 4-7, 4-6, 4-5, 5-9, 5-8, 5-7, 5-6, 6-9, 6-8, 6-7, 7-9, 7-8, 8-9, 9, 8, 7, 6, 5, 4, 3, 2, or 1). As used herein, the wild-type sequence of human insulin (chains A and B) has a chain A having the amino acid sequence GIVEQCCTSICSLYQLENYCN (SEQ ID NO: 1) and a chain B having the amino acid sequence FVNQHLCGSHLVEALYLVCGERGFFYTPKT (SEQ ID NO: 2). In some embodiments, the insulin analog has at least 70% sequence homology to wild-type human insulin. In some embodiments, the insulin analog has at least 80% sequence homology to wild-type human insulin. In some embodiments, the insulin analog has at least 90% sequence homology to wild-type human insulin. In some embodiments, the insulin analog has at least 95%, 96%, 97%, or 95% sequence homology to wild-type human insulin. In some embodiments, the insulin analog has at least 99% sequence homology to wild-type human insulin.

[0205] Human insulin differs from rabbit, pig, bovine, and sheep insulin at amino acids A8, A9, A10, and B30, respectively, as follows: Human: Thr, Ser, Ile, Thr; Rabbit: Thr, Ser, Ile, Ser; Pig: Thr, Ser, Ile, Ala; Sheep: Ala, Gly, Val, Ala; Bovine: Ala, Ser, Val, Ala. In some embodiments, modified insulin may be mutated at positions B1, B2, B28, or B29 of the B chain, or at positions B28 and B29. In some embodiments, modified insulin may be mutated at positions A1, A2, A21, or other positions of the A chain. For example, insulin lispro is a rapid-acting modified insulin in which the lysine and proline residues at the C-terminus of the B chain are reversed. Insulin aspart is a rapid-acting modified insulin in which proline is substituted with aspartic acid at position B28. In some embodiments of this disclosure, insulin mutated at B28 and B29 may further include additional mutations. For example, insulin glulysine is a rapid-acting modified insulin in which aspartic acid is replaced by a lysine residue at position B3 and lysine is replaced by a glutamic acid residue at position B29. In some embodiments, a long-acting, highly stable insulin analog is covalently modified as described by formula I or formula IB and may include mutations such as replacement of tyrosine at A14 with glutamic acid, replacement of tyrosine at B16 with histidine, and replacement of phenylalanine at B25 with histidine.

[0206] In some embodiments, the isoelectric point of the insulin herein may be shifted relative to wild-type human insulin by any preferred method, for example, by the addition or substitution of a preferred amino acid. In some embodiments, the isoelectric point of modified insulin may be modulated by glucose (for example, by interaction with glucose). For example, insulin glargine is basal insulin in which two arginine residues are added to the C-terminus of the B peptide and A21 is replaced by glycine. In some embodiments, insulin may not have one or more of the residues B1, B2, B3, B26, B27, B28, B29, and B30 (for example, insulin may be a deletion mutant in one or more of the listed residues). In some embodiments, the insulin molecule contains up to five additional amino acid residues on the N-terminus or C-terminus of the A or B chain. In some embodiments, one or more amino acid residues are located at or missing from positions A1, A21, B1, B29, B30, and / or B31. In some embodiments, the insulin molecule of the present disclosure is mutated such that one or more amino acids are replaced in an acidic form. In some embodiments, asparagine is replaced with aspartic acid or glutamic acid. In some embodiments, glutamine is replaced with aspartic acid or glutamic acid. In some embodiments, A21 may be aspartic acid, B3 may be aspartic acid, or both positions may contain aspartic acid. Those skilled in the art will recognize that any previously reported or widely accepted mutation or modification is possible to insulin that retains biological activity, and that such insulin analogs may be used in embodiments of the present disclosure. In some embodiments, insulin may be bound to a fatty acid at any position, or may be acylated with a fatty acid at any amino group, including one on the lysine side chain and an alpha-amino group at the N-terminus of insulin, and the fatty acid may include a C8, C9, C10, C11, C12, C14, C15, C16, C17, or C18 chain. In some embodiments, the fatty acid chain has a carbon length of 8 to 20 carbon atoms.In some embodiments, insulin detemir has myristic acid covalently bonded to lysine at B29, with B30 being deleted or absent. In some embodiments, the B28 position of the insulin molecule is lysine, and the epsilon (ε)-amino group of this lysine is conjugated to a fatty acid.

[0207] In some embodiments, the N-terminus or C-terminus of the modified insulin A-chain or B-chain is ligated using a peptide ligase. In some embodiments, the polypeptide is attached to the C-terminus or N-terminus of the insulin A and / or B-chain using a protein ligase, and in some embodiments, the ligase is selected from saltase, buterase, tripsiligase, subtilisin, peptiligases, or enzymes having at least 75% homology to these ligases. In some embodiments, ligation is achieved by expressed protein ligation as described in Muir TW, Sondhi D, Cole PA. "Expressed protein ligation: a general method for protein engineering." Proc Natl Acad Sci US A. 1998;95(12):6705-6710. In some embodiments, the polypeptide is ligated to modified insulin using Staudinger ligation, for example, as described in Nilsson, BL; Kiessling, LL., Raines, RT (2000). "Staudinger ligation: A peptide from a thioester and azide." Org. Lett. 2 (13): 1939-1941. In some embodiments, the polypeptide is conjugated to modified insulin using Ser / Thr, for example, as described in Zhang Y, Xu C, Kam HY, Lee CL, Li X. 2013. "Protein chemical synthesis by serine / threonine ligation." Proc. Natl. Acad. Sci. USA. 17: 6657-6662. In some embodiments, the B chain itself has fewer than 32 amino acids or 34 amino acids, and in some embodiments, insulin has 4 disulfide bonds instead of 3. Disulfide bonds are present in the A and B chains of insulin.For example, a disulfide bond exists between the cysteine ​​at position 6 of SEQ ID NO: 1 and the cysteine ​​at position 11 of SEQ ID NO: 1, a disulfide bond exists between the cysteine ​​at position 7 of SEQ ID NO: 1 and the cysteine ​​at position 7 of SEQ ID NO: 2, and a disulfide bond exists between the cysteine ​​at position 20 of SEQ ID NO: 1 and the cysteine ​​at position 19 of SEQ ID NO: 2.

[0208] In some embodiments, the modified insulin of this disclosure is, but is not limited to, the following insulin molecules: εB29 -Octanoyl-Arg B0 Gly A21 Asp B3 Arg B31 Arg B32 -HI,N εB29 -Octanoyl-Arg B31 Arg B32 -HI,N εB29 -Octanoyl-Arg A0 Arg B31 Arg B32 -HI,N εB28 -Milistil-Gly A21 Lys B28 Pro B29 Arg B31 Arg B32 -HI,N εB28 -Milistil-Gly A21 Gln B3 Lys B28 Pro B30 Arg B31 Arg B32 -HI,N εB28 -Milistil-Arg A0 Gly A21 Lys B28 Pro B29 Arg B31 Arg B32 -HI,N εB28 -Milistil-Arg A0 Gly A21 Gln B3 Lys B28 Pro B29 Arg B31 Arg B32 -HI,N εB28 -Milistil-Arg A0Gly A21 Asp B3 Lys B28 Pro B29 Arg B31 Arg B32 -HI,N εB28 -Milistil-Lys B28 Pro B29 Arg B31 Arg B32 -HI,N εB28 -Milistil-Arg A0 Lys B28 Pro B29 Arg B31 Arg B32 -HI,N εB28 -Octanoil-Gly A21 Lys B28 Pro B29 Arg B31 Arg B32 -HI,N εB28 -Octanoil-Gly A21 Gln B3 Lys B28 Pro B29 Arg B31 Arg B32 -HI,N εB28 -Octanoyl-Arg A0 Gly A21 Lys B28 Pro B29 Arg B31 Arg B32 -HI,N εB29 -Palmitoyl-HI, N εB29 -Milistil-HI, N εB28 -Palmitoil-Lys B28 Pro B29 -HI,N εB28 -Milistil-Lys B28 Pro B29 -HI,N εB29 -Palmitoil-des(B30)-HI, N εB30 -Milistil-Thr B29 Lys B30 -HI,N εB30 -Palmitoil-Thr B29 Lys B30 -HI,N εB29-(N-palmitoyl-γ-glutamyl)-des(B30)-HI,N εB29 -(N-litocoryl-γ-glutamyl)-des(B30)-HI, N εB29 -(ω-carboxyheptadecanoyl)-des(B30)-HI,N εB29 -(ω-carboxyheptadecanoyl)-HI,N εB29 -Octanoyl-HI, N εB29 -Milistil-Gly A21 Arg B31 Arg B31 -HI,N εB29 -Milistil-Gly A21 Gln B3 Arg B31 Arg B32 -HI,N εB29 -Milistil-Arg A0 Gly A21 Arg B31 Arg B32 -HI,N εB29 -Arg A0 Gly A21 Gln B3 Arg B31 Arg B32 -HI,N εB29 -Milistil-Arg A0 Gly A21 Asp B3 Arg B31 Arg B32 -HI,N εB29 -Milistil-Arg B31 Arg B32 -HI,N εB29 -Milistil-Arg A0 Arg B31 Arg B32 -HI,N εB29 -Octanoil-Gly A21 Arg B31 Arg B32 -HI,N εB29 -Octanoil-Gly A21 Gln B3 Arg B31 Arg B32 -HI,N εB29 -Octanoyl-Arg A0 Gly A21 ArgB31 Arg B32 -HI,N εB29 -Octanoyl-Arg A0 Gly A21 Gln B3 Arg B31 Arg B32 -HI,N εB28 -Octanoyl-Arg A0 Gly A21 Gln B3 Lys B28 Pro B29 Arg B31 Arg B32 -HI,N εB28 -Octanoyl-Arg A0 Gly A21 Asp B3 Lys B28 Pro B29 Arg B31 Arg B32 -HI,N εB28 -Octanoil-Lys B28 Pro B29 Arg B31 Arg B32 -HI,N εB28 -Octanoyl-Arg A0 Lys B28 Pro B29 Arg B31 Arg B32 -HI. N εB29 -Pentanoyl-Gly A21 Arg B31 Arg B32 -HI,N αB1 -Hexanoyl-Gly A21 Arg B31 Arg B32 -HI,N αA1 -Heptanoyl-Gly A21 Arg B31 Arg B32 -HI,N εB29 -Octanoil-N αB1 -Octanoil-Gly A21 Arg B31 Arg B32 -HI,N εB29 -Propionyl-N αA1 -Propionyl-Gly A21 Arg B31Arg B32 -HI,N αA1 -acetyl-N αB1 -Acetyl-Gly A21 Arg B31 Arg B32 -HI,N εB29 -Formyl-N αA1 -Formyl-N αB1 -Formyl-Gly A21 Arg B31 Arg B32 -HI,N εB29 -formyl-des(B26)-HI,N αB1 -acetyl-Asp B28 -HI,N εB29 -Propionyl-N αA1 -Propionyl-N αB1 -Propionyl-Asp B1 Asp B3 Asp B21 -HI,N εB29 -Pentanoyl-Gly A21 -HI,N αB1 -Hexanoyl-Gly A21 -HI,N αA1 -Heptanoyl-Gly A21 -HI,N εB29 -Octanoil-N αB1 -Octanoil-Gly A21 -HI,N εB29 -Propionyl-N αA1 -Propionyl-Gly A21 -HI,N αA1 -acetyl-N αB1 -Acetyl-Gly A21 -HI,N εB29 -Formyl-N αA1 -Formyl-N αB1 -Formyl-Gly A21 -HI,N εB29 -Butyryl-des(B30)-HI, N αB31 -Butyryl-des(B30)-HI, N αA1 -Butyryl-des(B30)-HI, N εB29 -Butchiril-N αB31 -Butyryl-des(B30)-HI, N εB29 -Butchiril-N αA1-Butyryl-des(B30)-HI, N αA1 -Butchiril-N αB31 -Butyryl-des(B30)-HI, N εB29 -Butchiril-N αA1 -Butchiril-N αB31 -Butyryl-des(B30)-HI, Lys B28 Pro B29 -HI (insulin lispro), Asp B28 -HI (insulin aspart), Lys B3 Glu B29 -HI (insulin glulisine), Arg B31 Arg B32 -HI (insulin glargine), N εB29 -Myristoyl-des(B30)-HI (insulin detemir), Ala B26 -HI, Asp B1 -HI, Arg A0 -HI, Asp B1 Glu B13 -HI EntryGly A21 -HI EntryGly A21 Arg B31 Arg B32 -HI, Arg A0 Arg B31 Arg B32 -HI, Arg A0 Gly A21 Arg B31 Arg B32 -HI, des(B30)-HI, des(B27)-HI, des(B28-B30)-HI, des(B1)-HI, des(B1-B3)-HIN εB29 -Tridecanoyl-des(B30)-HI,N εB29 -Tetradecanoyl-des(B30)-HI,N εB29 -Decanoyl-des(B30)-HI, N εB29 -Dodecanoyl-des(B30)-HI,N εB29 -Tridecanoil-Gly A21 -des(B30)-HI, N εB29 -Tetradecanoil-Gly A21 -des(B30)-HI, N εB29 -Decanoil-Gly A21-des(B30)-HI, N εB29 - Dodecanoil - Gly A21 -des(B30)-HI, N εB29 -Tridecanoil-Gly A21 Gln B3 -des(B30)-HI, N εB29 -Tetradecanoil-Gly A21 Gln B3 -des(B30)-HI, N εB29 -Decanoil-Gly A21 -Gln B3 -des(B30)-HI, N εB29 - Dodecanoil - Gly A21 -Gln B3 -des(B30)-HI, N εB29 -Tridecanoil-Ala A21 -des(B30)-HI, N εB29 -Tetradecanoil-Ala A21 -des(B30)-HI, N εB29 -Decanoil-Ala A21 -des(B30)-HI, N εB29 -Dodecanoil-Ala A21 -des(B30)-HI, N εB29 -Tridecanoil-Ala A21 -Gln B3 -des(B30)-HI, N εB29 -Tetradecanoil-Ala A21 Gln B3 -des(B30)-HI, N εB29 -Decanoil-Ala A21 Gln B3 -des(B30 )-HI, N εB29 -Dodecanoil-Ala A21 Gln B3 -des(B30)-HI, N εB29 -Tridecanoil-Gln B3 -des(B30)-HI, N εB29 -Tetradecanoil-Gln B3 -des(B30)-HI, N εB29 -Decanoil-Gln B3 -des(B30)-HI, NεB29 -ドデカノイル-Gln B3 -des(B30)-HI、N εB29 -Z1-Gly A21 -HI、N εB29 -Z2-Gly A21 -HI、N εB29 -Z4-Gly A21 -HI、N εB29 -Z3-Gly A21 -HI、N εB29 -Z1-Ala A21 -HI、N εB29 -Z2-Ala A21 -HI、N εB29 -Z4-Ala A21 -HI、N εB29 -Z3-Ala A21 -HI、N εB29 -Z1-Gly A21 Gln B3 -HI、N εB29 -Z2-Gly A21 Gln B3 -HI、N εB29 -Z4-Gly A21 Gln B3 -HI、N εB29 -Z3-Gly A21 Gln B3 -HI、N εB29 -Z1-Ala A21 Gln B3 -HI、N εB29 -Z2-Ala A21 Gln B3 -HI、N εB29 -Z4-Ala A21 Gln B3 -HI、N εB29 -Z3-Ala A21 Gln B3 -HI、N εB29 -Z1-Gln B3 -HI、N εB29 -Z2-Gln B3 -HI、N εB29 -Z4-Gln B3 -HI、N εB29 -Z3-Gln B3 -HI、N εB29 -Z1-Glu B30 -HI、N εB29 -Z2-GluB30 -HI、N εB29 -Z4-Glu B30 -HI、N εB29 -Z3-Glu B30 -HI、N εB29 -Z1-Gly A21 Glu B30 -HI、N εB29 -Z2-Gly A21 Glu B30 -HI、N εB29 -Z4-Gly A21 Glu B30 -HI、N εB29 -Z3-Gly A21 Glu B30 -HI、N εB29 -Z1-Gly A21 Gln B3 Glu B30 -HI、N εB29 -Z2-Gly A21 Gln B3 Glu B30 -HI、N εB29 -Z4-Gly A21 Gln B3 Glu B30 -HI、N εB29 -Z3-Gly A21 Gln B3 Glu B30 -HI、N εB29 -Z1-Ala A21 Glu B30 -HI、N εB29 -Z2-Ala A21 Glu B30 -HI、N εB29 -Z4-Ala A21 Gln B30 -HI、N εB29 -Z3-Ala A21 Glu B30 -HI、N εB29 -Z1-Ala A21 Gln B3 Glu B30 -HI、N εB29 -Z2-Ala A21 Gln B3 Glu B30 -HI、N εB29 -Z4-Ala A21 Gln B3 GluB30 -HI, N εB29 -Z3-Ala A21 Gln B3 Glu B30 -HI, N εB29 -Z1-Gln B3 Glu B30 -HI, N εB29 -Z2-Gln B3 Glu B30 -HI, N εB29 -Z4-Gln B3 Glu B30 -HI, N εB29 -Z3-Gln B3 Glu B30 -HI contains one or more mutations and / or chemical modifications, Z1 is tridecanoyl, Z2 is tetradecanoyl, Z3 is dodecanoyl, Z4 is decanoyl, and HI is human insulin.

[0209] In some embodiments, insulin has the following mutations and / or chemical modifications: N εB28 -XXXXX-Lys B28 Pro B29 -HI, N αB1 -XXXXX-Lys B28 Pro B29 -HI, N αA1 -XXXXX-Lys B28 Pro B29 -HI, N εB28 -XXXXX-N αB1 -XXXXX-Lys B28 Pro B29 -HI, N εB28 -XXXXX-N αA1 -XXXXX-Lys B28 Pro B29 -HI, N αA1 -XXXXX-N αB1 -XXXXX-Lys B28 Pro B29 -HI, N εB28 -XXXXX-N αA1 -XXXXX-N αB1 -XXXXX-Lys B28 Pro B29 -HI, N εB29 -XXXXX-HI, NαB1 -XXXXX-HI、N αA1 -XXXXX-HI、N εB29 -XXXXX-N αB1 -XXXXX-HI、N εB29 -XXXXX-N αA1 -XXXXX-HI、N αA1 -XXXXX-N αB1 -XXXXX-HI、N εB29 -XXXXX-N αA1 -XXXXX-N αB1 -XXXXX-HI、N εB29 -YYYYY-HI、N αB1 -YYYYY-HI、N αA1 -YYYYY-HI、N εB29 -YYYYY-N αB1 -YYYYY-HI、N εB29 -YYYYY-N αA1 -YYYYY-HI、N αA1 -YYYYY-N αB1 -YYYYY-HI、N εB29 -YYYYY-N αA1 -YYYYY-N αB1 -YYYYY-HI、N εB28 -YYYYY-Lys B28 Pro B29 -HI、N εB21 -YYYYY-Lys B28 Pro B29 -HI、N αA1 -YYYYY-Lys B28 Pro B29 -HI、N εB28 -YYYYY-N αB1 -YYYYY-Lys B28 Pro B29 -HI、N εB28 -YYYYY-N αA1 -YYYYY-Lys B28 Pro B29 -HI、N αA1 -YYYYY-N αB1 -YYYYY-Lys B28 Pro B29 -HI、N εB28 -YYYYY-N αA1 -YYYYY-N αB1 -YYYYY-Lys B28Pro B29 -Contains one or more of the following: YYYYY is one of acetyl or formyl, XXXXX is one of propionyl, butyryl, pentanoyl, hexanoyl, heptanol, octanoyl, nonanoyl, or decanoyl, and HI is human insulin.

[0210] In some embodiments, insulin may be conjugated via reactive moieties that are naturally present in the insulin structure and / or added before binding, including, for example, carboxyl or reactive esters, amines, hydroxyls, aldehydes, sulfhydryls, maleimidyls, alkynyls, and azides. Insulin naturally contains reactive alpha-terminal amines and epsilon-aminelysine groups that can covalently bond NHS-esters, isocyanates, or isothiocyanates. In some embodiments, modified insulin may be used in which a suitable amino acid (e.g., lysine or a non-natural amino acid) is added or substituted into the amino acid sequence to provide alternative conjugation sites in addition to the modified amino acids of the embodiments described herein. In some embodiments, the binding process may be controlled by selectively blocking a particular reactive moiety that is present before binding. In some embodiments, insulin may include any combination of modifications, and this disclosure also includes modified forms of non-human insulin (e.g., porcine insulin, bovine insulin, rabbit insulin, sheep insulin, etc.) that include any one of the modifications described herein. Some embodiments use these and other previously described modified insulins, e.g., U.S. Patent No. 5,474,978; No. 5,461,031, No. 4,421,685, No. 7,387,996, No. 6,869,930, No. 6,174,856, No. 6,011,007, No. 5,866,538, No. 5,750,4976, No. 906,028, No. 6,551,992, No. 6,465,426, No. 6,444,641, No. 6,335,316, No. 6 It is understood that this includes those described in U.S. Patent Publication No. 268,335, No. 6,051,551, No. 6,034,054, No. 5,952,297, No. 5,922,675, No. 5,747,642, No. 5,693,609, No. 5,650,486, No. 5,547,929, No. 5,504,188, and U.S. Patent Application Publication No. 2015 / 0353619, and includes non-natural amino acids described or referenced herein, and includes such modifications to non-human insulin described herein.It should also be understood that in some embodiments, insulin may be covalently bound to a polyethylene glycol polymer, such as a polyethylene glycol polymer with a Mn of 60,000 or less, or to albumin via either permanent or reversible binding.

[0211] In some embodiments, a compound of the present disclosure (e.g., formula I or formula IB) is conjugated to a chelating agent, and in some embodiments, the chelating agent can be used to capture a radioactive payload such as gallium-68, copper-64, lutetium-177, or actinium-225. In some embodiments, the chelating agent is based on DOTA, NOTA, TETA, or 4-arm DOTA, and in some embodiments, the chelating agent can be linked to a peptide using a PEG linker via an amide bond between the chelating agent and the peptide.

[0212] In some embodiments, the activity, bioavailability, solubility, isoelectric point, charge, and / or hydrophobicity of modified insulin can be controlled by chemical modification and / or as a result of interactions of small molecules, such as sugars, with compounds that are either covalently bonded to or mixed with insulin, such as compounds described herein.

[0213] In some embodiments, for example, in formulas FF1-FF11, FF12, FF12A, FF12B, FF12C, FF12D, FF13-FF115, FF116, FF116A, FF116B, FF116C, FF116D, and FF117-FF231, one or more elements, functional groups, or atoms may be specifically omitted or excluded from the described structure (for example, terminal functional groups may be replaced by hydrogen atoms, or linking groups may be replaced by bonds), and it will be understood that such omitted or excluded elements make these groups (structures) distinct and not equivalent. For example, if another version (variation) of the formula structure does not have a nitro group at R1 of B1 or B2, that variation is not equivalent to the structure containing the nitro group (for example, not structurally and chemically equivalent), at least because the nitro group alters the pKa of B1 and B2 under physiological conditions and therefore alters the overall affinity of Z1c to glucose.

[0214] A rotationally constrained tethered boron conjugate. In some embodiments, the aromatic boron-containing compound and / or aromatic boron-containing group is a rotationally constrained tethered boron conjugate. In some embodiments, the rotationally constrained tethered boron conjugates presented herein contain a skeleton whose rotation is inhibited by undesirable steric interactions (e.g., gauche-anti interactions of substituents), bound rotation due to bond hybridization (e.g., cis-to-trans-amide rotation), or via a rigid covalent bond (e.g., (E)-to-(Z) configuration of the alkene moiety). For example, formulas FF50-FF62, FF116, FF116A, FF116B, FF116C, FF116D, and FF121-134 contain a geminal (e.g., bonded to the same atom) alkyl functional group relative to the amine group covalently bonded to the boronic acid functionalized moiety. The alkyl functional group may restrict the accessible dihedral angle and the freedom of rotation around the CC or CX bond (commonly referred to as the χ (chi) dihedral angle of the amino acid). For example, the hydroxyl side chains of serine residues can access dihedral angles of 60°, 180°, or 240°(-60°) with nearly equal distributions, while the hydroxyl side chains of threonine can only adopt dihedral angles of 180° or 240°(-60°). The presence of a geminal methyl group on the hydroxyl of threonine provides steric bulk, which can create undesirable interactions if other bulky substituents are in a gauche conformation relative to the methyl group. Formulas FF50-FF62, FF116, FF116A, FF116B, FF116C, and FF116D, and FF121-134 contain geminal alkyl substituents that may limit the accessible dihedral angles adopted by boron conjugate amines, influencing the adopted dihedral angles, bringing the boron functional groups closer together, and enabling increased binding of the conjugate to target molecules such as proteins or sugars.

[0215] In some embodiments, the insulin receptor agonists disclosed herein may have an onset of action within 1 to 2 hours or longer. In certain embodiments, the insulin receptor agonists may have a peak efficacy within 6 to 20 hours or a long-lasting effect. In some embodiments, the insulin receptor agonists may be administered once daily or, for example, once weekly.

[0216] In some embodiments, insulin receptor agonists have an extended duration of bioavailability (e.g., an extended in vivo plasma half-life). In some embodiments, the insulin receptor agonists disclosed herein comprise one or more linker moieties (e.g., one or more Z1b) and / or diboronates (e.g., F7) that result in an increased terminal phase half-life and / or decreased blood clearance (CL) of the compounds disclosed herein in the blood. In some embodiments, the compounds disclosed herein have a terminal phase half-life of at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, at least 3 hours, at least 3.5 hours, at least 4 hours, at least 4.5 hours, or at least 5 hours. In some embodiments, the compounds disclosed herein have a half-life of up to 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours. In some embodiments, the compounds disclosed herein have CL values ​​in the range of about 0.13 ml / min / kg to about 2.4 ml / min / kg.

[0217] In some embodiments, the linker is C2-C, optionally terminated with an acid group selected from A'' (e.g., AB-1-AB-39). 20 It contains an acyl group. In some embodiments, the linker contains a lipophilic side chain selected from A'' (e.g., AB1-AB7, AB15-AB28, AB-32).

[0218] In some embodiments, the compound is optionally terminated with an acid group C2-C 20The compound comprises one or more linkers containing an acyl group. In some embodiments, the compound comprises one or more Z1c containing at least one F7. In further embodiments, the compound has a long terminal phase half-life and / or reduced clearance.

[0219] In some embodiments, the stereochemistry of the isomer structure (e.g., the stereochemistry of the compound, (e.g., within the Z1c moiety)) can selectively increase the affinity of the conjugate (e.g., the Z1c moiety) to a specific target diol such as glucose. For example, in some embodiments, one or more stereoisomers of Z1c (e.g., cis or trans, (R) or (S), and (E) or (Z)) can be selected to increase or decrease the affinity of Z1c (and the entire molecular structure or conjugate) to glucose. In some embodiments, the cis forms of formulas FF1-FF231 (e.g., FF12, FF12B, FF12C, FF12D, FF114, FF115, FF116, FF116A, FF116B, FF116C, FF116D, FF117, FF193, and FF203) are used where applicable (e.g., Z1c has cis stereochemistry). In some embodiments, the trans forms of formulas FF1-FF231 (e.g., FF12, FF12B, FF12C, FF12D, FF115, FF116, FF116A, FF116B, FF116C, FF116D, FF117, FF193, and FF203) are used where applicable, for example, when those formulas include two stereocenters linked by a bond (e.g., Z1c has trans stereochemistry). In some embodiments, the R form of formulas FF1 to FF231 (e.g., FF12, FF114, FF115, FF116, FF117, FF193, and FF203) is used where applicable, for example, when formulas FF12, FF114, FF115, FF116, FF117, FF193, and FF203 contain at least one stereocenter (e.g., Z1c contains a structure having R stereochemistry). In some embodiments, the S form of formulas FF1 to FF231 (e.g., FF12, FF114, FF115, FF116, FF117, FF193, and FF203) is used where applicable, for example, when formulas FF12, FF114, FF115, FF116, FF117, FF193, and FF203 contain at least one stereocenter (e.g., Z1c contains a structure having S stereochemistry).In some embodiments, the S,S form of formulas FF1 to FF231 (e.g., FF12, FF114, FF115, FF116, FF117, FF193, and FF203) is used where applicable, for example, when formulas FF12, FF114, FF115, FF116, FF117, FF193, and FF203 contain two stereocenters linked by a bond (e.g., Z1c contains a structure having S,S stereochemistry). In some embodiments, the S,R form of formulas FF1 to FF231 (e.g., FF12, FF114, FF115, FF116, FF117, FF193, and FF203) is used where applicable, for example, when formulas 12, FF114, FF115, FF116, FF117, FF193, and FF203 contain two stereocenters linked by a bond (e.g., Z1c contains a structure having S,R stereochemistry). In some embodiments, the R,R form of formulas FF1 to FF231 (e.g., FF12, FF114, FF115, FF116, FF117, FF193, and FF203) is used where applicable, for example, when formulas FF12, FF114, FF115, FF116, FF117, FF193, and FF203 contain two stereocenters linked by a bond (e.g., Z1c contains a structure having R,R stereochemistry). In some embodiments, the R,S forms of formulas FF1 to FF231 (e.g., FF12, FF114, FF115, FF116, FF117, FF193, and FF203) are used where applicable, for example, when formulas FF12, FF114, FF115, FF116, FF117, FF193, and FF203 contain two stereocenters linked by a bond (e.g., Z1c contains a structure having R,S stereochemistry). In some embodiments, the compound comprises one or more tautomers of the compounds disclosed herein. In some embodiments, the compound comprises one or more stereoisomers or mixtures of stereoisomers of the compounds disclosed herein.

[0220] In some embodiments, the compound is covalently bonded to glucagon, GLP-1, GLP-2, or any variation thereof (e.g., any variation involving the deletion, insertion, and / or substitution of one or more amino acids). In some embodiments, any preferred chemical modification performed on insulin as considered herein can be performed on glucagon. In some embodiments, the conjugate is second or active pharmaceutical ingredient or aminoethyl glucose, aminoethyl bimannose, aminoethyltrimannose, D-glucose, D-galactose, D-allose, D-mannose, D-glucose, D-idose, D-talose, N-azidomannasamine (ManNAz) or N-azidogalactoseamine (GalNAz), or N-azidoglucosamine (GlcNAz), 2'-fluororibose, 2'-deoxyribose, glucose, sucrose, maltose, mannose, or derivatives thereof. (For example, glucosamine, mannosamine, methyl glucose, methyl mannose, ethyl glucose, ethyl mannose, etc.), sorbitol, inositol, galactitol, dulcitol, xylitol, arabitol, and / or higher-order combinations thereof (linear and / or branched bimannose, linear and / or branched trimannose, etc.), molecules containing cis-diols, catechol, tris, and DOPA molecules, for example, one or more compounds selected from L-DOPA or L-3,4-dihydroxyphenylalanine.

[0221] Furthermore, those skilled in the art will recognize that in some embodiments, one or more of the suitable proteogenic artificial amino acids may be used (included) in chain A or chain B. For example, in some embodiments, one or more of the following artificial amino acids may be used based on the methods described and referenced therein in Liu, CC; Schultz, PG (2010). "Adding new chemistries to the genetic code." Annual Review of Biochemistry 79:413-44, and the list of amino acids provided therein. Those skilled in the art will recognize that in some embodiments, artificial amino acids may be incorporated into drugs or insulin (e.g., by adding amino acids to chain A or chain B), and these may include the amino acids referenced herein and previously reported non-proteinogenic amino acids.In some embodiments, artificial amino acids are present in insulin (for example, may be included), and in some embodiments, the protein artificial amino acids are U.S. Patent Publication No. 2008 / 0044854, U.S. Patent No. 8518666, U.S. Patent No. 8980581, U.S. Patent Publication No. 2008 / 0044854, U.S. Patent No. 20140045261, U.S. Patent No. 2004 / 0053390, U.S. Patent No. 7229634, U.S. Patent No. 8236344, U.S. Patent Publication No. 2005 / 0196427, U.S. Patent No. 2010 / 0247433, U.S. Patent No. 7198915, U.S. Patent No. 7723070, U.S. Patent Publication No. 2002 / 0042097, U.S. Patent No. 2004 / 0058415, U.S. Patent No. 2 Recombinant protein expression can be introduced using preferred methods and approaches, including those described in U.S. patents and patent applications, including U.S. Patent Nos. 008 / 0026422, 2008 / 0160609, 2010 / 0184193, 2012 / 0077228, 2014 / 025599, U.S. Patent Nos. 7198915, 7632492, and 7723070. Other protein artificial amino acids can be recombinantly introduced using methods and approaches described in U.S. Patent Nos. 7736872, 7816320, 7829310, 7829659, 7883866, 8097702, and 8946148.

[0222] In some embodiments, cyclic amino acids, such as 3-hydroxyproline, 4-hydroxyproline, aziridine-2-carboxylic acid, azetidine-2-carboxylic acid, piperidine-2-carboxylic acid, 3-carboxymorpholine, 3-carboxythiamorpholine, 4-oxaproline, pyroglutamic acid, l,3-oxazolidine-4-carboxylic acid, l,3-thiazolidine-4-carboxylic acid, 3-thiaproline, 4-thiaproline, 3-selenoproline, 4-selenoproline, 4-ke Toproline, 3,4-dehydroproline, 4-aminoproline, 4-fluoroproline, 4,4-difluoroproline, 4-chloroproline, 4,4-dichloroproline, 4-bromoproline, 4,4-dibromoproline, 4-methylproline, 4-ethylproline, 4-cyclohexylproline, 3-phenylproline, 4-phenylproline, 3,4-phenylproline, 4-azidoproline, 4-carboxyproline, α-methylproline, α-ethylproline, α-propylproline Phosphorus, α-allylproline, α-benzylproline, α-(4-fluorobenzyl)proline, α-(2-chlorobenzyl)proline, α-(3-chlorobenzyl)proline, α-(2-bromobenzyl)proline, α-(4-bromobenzyl)proline, α-(4-methylbenzyl)proline, α-(diphenylmethyl)proline, α-(naphthylmethyl)-proline, D-proline, or S-homoproline, (2S,4S)-4-fluoro-L-proline, (2S,4R)-4-flu Oro-L-proline, (2S)-3,4-dihydro-L-proline, (2S,4S)-4-hydroxy-L-proline, (2S,4R)-4-hydroxy-L-proline, (2S,4S)-4-azido-L-proline, (2S)-4,4-difluoro-L-proline, (2S)-azetidine-2-carboxylic acid, (2S)-piperidine-2-carboxylic acid, or (4R)-1,3-thiazolidined-4-carboxylic acid can be used in the molecular structure conjugated to insulin.

[0223] In some embodiments, the specific orientation of amino acids is understood to be achieved, for example, using the method described in Albericio, F. (2000). Solid-Phase Synthesis: A Practical Guide (1st ed.). Boca Raton: CRC Press. p. 848. In some embodiments, the compounds of the present disclosure, for example, compounds of formula I, formula IB, or formula IF, can be bound to diols, catechols, hexose sugars, glucose, xylose, fucose, galactosamine, glucosamine, mannosamine, galactose, mannose, fructose, galacturonic acid, glucuronic acid, iduronic acid, mannuronic acid, acetylgalactosamine, acetylglucosamine, acetylmannosamine, acetylmuramic acid, 2-keto-3-deoxy-glycero-galactonononic acid, acetylneuraminic acid, glycolylneuraminic acid, neurotransmitters, dopamine, or disaccharides, or polymers of sugars or diols.

[0224] In some embodiments, the modification or intermediate may involve using an N-methyliminodiacetic acid (MIDA) group to produce a MIDA-conjugated boronate or MIDA boronate, and such modification may be used during the preparation of the boronate toward the final structure of use (for example, in embodiments of the method for preparing the conjugate described herein). In some embodiments, pinacol boronic acid ester is used toward the final structure, and the pinacol group can be readily removed by those skilled in the art using standard techniques. The MIDA-protected boronic acid ester is readily handled, stable in air, chromatographically compatible, nonreactive under standard anhydrous cross-coupling conditions, and under mild aqueous basic conditions such as 1 M NaOH, or even NaHCO3, or Lee, S.Jet al. (2008). J.Am.Chem.Soc.130:466.

[0225] The biological mechanism by which wild-type insulin binds to the insulin receptor has been previously reported in Menting, J. Get al. (2013). Nature 493, 241-245; and Menting, J. Get al. (2014). "Protective hinge in insulin opens to enable its receptor engagement." Proc. Natl. Acad. Sci. USA 111, E3395-3404. The activity of such insulin is, for example, TyrA14- 125I. Measurement can be performed using any preferred technique by using an in vitro insulin receptor that binds to human insulin as a tracer and utilizing antibody-conjugated beads with an insulin receptor monoclonal antibody. In some embodiments, animal models can be used for in vivo evaluation of insulin activity during glucose administration using methods known to those skilled in the art. In some embodiments, the compounds disclosed herein are partially or completely expressed with the recombinant protein of interest, such as insulin. The process for insulin expression in E. coli is known and can be easily carried out by those skilled in the art using the procedures outlined, for example, in Jonasson (1996). Eur. J. Biochem. 236:656-661; Cowley (1997). FEBS Lett. 402:124:130; Cho (2001). Biotechnol. Bioprocess Eng 6:144-149; Tikhonov (2001). Protein Exp. Pur. 21:176-182; Malik (2007). Protein Exp. Pur. 55:100-111; and Min (2011). J. Biotech. 151:350-356. In the most common process, the protein is expressed as a splitting protein or a single-chain proinsulin construct with an affinity tag. The compound (e.g., compound of formula I or formula IB) can be expressed as part of proinsulin and then chemically modified to conjugate to the desired structure via an amide bond. This approach provides good yields, reduces experimental complexity by decreasing the number of processing steps, and allows refolding in innate insulin (see, for example, Jonasson, Eur. J. Biochem. 236:656-661 (1996); Cho, Biotechnol Bioprocess Eng. 6:144-149 (2001); Tikhonov, Honov Protein Exp. Pur. 21:176-182 (2001); Min, J. Biotech. 151:350-356 (2001)). When expressed in E. coli, proinsulin is usually found in inclusion bodies and can be readily purified by those skilled in the art.

[0226] In some embodiments, proinsulin can be expressed using standard IPTG (isopropylthio-β-galactoside) induction of IPTG-inducible expression constructs and vectors in e coli strains such as strain B21. For example, the expression construct consists of a B chain, a C peptide, and an A chain. For instance, the c-peptide sequence EAEDLQVGQVELGGGPGAGSLQPLALEGSLQR can be used for proinsulin expression. Proinsulin is expressed in an inclusion body (IB), which is captured, washed, and further purified via an existing his tag, for example, before sensor conjugation. The expression of the desired proinsulin can be achieved by procedures known in the art. See, for example, U.S. Patents 5,457,066, 5,700,662, 5,514,646, 9,050,371, and 1,040,000,21.

[0227] In some embodiments, the compounds of this disclosure (e.g., formulas I, IB, and IF) can be formulated for injection. For example, they can be formulated for injection into subjects such as humans. In some embodiments, the composition may be a pharmaceutical composition such as a sterile injectable pharmaceutical composition. In some embodiments, the composition may be formulated for subcutaneous injection. In some embodiments, the composition may be formulated for transdermal, intradermal, transmucosal, transnasal, inhalation, or intramuscular administration. In some embodiments, the composition may be formulated in an oral or pulmonary administration form. Pharmaceutical compositions suitable for injection may include, for example, a sterile aqueous solution containing sugars, polyalcohols such as mannitol and sorbitol, phenol, metacresol, and sodium chloride; dispersions may be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof, and in oil; and carriers may be, for example, a solvent or dispersion medium containing water, sugars, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof. Those skilled in the art will recognize that specific formulations can be developed to best suit the application and use of the molecular structures of this disclosure. General considerations regarding the formulation and manufacture of pharmaceutical compositions, routes of administration, and suitable pharmaceutically acceptable carriers can be found, for example, in Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Co., Easton, Pa., 1995. In some embodiments, the pharmaceutical composition may contain, if the compound (e.g., a compound of formula I or formula IB) contains insulin, zinc together with insulin, for example, Zn 2+It may include. Such zinc preparations are described, for example, in U.S. Patent No. 9,034,818. For example, a pharmaceutical composition may contain zinc in a molar ratio of about M:N to modified insulin, where M is 1 to 11 and N is 6 to 1. In some embodiments, such modified insulin may be stored in a pump, which is either outside or inside the body, and releases the modified insulin. In some embodiments, the pump may be used to release a fixed amount of modified insulin, which is glucose-responsive and can automatically adjust its activity based on the level of glucose in the blood and / or the rate of release from the injection site. In some embodiments, the composition may be formulated in dose unit form for ease of administration and uniformity of dosage. In some embodiments, the pharmaceutical composition may further include a second insulin type that provides rapid-acting or basal insulin in addition to the effect provided by the molecular structure. In some embodiments, the compounds of the present disclosure (e.g., compounds of formula I or formula IB) are injected separately from insulin but modulate the activity of insulin by binding to insulin, and in some embodiments, this change in activity is glucose-dependent.

[0228] In some embodiments, the pharmaceutical composition comprises one or more compounds disclosed herein and at least one additional component selected from pharmaceutically acceptable carriers, pharmaceutically acceptable vehicles, and pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises a compound of formula I or formula IB and at least one additional component selected from pharmaceutically acceptable carriers, pharmaceutically acceptable vehicles, and pharmaceutically acceptable excipients.

[0229] In some embodiments, the disclosure includes compounds that may form part of a kit, which may include a compound of formula I or formula IB containing modified insulin, and a pharmaceutically acceptable carrier, and may include a syringe or pen for injection. In some embodiments, the kit may include a syringe or pen pre-filled with a pharmaceutically acceptable composition containing a compound of formula I or formula IB together with a liquid carrier. Alternatively, the kit may include a separate container, such as a vial, containing a pharmaceutically acceptable composition containing a compound of formula I or formula IB together with a dry carrier, and an empty syringe or pen. In some embodiments, such a kit may include a separate container having a liquid carrier that can be used to reconstitute a given composition that can then be taken up by the syringe or pen. In some embodiments, the kit may include instructions. In some embodiments, the kit may include a blood glucose measuring device for calculating an appropriate dose of modified insulin to be injected at a given time or at regular intervals, either locally or remotely. Such a dosing regimen may be patient-specific and may be provided, for example, as instructions for programming a pump, either by a human or a computer. The kit may include an electronic device that transfers blood glucose measurements to a second computer, either locally or elsewhere (e.g., in the cloud), which then calculates the correct amount of a compound of formula I or formula IB containing modified insulin that needs to be used by the patient at a specific time.

[0230] In some embodiments, this disclosure relates to a method for treating a disease or condition of interest, comprising administering a composition comprising the compounds described herein to the subject. In some embodiments, the disease or condition may be hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, metabolic syndrome X, or dyslipidemia, diabetes during pregnancy, prediabetes, Alzheimer's disease, MODY 1, MODY 2, or MODY 3 diabetes, mood disorders, and psychiatric disorders. It will be understood that this combination approach may also be used in insulin-resistant patients receiving insulin sensitizers or secondary drugs for diabetes (e.g., biguanides such as metformin, glitazone, etc.) or insulin secretagogues (e.g., sulfonylureas, GLP-1, exendin-4, etc.) and / or amylin.

[0231] In some embodiments, the compounds of the Disclosure (e.g., compounds of formula I or formula IB) may be administered to a patient receiving at least one additional therapy or taking at least one additional drug or therapeutic protein. In some embodiments, at least one additional therapy is intended to treat the same disease or disorder as the administered compound (e.g., compounds of formula I or formula IB). In some embodiments, at least one additional therapy is intended to treat side effects of the compound (e.g., compounds of formula I or formula IB) or as an adjuvant. The timeframes of the two therapies may be different or the same, and they may be administered on the same or different schedules, as long as there is a period during which the patient benefits from both therapies. Two or more therapies may be administered in the same or different formulations, as long as there is a period during which the patient benefits from both therapies. Any of these approaches may be used to target and administer two or more antidiabetic drugs.

[0232] In some embodiments, a therapeutically effective amount of the compound (e.g., a compound of formula I or formula IB) is used, which is sufficient to treat a disease or condition with a reasonable benefit-to-risk ratio (e.g., improving its symptoms, slowing its progression, preventing its recurrence, or delaying its onset). In some embodiments, this may involve balancing efficacy with additional safety and toxicity. Additional safety means that the compound (e.g., a compound of formula I or formula IB) may be responsive to changes in blood glucose levels or other molecular levels, even when the patient is not actively monitoring the levels of the molecule, such as blood glucose levels, during a given time frame, for example, while sleeping. In some embodiments, therapeutic efficacy and toxicity are measured using standard pharmacological procedures with cell cultures or in vivo experimental animals, e.g., the therapeutic index ED of the drug. 50 and LD 50 This can be determined by measuring [the relevant parameters]. In some embodiments, the average daily dose of insulin, including the molecular structure, is in the range of 5 to 400 U (e.g., 30 to 150 U, where 1 unit of insulin is approximately 0.04 mg). In some embodiments, the amount of the compound (e.g., the compound of formula I or formula IB) and these insulin doses are administered daily, every other day, every three days, or every four days.

[0233] In some embodiments, the standard is determined by an algorithm that can be calculated by computer. In some embodiments, 5 to 10 times the amount of this dose of the compound, for example, the compound of formula I or formula IB, is administered weekly or at regular intervals. In some embodiments, 10 to 20 times the amount of these doses of the conjugate is administered every other week or at regular intervals. In some embodiments, 20 to 40 times the amount of these doses of the compound (for example, the compound of formula I or formula IB) is administered monthly or at regular intervals. In some embodiments, the C-terminus of the A chain of insulin may be further extended with a peptide (amino acid sequence) containing 1 to 20 amino acid residues. In some embodiments, the insulin analog is desB30 insulin.

[0234] In some embodiments, Z1a is an amino acid or a peptide. In at least some embodiments, Z1a comprises (or consists of) 1 to 50 amino acid residues, e.g., 1 residue, 50 residues, or any intermediate number of residues (e.g., 10, 15, 25, 30, 42 residues, etc.). In some embodiments, Z1a comprises 1 to 15 amino acids. In at least some embodiments, the peptide Z1a comprises 1 to 8 amino acids. In some embodiments, Z1a comprises 5 to 6 amino acids. In some embodiments, Z1a comprises at least one amino acid independently selected from alanine (A), asparagine (N), glutamine (Q), threonine (T), methionine (M), histidine (H), cysteine ​​(C), valine (V), isoleucine (I), lysine (K), and leucine (L), and the remaining amino acids, each independently selected from any of the 20 native amino acids. In some embodiments, Z1a may contain diaminopropionic acid, diaminobutyric acid, or ornithine. In some embodiments, Z1a contains 1 to 5 lysine (K) molecules. In some embodiments, Z1a contains 1 to 3 K amino acids. In some embodiments, Z1a contains 5 to 6 amino acids, of which at least one is K. In some embodiments, Z1a contains 5 to 6 amino acids, of which 1 to 3 are K.In some embodiments, Z1a is selected from any of KA, KD, KE, KF, KG, KH, KI, KL, KN, KP, KQ, KR, KS, KT, KY, KAA, KAD, KAE, KAF, KAG, KAH, KAI, KAL, KAN, KAQ, KAR, KAS, KAT, KAY, KDA, KDD, KDE, KDF, KDG, KDH, KDI, KDL, KDN, KDQ, KDR, KDS, KDT, KDY, KEA, KED, KEE, KEF, KEG, KEH, KEI, KEL, KEN, KEQ, KER, KES, KET, KEY, KFA, KFD, KFE, KFF, KFG, KFH, KFI, KFL, KFN, KFQ, KFR, KFS, KFT, KFY, KGA, KGD, KGE, KGF, KGG, KGH, KGI, KGL, KGN, KGQ, KGR, KGS, KGT, KGY, KHA, KHD, KHE, KHF, KHG, KHH, KHI, KHL, KHN, KHQ, KHR, KHS, KHT, KHY, KIA, KID, KIE, KIF, KIG, KIH, KII, KIL, KIN, KIQ, KIR, KIS, KIT, KIY, KLA, KLD, KLE, KLF, KLG, KLH, KLI, KLL, KLN, KLQ, KLR, KLS, KLT, KLY, KNA, KND, KNE, KNF, KNG, KNH, KNI, KNL, KNN, KNQ, KNR, KNS, KNT, KNY, KPA, KPD, KPE, KPF, KPG, KPH, KPI, KPL, KPN, KPQ, KPR, KPS, KPT, KPY, KQA, KQD, KQE, KQF, KQG, KQH, KQI, KQL, KQN, KQQ, KQR, KQS, KQT, KQY, KRA, KRD, KRE, KRF, KRG, KRH, KRI, KRL, KRN, KRQ, KRR, KRS, KRT, KRY, KSA, KSD, KSE, KSF, KSG, KSH, KSI, KSL, KSN, KSQ, KSR, KSS, KST, KSY, KTA, KTD, KTE, KTF, KTG, KTH, KTI, KTL, KTN, KTQ, KTR, KTS, KTT, KTY, KYA, KYD, KYE, KYF, KYG, KYH, KYI, KYL, KYN, KYQ, KYR, KYS, KYT, KYY, and any of SEQ ID NOs: 75 to 24014, 24037 to 24046.In some embodiments, Z1a is selected from KSNAPQK (sequence number 24037), KNASPQK (sequence number 24038), KLWAVK (sequence number 24039), KGARLK (sequence number 24040), ADKKTLN (sequence number 24041), KGSHK (sequence number 4238), KNSTK (sequence number 5085), GKNSTK (sequence number 13989), GKGSHK (sequence number 13198), GSHKGSHK (sequence number 24042), GKPSHKP (sequence number 24043), GKGPSK (sequence number 24044), GKGSKK (sequence number 24045), and GKKPGKK (sequence number 24046).

[0235] In some embodiments, Z1a is added to the N-terminus and / or C-terminus and / or inserted into the A-chain or B-chain sequence of insulin.

[0236] compound In some embodiments, the disclosure provides compounds comprising at least two aromatic boron-containing groups, or tautomers, stereoisomers or mixtures thereof, or pharmaceutically acceptable salts, hydrates or isotopic derivatives thereof, wherein at least one aromatic boron-containing group is covalently bonded to the compound and selected from F3 to F11, and the other aromatic boron-containing group is covalently bonded to the compound and is F1 to F11 or a boronic acid.

[0237] [ka] Selected arbitrarily from, In each of F1 to F11, at least one R1 is covalently bonded to the compound, and each of the remaining R1 and R2 is independently H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, m is 1, 2, 3, 4, 5, 6, or 7, and for equations F3 to F4, Rw is O or S, For formulas F5 - F10, when Y8 is O, i is 2, 3, 4, or 5, or when Y8 is NR, R is an alkyl group or H, and i is 1, 2, 3, 4, or 5, Y9 is H, CH3, or an alkyl group, provided that when Y8 is O, Y9 is CH3 or an alkyl group, each Y10 is independently selected from H, CH3, F, CF3, and OCH3, provided that at least one Y10 is not H.

[0238] In some embodiments, the present disclosure provides a compound comprising at least one diboronato, the diboronato comprising at least two aromatic boron - containing groups, at least one aromatic boron - containing group being covalently bonded to the compound and selected from F3 - F11, and the other aromatic boron - containing group being covalently bonded to the compound and being F1 - F11 or boric acid,

[0239]

Chemical formula

[0240] In some embodiments, the compound comprises at least two aromatic boron-containing groups, or tautomers, stereoisomers, or mixtures of stereoisomers thereof, or pharmaceutically acceptable salts, hydrates, or isotopic derivatives thereof.

[0241] In some embodiments, the compound is a diboron-containing compound (for example, having at least two aromatic boron-containing groups as covalent bonds). In some embodiments, at least one aromatic boron-containing group is F7. In some embodiments, if at least one aromatic boron-containing group is F7 and Y8 is O, then each Y10 is CH3. In some embodiments, the compound containing at least two aromatic boron-containing groups includes X1 and one or more Z1c, or tautomers, stereoisomers or mixtures of stereoisomers thereof, or pharmaceutically acceptable salts or hydrates or isotopic derivatives.

[0242] In some embodiments, the disclosure provides compounds comprising X1 and one or more Z1c, or tautomers, stereoisomers or mixtures of stereoisomers thereof, or pharmaceutically acceptable salts, hydrates, or isotopic derivatives thereof, wherein X1 is (i) NH2 or OH (for example, X1 is NH2 or OH), (ii) Active pharmaceutical ingredients containing amines, (iii) Active pharmaceutical ingredients covalently bonded to an amine-containing linker, (iv) an amine configured to be covalently bonded to the active pharmaceutical ingredient, Each Z1c is independently selected from formulas FF1 to FF231, and each Z1c is directly or indirectly covalently bonded to the amine of X1, or to the OH group if X1 is OH.

[0243] In some embodiments, Z1c is independently selected from formulas FF1-FF48, FF49-FF88, FF89-FF112, FF113-FF136, FF137-FF160, FF161-FF164, FF165-FF166, FF167-FF192, FF193-FF209, and FF210-FF231, and each a) Formulas FF1~FF48 (Formulas FF1~FF48 are,

[0244] [ka]

[0245] [ka]

[0246] [ka] And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, 5, 6, or 7. j is 1, 2, 3, 4, 5, 6, or 7, and B1 and B2 may be the same or different, each independently representing an aromatic boron-containing group. b) Models FF49~FF88 (Models FF49~FF88 are,

[0247] [ka]

[0248] [ka] And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, 5, 6, or 7. j is 1, 2, 3, 4, 5, 6, or 7, R1a is selected from COOH, CH3, H, and OH, R2, R3, R4, and R5 are each independently selected from CH3, H, OH, and COOH, at least one of R2, R3, R4, and R5 is CH3 or OH, B1 and B2 may be the same or different, and each is independently an aromatic boron-containing group. c) Formulas FF89~FF112 (Forms FF89~FF112 are,

[0249] [ka] And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, 5, 6, or 7. B1, B2, and B3 may be the same or different, and each is independently an aromatic boron-containing group, a carboxylic acid derivative, or H, and in each FF89-FF112 structure containing B1, B2, and B3 groups, at least two of B1, B2, and B3 groups are independently aromatic boron-containing groups. d) Formulas FF113~FF136 (Formulas FF113~FF136 are,

[0250] [ka] And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 0, 1, 2, 3, 4, 5, 6, or 7. j is 0, 1, 2, 3, 4, 5, 6, or 7. k is 0, 1, 2, 3, 4, 5, 6, or 7. m is 0, 1, 2, 3, 4, 5, 6, or 7. i+j+k+m is greater than 0. Each R1 is independently selected from H, alkyl groups, acyl groups, cycloalkyl groups, haloalkyl groups, aryl groups, and heteroaryl groups, and each R1 optionally contains one or more alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyls, alkyls, or aryl groups. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group. e) Formulas FF137~FF160 (Formulas FF137~FF160 are,

[0251] [ka] And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 0, 1, 2, 3, 4, 5, 6, or 7. j is 0, 1, 2, 3, 4, 5, 6, or 7. k is 0, 1, 2, 3, 4, 5, 6, or 7. m is 0, 1, 2, 3, 4, 5, 6, or 7. i+j+k+m is greater than 0. Each R1 is independently selected from H, alkyl groups, acyl groups, cycloalkyl groups, haloalkyl groups, aryl groups, and heteroaryl groups, and each R1 optionally contains one or more alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyls, alkyls, or aryl groups. B1 and B2 may be the same or different, and each is independently selected from the aromatic boron-containing groups. In one embodiment, B1 and B2 may be the same or different. f) Formulas FF161~FF164 (Formulas FF161~FF164 are,

[0252] [ka] And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, or 5 (for example, 1, 2, 3, or 5), j is 1, 2, 3, 4, or 5 (for example, 1, 2, 3, or 5), For different values ​​of j, each R6, R7, R8, and R9 independently corresponds to H, CF3, CH3, CHF2, and (CH2). m Selected from CH3, where m is 1, 2, 3, 4, or 5. Y3, Y4, Y5, Y6, and Y7 are each independently selected from H, CH2-X4, and formulas IV-1 to IV-135. X4 is -COOH, -(CH2) mSelected from COOH, alkyl groups, acyl groups, cycloalkyl groups, haloalkyl groups, aryl groups, and heteroaryl groups, each X4 optionally contains one or more alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyls, alkyls, or aryl groups, where m is 1, 2, 3, 4, or 5. At least one of Y5, Y6, and Y7 in formulas FF162 and FF163 is not H, and at least one of Y7, R8, and R9 in FF164 is not H. Equations IV-1 to IV-135 are,

[0253] [ka]

[0254] [ka]

[0255] [ka] And, Xa represents CH=O, CHF2, CF3, CH2F, COOH, CH2OH, CH2NO2, CH2NH2, CH3, C(CH3)3, CH(CH3)2, CH((CH2)3CH3)2, or CH(CH2CH3)2. Xb represents O, NH, CH2, or S. Xc represents CH or N, Each R 10 These are independently H, F, Cl, Br, CH3, CF3, CH=O, OH, COOH, and (CH2) n Selected from CH3, m is 1, 2, 3, 4, or 5, and n is 1, 2, 3, 4, or 5. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group. Formulas IV-1 to IV-135 * (This represents the connection point to the corresponding equations FF161~164), g) Formulas FF165~FF166 (Forms FF165~FF166 are,

[0256] [ka] And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. m is 1, 2, 3, 4, 5, 6, or 7. n is 1, 2, 3, 4, 5, 6, or 7. X5 is S, O, or NH. Each R1 independently contains H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, where m is 1, 2, 3, 4, 5, 6, or 7), h) Formulas FF167~FF192 (Forms FF167~FF192 are,

[0257] [ka] And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group. i) Formulas FF193~FF209 (Forms FF193~FF209 are,

[0258] [ka] And, In the formulas, R in FF208 and FF209 is an alkyl, aryl, or halide covalently bonded to the amino group of the side chain of FF208 or FF209 via at least one CH2 group. R1 and R2 are independently selected from H, CH3, alkyl, and formulas IV-1 to IV-135. i is 1, 2, 3, 4, or 5. j is 1, 2, 3, 4, or 5. X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group. j) Formula FF210~FF224 (Formula FF210~FF224 is,

[0259] [ka] And, In the formulas, R11 in FF210 to FF212 is selected from formulas IV-1 to IV-135, and R12 is selected from amine, hydroxyl, alkyl, and halide groups. Each R13 is independently selected from H, CH3, alkyl, aryl and formulas IV-1 to IV-135, and R14 is selected from H, CH3, alkyl, aryl and heteroaryl. In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. X'' represents a covalent bond to the amine--N of the compound, and -- represents a monocovalent bond to the CH2 or CH group of the compound. i is 1, 2, 3, 4, or 5. j is 1, 2, 3, 4, or 5. B1, B2, B3, B4, B5, and B6 each independently represent an aromatic boron-containing group, and in each FF structure containing B1, B2, and B3 groups, at least two of B1, B2, and B3 groups are independently aromatic boron-containing groups), and k) Model FF225~FF231 (Model FF225~FF231 is,

[0260] [ka] And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, 5, 6, or 7. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group. At least one primary or secondary amine from FF1-FF223 and FF225-231 is selected (and optionally covalently bonded to B6).

[0261] In some embodiments, B1, B2, B3, B4, B5, and B6 each independently represent an aromatic boron-containing group, and in each FF structure containing B1, B2, and B3 groups, at least two of the B1, B2, and B3 groups are independently aromatic boron-containing groups.

[0262] In some embodiments, at least one Z1c is

[0263] [ka] In some embodiments, at least one Z1c is FF227, and i is 1.

[0264] In some embodiments, at least one Z1c is selected from FF12-FF35, FF104-FF117, FF180-FF193, and FF196-FF205. In some embodiments, Z1c is selected from FF12, FF116, FF193, and FF203.

[0265] In some embodiments, B1 and B2 in formulas FF225 to FF231 are not boronic acids or F2 or F6 aromatic boron-containing groups, Formulas F2 and F6 are,

[0266] [ka] And, R1 in 5th place is (C=O)--- * This represents, --- * This represents the connection point to the rest of Z1c, 0, 1, or 2 R1 represent F, Cl, CF2, CF3, SF5, OCF3, SO2CH3, and / or SO2CF3, and each of the remaining R1 represents H. Y8 is O, i is 1.

[0267] In some embodiments, the aromatic boron-containing groups are not the aromatic boron-containing groups disclosed in patent application PCT / US2020 / 058641 (filed March 27, 2020) as formulas R1a, R1b, R1c, R2a, R2b, and R2c, which are expressly incorporated herein by reference in their entirety.

[0268] In some embodiments, the present disclosure provides a compound of formula (I) or a molecular conjugate represented by formula I, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

[0269] [ka] In the formula, X1 is (i) NH2 or OH (for example, X1 is NH2 or OH), (ii) Polypeptide active pharmaceutical ingredient containing an amine, (iii) polypeptide active pharmaceutical ingredient covalently bonded to an amine-containing linker, (iv) comprising an amine configured to be covalently bonded to a polypeptide drug substance, Each Z1c is independently selected from formulas FF1 to FF231, each Z1a independently contains 1 to 50 amino acids linked together using amide or peptide bonds, each Z1b independently is a small molecule linker, each m' is independently 0 or 1, each n' is independently 0 or a positive integer, each o' is independently an integer of 1 or more, each p' is a positive integer, and q' is a positive integer of at least 1 and not more than twice the total number of amine groups of X1. If any of n', o', p', or q' is 2 or more, the corresponding groups Z1a, Z1b, and Z1c are independently selected and may be the same or different, each Z1c is independently covalently bonded directly or indirectly to the amine of Z1a, the amine of Z1b, or X1, and optionally the molecular conjugate may contain one or more isotopes at any position of the molecular conjugate of formula I.

[0270] In at least some embodiments, X1 is (i) NH2 or OH (for example, X1 is NH2 or OH), (ii) Polypeptide active pharmaceutical ingredient containing an amine, (iii) polypeptide active pharmaceutical ingredient covalently bonded to an amine-containing linker, (iv) comprising one of the amines configured to covalently bond to a polypeptide drug substance.

[0271] In some embodiments, the compound is a molecular conjugate represented by formula I, or a stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt.

[0272] [ka] During the ceremony, X1 is either NH2 or OH, or X1 is i. Polypeptide active pharmaceutical ingredient containing amines, ii. A polypeptide active pharmaceutical ingredient covalently bonded to an amine-containing linker, or iii. An amine configured to be covalently bonded to a polypeptide active pharmaceutical ingredient, Each Z1c is independently selected from formulas FF1 to FF231. Each Z1a independently contains 1 to 50 amino acids linked together using amide or peptide bonds, and each Z1b independently is a small molecule linker. Each m' is independently either 0 or 1. Each n' is independently either 0 or a positive integer. Each o' is an independent integer greater than or equal to 1. Each p' is a positive integer, q' is a positive integer of at least one and no more than twice the total number of amine groups in X1, and if any of n', o', p', or q' is two or more, the corresponding groups Z1a, Z1b, and Z1c are independently selected and may be the same or different, and each Z1c is independently covalently bonded directly or indirectly to the amine of Z1a, the amine of Z1b, or X1, and optionally the molecular conjugate may contain one or more isotopes at any position of the molecular conjugate of formula I. In some embodiments, the compound is additionally covalently bonded as described by formula I, and / or one or more amines are each independently acetylated and / or independently alkylated.

[0273] In some embodiments, the compound of formula I is covalently bonded to B1 using a covalent bond X-B1, where X is the amino group of formula I.

[0274] In some embodiments, X1 comprises a polypeptide drug substance, and the covalent bond to X1 is to the amino group of one or more lysine residues and / or to the N-terminal amino group of X1.

[0275] In some embodiments, the compound independently comprises at least one of B1, B2, and B3 selected from formulas F1 to F11, or the compound independently comprises at least one of B4, B5, and B6 selected from formulas F1 to F11. Formulas F1 to F11 are,

[0276] [ka] And, For B1, B2, and B3: One R1 is (C=O)--- * , S(=O)(=O)--- * , (CH2) m (C=O)--- * , or (CH2) m --- * This represents, --- * represents the rest of Z1c or the bond site to the compound, and m is 1, 2, 3, 4, 5, 6, or 7. Each of the remaining R1 or R2 can independently be H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, where m is 1, 2, 3, 4, 5, 6, or 7. For B4 and B5 sizes: In the case of B4, one R1 is (CH2) m --- Represents φ, where φ represents the rest of Z1c or the bond point to the compound, and in the case of B5, one R1 is (C=O) --- * , S(=O)(=O)--- * , (CH2) m (C=O)--- * , or (CH2) m --- * This represents, --- * represents the rest of Z1c or the bond site to the compound, and m is 1, 2, 3, 4, 5, 6, or 7. Each of the remaining R1 or R2 can independently be H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, where m is 1, 2, 3, 4, 5, 6, or 7. For B6: In the case of B6, one R1 is (CH2) m ---Represents φ, where ---φ represents the bond point to the rest of the compound, and m is 1, 2, 3, 4, 5, 6, or 7. Each remaining R1 or R2 is independently H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, where m is 1, 2, 3, 4, 5, 6, or 7. Regarding formulas F3 to F4, R w is either O or S, Regarding formulas F5 to F10, If Y8 is O, then i is 1, 2, 3, 4, or 5, or If Y8 is NR, then R is an alkyl group or H, and i is 1, 2, 3, 4, or 5. Y9 is H, CH3, or an alkyl group, however, if Y8 is O, then Y9 is CH3 or an alkyl group. Each Y10 is independently selected from H, CH3, F, CF3, and OCH3, except that at least one Y10 is not H.

[0277] In some embodiments, regarding formulas F5 to F10, If Y8 is O, then i is 2, 3, 4, or 5, or If Y8 is NR, then R is an alkyl group or H, and i is 1, 2, 3, 4, or 5. Y9 is H, CH3, or an alkyl group, however, if Y8 is O, then Y9 is CH3 or an alkyl group. Each Y10 is independently selected from H, CH3, F, CF3, and OCH3, except that at least one Y10 is not H.

[0278] In at least some embodiments, B1, B2, and B3 may be the same or different. When B1, B2, and B3 are all present in the compounds of the Disclosure, each is independently an aromatic boron-containing group, a carboxylic acid derivative, or H, and in each FF structure containing B1, B2, and B3 groups (i.e., FF1 to FF231), at least two of B1, B2, and B3 are independently aromatic boron-containing groups.

[0279] In some embodiments, the compound comprises at least one group selected from B1, B2, B3, B4, B5, and B6, each independently selected from F2, F7, F8, and F11. Formulas F2, F7, F8, and F11 are,

[0280] [ka] And, For B1, B2, and B3: One R1 is (C=O)--- * , or (CH2) m (C=O)--- * This represents, --- * represents the rest of Z1c or the bond site to the compound, and m is 1, 2, 3, 4, 5, 6, or 7. Each of the remaining R1 or R2 can independently be H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) mSelected from CH3 and OCF3, where m is 1, 2, 3, 4, 5, 6, or 7. For B4 and B5 sizes: In the case of B4, one R1 is (CH2) m --- Represents φ, where φ represents the rest of Z1c or the bond point to the compound, and in the case of B5, one R1 is (C=O) --- * , S(=O)(=O)--- * , (CH2) m (C=O)--- * , or (CH2) m --- * This represents, --- * represents the rest of Z1c or the bond site to the compound, and m is 1, 2, 3, 4, 5, 6, or 7. Each of the remaining R1 or R2 can independently be H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, where m is 1, 2, 3, 4, 5, 6, or 7. For B6: In the case of B6, one R1 is (CH2) m ---Represents φ, where ---φ represents the bond point to the rest of the compound, and m is 1, 2, 3, 4, 5, 6, or 7. Each of the remaining R1 or R2 can independently be H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, where m is 1, 2, 3, 4, 5, 6, or 7. Regarding formula F7, Y8 is O or NR, and R is an alkyl group or H. Each Y10 is independently selected from CH3, F, CF3, and OCH3. Regarding formula F8, If Y8 is O, then i is 1, 2, 3, 4, or 5. If Y8 is NR, then R is an alkyl group or H, and i is 1, 2, 3, 4, or 5. Each Y10 is independently selected from H, CH3, F, CF3, and OCH3, except that at least one Y10 is not H. --- represents the remaining portion of Z1c or the bond site to the compound.

[0281] In some embodiments, the compound comprises at least one group selected from B1, B2, B3, B4, B5, and B6, each independently of the other.

[0282] [ka] Selected from, For B1, B2, and B3: One R1 is (C=O)--- * This represents, --- * This represents the remaining part of Z1c or the bond site to the compound. Each of the remaining R1 or R2 can independently be H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, where m is 1, 2, 3, 4, 5, 6, or 7. For B4 and B5 sizes: In the case of B4, one R1 is (CH2) m --- Represents φ, where φ represents the rest of Z1c or the bond point to the compound, and in the case of B5, one R1 is (C=O) --- * , S(=O)(=O)--- * , (CH2) m (C=O)--- * , or (CH2) m --- * This represents, ---* represents the rest of Z1c or the bond site to the compound, and m is 1, 2, 3, 4, 5, 6, or 7. Each of the remaining R1 or R2 can independently be H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, where m is 1, 2, 3, 4, 5, 6, or 7. For B6: In the case of B6, one R1 is (CH2) m ---Represents φ, where ---φ represents the bond point to the rest of the compound, and m is 1, 2, 3, 4, 5, 6, or 7. Each of the remaining R1 or R2 can independently be H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, where m is 1, 2, 3, 4, 5, 6, or 7. Regarding formula F7, Y8 is O, Each Y10 is independently selected from CH3, F, and CF3. Regarding formula F8, Y8 is O, i is 1, 2, 3, 4, or 5. Each Y10 is independently selected from H, CH3, F, and CF3, except that at least one Y10 is not H. --- represents the remaining portion of Z1c or the bond site to the compound.

[0283] In some embodiments, the compound comprises at least one group selected from B1, B2, B3, B4, B5, and B6, each independently.

[0284] [ka] Selected from, For B1, B2, and B3: R1 in 5th place is (C=O)--- * This represents, --- * This represents the remaining part of Z1c or the bond site to the compound. Each of the remaining R1 or R2 can independently be H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, where m is 1, 2, 3, 4, 5, 6, or 7. For B4 and B5 sizes: In the case of B4, one R1 is (CH2) m --- Represents φ, where φ represents the rest of Z1c or the bond point to the compound, and in the case of B5, one R1 is (C=O) --- * , S(=O)(=O)--- * , (CH2) m (C=O)--- * , or (CH2) m --- * This represents, --- * represents the rest of Z1c or the bond site to the compound, and m is 1, 2, 3, 4, 5, 6, or 7. Each of the remaining R1 or R2 can independently be H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, where m is 1, 2, 3, 4, 5, 6, or 7. For B6: In the case of B6, one R1 is (CH2) m---Represents φ, where ---φ represents the bond point to the rest of the compound, and m is 1, 2, 3, 4, 5, 6, or 7. Each of the remaining R1 or R2 can independently be H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, where m is 1, 2, 3, 4, 5, 6, or 7. Regarding formulas F7A and F8A, Y8 is O, i is 1, 2, 3, 4, or 5. --- represents the remaining portion of Z1c or the bond site to the compound.

[0285] In some embodiments, with respect to formulas F7A and F8A, Y8 is O, i is 2, 3, 4, or 5.

[0286] In some embodiments, the compound comprises at least one group selected from B1, B2, B3, B4, B5, and B6, each of which is of formula F7A.

[0287] [ka] For B1, B2, and B3: R1 in 5th place is (C=O)--- * This represents, --- * This represents the remaining part of Z1c or the bond site to the compound. The remaining R1 cells are, independently, H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) mSelected from CH3 and OCF3, where m is 1, 2, 3, 4, 5, 6, or 7. For B4 and B5 sizes: In the case of B4, one R1 is (CH2) m --- Represents φ, where φ represents the rest of Z1c or the bond point to the compound, and in the case of B5, one R1 is (C=O) --- * , S(=O)(=O)--- * , (CH2) m (C=O)--- * , or (CH2) m --- * This represents, --- * represents the rest of Z1c or the bond site to the compound, and m is 1, 2, 3, 4, 5, 6, or 7. The remaining R1 cells are, independently, H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, where m is 1, 2, 3, 4, 5, 6, or 7. For B6: In the case of B6, one R1 is (CH2) m ---Represents φ, where ---φ represents the bond point to the rest of the compound, and m is 1, 2, 3, 4, 5, 6, or 7. The remaining R1 cells are, independently, H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, where m is 1, 2, 3, 4, 5, 6, or 7. Y8 is O, --- represents the remaining portion of Z1c or the bond site to the compound.

[0288] In some embodiments, at least one Z1c is covalently bonded indirectly via a linker to the amine of X1, or to NH2 if X1 is NH2, or to OH if X1 is OH, or to the amine of Z1a. The linker is given by equation (X'') n1 It is expressed by, in the formula Each n1 is independently selected from 1, 2, 3, 4, and 5. Each X'' is independent, L- or D-amino acids, wherein the amine functional group of the L- or D-amino acid is directly or indirectly covalently bonded to Z1c, and the acid functional group of the L- or D-amino acid is directly or indirectly conjugated to X1 or Z1a; and ii. Selected from formulas FL(IA), FL(IB), FL69, and FL70, Formulas FL(IA) and FL(IB) are,

[0289] [ka] and its stereoisomers, During the ceremony, G is selected from 3-6 membered cycloalkyl groups, 3-10 membered heterocyclyl groups, heteroaryl groups, and aryl groups, and each group is independently optionally substituted with 1-3 groups selected from hydroxy, amino, halogen, cycloalkyl, alkoxy, and alkyl groups. E is an alkylene group that is either absent or may be substituted with 1 to 3 groups independently selected from halogen, hydroxyl, and amino groups. Q is either absent or selected from hydrogen, alkyl, halo, cyano, alkoxy, carboxylic acid, amino, hydroxy, amide, haloalkyl, cycloalkyl, heterocyclic, heteroaryl, and aryl, and each alkyl, alkoxy, cycloalkyl, heterocyclic, heteroaryl, and aryl is independently optionally substituted with 1 to 5 groups selected from alkyl, amino, amide, halo, hydroxy, cyano, haloalkyl, and alkoxy. Q' is selected from hydrogen, alkyl, and acyl groups. Q and Q', together with the carbon and nitrogen atoms to which they are bonded, optionally form a 4-membered heterocycline, a 5-membered heterocycline, a 6-membered heterocycline, a 9-membered bicyclic heterocycline, or a 10-membered bicyclic heterocycline, each of which is independently optionally substituted with 1 to 5 groups selected from alkyl, amino, halo, hydroxy, cyano, amide, haloalkyl, and alkoxy groups. p is 0, 1, 2, 3, 4, or 5. q is 0, 1, 2, 3, 4, or 5. R'' represents a direct or indirect covalent bond to Z1c. Z'' represents a direct or indirect covalent bond to X1 or Z1a. Any primary amine is optionally acetylated or alkylated. Formulas FL69 and FL70 are,

[0290] [ka] and its stereoisomers, During the ceremony, R'' represents a direct or indirect covalent bond to Z1c. Z'' represents a direct or indirect covalent bond to X1 or Z1a. A' is selected from H, alkyl, saturated fatty acids, unsaturated fatty acids, cycloalkyl, haloalkyl, aryl, and heteroaryl. A'' is, (i) Bile acids conjugated directly or indirectly via their acidic groups to an amine in FL69 or FL70, (ii) C2-C2 groups optionally terminated by an acid group 20 Acyl group (C2~C 20One or more carbon atoms of the acyl group may be optionally and independently replaced by a group selected from C(=O), O, NH, NH2, S, S(O), SO2, phenyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heteroaryl, or 6-membered heteroaryl, C2~C 20 One or more carbon atoms in the acyl group, NH, NH2, SO2, phenyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heteroaryl, and 6-membered heteroaryl are each independently 0, 1, 2, 3, or 4 R x (It is replaced by) R x These are selected from C1-C5 alkyl groups, halogens, C1-C5 haloalkyl groups, carboxylic acids, hydroxyls, -O-C1-C5 alkyl groups, NH2 groups, and substituted or unsubstituted 5-membered heterocyclines, 6-membered heterocyclines, 5-membered heteroaryl groups, and 6-membered heteroaryl groups. p is 1, 2, 3, 4, or 5. q is 1, 2, 3, 4, or 5. Any primary amine is optionally acetylated or alkylated.

[0291] In some embodiments, each A'' is independently

[0292] [ka]

[0293] [ka] Selected from.

[0294] In some embodiments, the compound comprises at least one Z1b selected from formulas IIa-IIai or IIIa-IIIai. Equations IIa to IIai are,

[0295] [ka]

[0296] [ka] And, During the ceremony, r is 0, 1, 2, 3, 4, or 5. s is 0, 1, 2, 3, 4, or 5. W represents CH2---~ or (C=O)---~, where ---~ is a covalent bond to X1. Each V1 is independently selected from NH---†, CH2---†, and (C=O)---†, each V2 is N---†, where ---† is a covalent bond to a successive Z1b, Z1a, or Z1c, except that V1 is NH---† when connected to Z1c, and the covalent bonds between the Z1a and Z1b units each independently include an amine bond or an amide bond, and when n'=0 and m'=1, Z1a is directly conjugated to X1 by an amine bond or an amide bond. Equations IIIa to IIIai are,

[0297] [ka]

[0298] [ka] And, During the ceremony, r is 1, 2, 3, 4, or 5. s is 1, 2, 3, 4, or 5. Each V1 is independently selected from NH---†, CH2---†, and (C=O)---†, each V2 is N---†, where ---† is covalently bonded to a successive Z1b, Z1a, or Z1c, except that V1 is NH---† when connected to Z1c, and the covalent bonds between Z1a and Z1b units each independently include an amine bond or an amide bond, and when n'=0 and m'=1, Z1a is directly conjugated to X1 by an amine bond or an amide bond.

[0299] In some embodiments, at least one Z1c is indirectly covalently bonded to a compound (e.g., a compound of formula I) via a linker (indirect linker). In some embodiments, the linker is (i) FL1-FL19, FL5A, FL5B, FL65A, FL65B, FL69, FL69A, FL69B, FL70, FL70A, and FL70B;

[0300] [ka]

[0301] [ka] (In formulas FL1~FL19, FL5A, FL5B, FL65A, FL65B, FL69, FL69A, FL69B, FL70, FL70A, and FL70B, Z'' represents the connection point to X1, R'' represents the connection point to Z1c, p is 1, 2, 3, 4, or 5. q is 1, 2, 3, 4, or 5. r is 1, 2, 3, 4, or 5. Any primary amine is optionally acetylated or alkylated, and (ii) Selected from L- or D-amino acids containing at least one amine group directly conjugated to Z1c (the acid functional group of the amino acid is conjugated to X1 in formula I).

[0302] In some embodiments, n' is 1, and each of Z1b is independently (i)FL1-FL19, FL5A, FL5B, FL65A, FL65B, FL69, FL69A, FL69B, FL70, FL70A, and FL70, (In formulas FL1~FL19, FL5A, FL5B, FL65A, FL65B, FL69, FL69A, FL69B, FL70, FL70A, and FL70B, Z'' represents the connection point to X1, R'' represents the connection point to Z1c, p is 1, 2, 3, 4, or 5. q is 1, 2, 3, 4, or 5. r is 1, 2, 3, 4, or 5. Any primary amine is optionally acetylated or alkylated, and (ii) Selected from L- or D-amino acids containing at least one amine group directly conjugated to Z1c (the acid functional group of the amino acid is conjugated to X1 in formula I).

[0303] In some embodiments, in formula I, Z1c is directly bonded to X1 via an arbitrary shared spacer, and the arbitrary shared spacer is independently bonded to γ-glutamic acid, β-alanine, and

[0304] [ka] Formula FL3 (wherein p is 1 or 2), and

[0305] [ka] Selected from formula FL5 (where p is 2, 3, or 4), In some embodiments, X1 is OH or NH2, and X1 further comprises an active pharmaceutical ingredient directly or indirectly covalently bonded to the compound.

[0306] In at least some embodiments, the compounds of the present disclosure include a drug substance comprising a hybrid polypeptide comprising a polypeptide hormone, a human polypeptide hormone and / or insulin, or an analog thereof, or a combination of one or more thereof.

[0307] In at least some embodiments, the compounds of the present disclosure contain an amine in the compound conjugated via an amide bond to an aromatic boron-containing compound (e.g., a group). In some embodiments, the aromatic boron-containing group is selected from phenylboronic acid, boroxol, and phenylboronic acid.

[0308] In at least some embodiments, the compounds of the present disclosure are dehydrated (lost) by 1, 2, 3, 4, 5, 6, 7, 8, or more water molecules.

[0309] In at least some embodiments, the compounds of the present disclosure are formulated into solutions containing one or more buffers, stabilizers, vasodilators, preservatives, surfactants, salts, sugars, or compounds comprising one or more hydroxyls, alcohols, diols, or phenols. For example, the solution may contain one or more citrates, zinc, and / or cresols.

[0310] In at least some embodiments, X1 includes human pancreatic polypeptide hormones, insulin, glucagon, GLP-1, somatostatin, gastric suppressor polypeptides, glucose-dependent insulin-secreting polypeptides, hybrid peptides comprising sequences from two or more human polypeptide hormones, or analogs thereof.

[0311] In some embodiments, X1 comprises human insulin or a human insulin analog comprising an A chain and a B chain, wherein the A chain comprises a sequence selected from SEQ ID NOs: 1 and 3-33, and the B chain comprises a sequence selected from SEQ ID NOs: 2 and 34-74, 24047, and 24048. Each Z1c is independently selected from FF1, FF10, FF12, FF14, FF15, FF114, FF115, FF116, FF163, FF193, FF194, FF203, and FF221~FF231, and is covalently coupled to Z1a and / or Z1b, or X1, either directly or indirectly via a linker. Each Z1a is either absent or, independently, K, GK, KGSH (sequence number 24049), KGSHK (sequence number 4238), KNSTK (sequence number 5085), GKASHK (sequence number 12414), GKEEEK (sequence number 12677), GKEEHK (sequence number 12680), GKGHSK (sequence number 13120), GKGSH (sequence number 24050), GKGSHK (sequence number 13198), GKGSTK (sequence number 1320) 5) Includes sequences selected from GKHENK (sequence number 13271), GKNSHK (sequence number 13982), GKNSTK (sequence number 13989), GKQSSK (sequence number 14380), GKYQFK (sequence number 15128), GKGSKK (sequence number 24045), GKKPGKK (sequence number 24046), GKGPSK (sequence number 24044), GKPSHKP (sequence number 24043), and GSHKGSHK (sequence number 24042), Each linker is selected from FL1, FL3, FL4, and FL5. Each m' is independently either 0 or 1. Each n' is independently 0, 1, 2, or 3. Each o' is independently 1, 2, 3, 4, or 5. Each p' is 1, 2, 3, 4, or 5. q' is 1, 2, 3, or 4, and if any of n', o', p', or q' is 2 or more, the corresponding bases Z1a, Z1b, and Z1c are independently selected and may be the same or different. Each Z1c is independently covalently bonded, directly or indirectly, to the amine of Z1a, the amine of Z1b, or X1.

[0312] In some embodiments, X1 comprises human insulin or a human insulin analog comprising an A chain and a B chain, wherein the A chain comprises SEQ ID NO: 1, and the B chain is selected from SEQ ID NOs: 2, 36, 24047, and 24048. Each Z1c is independently selected from FF1, FF10, FF12, FF14, FF15, FF114, FF115, FF116, FF193, FF194, FF203, and FF221~FF224, and is covalently coupled to Z1a and / or Z1b, or X1, either directly or indirectly via a linker. Each Z1a independently corresponds to K, GK, KGSH (sequence number 24049), KGSHK (sequence number 4238), KNSTK (sequence number 5085), GKASHK (sequence number 12414), GKEEEK (sequence number 12677), GKEEHK (sequence number 12680), GKGHSK (sequence number 13120), GKGSH (sequence number 24050), GKGSHK (sequence number 13198), GKGSTK (sequence number 13205), GKHE The sequence includes a sequence selected from NK (sequence number 13271), GKNSHK (sequence number 13982), GKNSTK (sequence number 13989), GKQSSK (sequence number 14380), GKYQFK (sequence number 15128), GKGSKK (sequence number 24045), GKKPGKK (sequence number 24046), GKGPSK (sequence number 24044), GKPSHKP (sequence number 24043), and GSHKGSHK (sequence number 24042). Each linker either does not exist independently, or is independently selected from FL3 and FL5. Each m' is independently either 0 or 1. Each n' is independently either 0 or 2. Each o' is independently 1, 2, or 3. Each p' is 1, 2, or 3. q' is 1, 2, or 3, and if any of n', o', p', or q' is 2 or more, the corresponding bases Z1a, Z1b, and Z1c are independently selected and may be the same or different. Each Z1c is independently covalently bonded, directly or indirectly, to the amine of Z1a, the amine of Z1b, or X1.

[0313] In some embodiments, each of Z1a is either not present independently or independently includes a sequence selected from K, GK, KGSH (sequence number 24049), GKGSH (sequence number 24050), KGSHK (sequence number 4238), and GKGSHK (sequence number 13198).

[0314] In some embodiments, each of Z1c is independently selected from FF1, FF10, FF12, FF14, FF15, FF114, FF115, FF116, and FF221-FF231. In some embodiments, B1 and B2 are independently selected from formulas F1 and F2. In some embodiments, B1 and B2 are independently selected from F2 and F7. In some embodiments, B1 and B2 are F2. In some embodiments, B1 and B2 are F7. In some embodiments, B1 is F2 and B2 is F7. In some embodiments, B1 is F7 and B2 is F2. In some embodiments, at least one R1 of B1 or B2 is F or CF3. In some embodiments, Z1b is independently non-existent, FL3, or FL5. In some embodiments, each of Z1c is independently selected from FF10, FF12, FF116, FF221, FF222, and FF224.

[0315] In some embodiments, each B1 and B2 is independently selected from F2 and F7 and covalently bonded to Z1c using an amide bond. Each Z1b is independently a non-existent FL3 (where p is 1, 2, or 3) or FL5 (where p is 2, 3, or 4), Each FF is independently selected from FF10, FF12, FF116, FF134, FF163, FF193, FF203, FF221, FF222, and FF224, and FF12 and FF222 have either (S,R) or (S,S) stereochemistry. Each Z1c is conjugated either directly or indirectly to one or more lysine side chains of X1 or the N-terminal amine group of X1 via FL3 or FL5. X1 is insulin having optionally 0 to 4 residues that are replaced, inserted, or mutated by the polypeptide drug substance and / or lysine, with lysine being directly or indirectly conjugated to Z1c.

[0316] In some embodiments, each B1 and B2 is F2 and is covalently bonded to Z1c using an amide bond. Each Z1b is independently a non-existent FL3 (where p is 1, 2, or 3) or FL5 (where p is 2, 3, or 4), Each FF is independently selected from FF10, FF12, FF116, FF134, FF163, FF193, FF203, FF221, FF222, and FF224, and FF12 and FF222 have either (S,R) or (S,S) stereochemistry. Each Z1c is conjugated either directly or indirectly to one or more lysine side chains of X1 or the N-terminal amine group of X1 via FL3 or FL5. X1 is insulin having optionally 0 to 4 residues that are replaced, inserted, or mutated by the polypeptide drug substance and / or lysine, with lysine being directly or indirectly conjugated to Z1c.

[0317] In some embodiments, each B1 and B2 is F7 and is covalently bonded to Z1c using an amide bond. Each Z1b is independently a non-existent FL3 (where p is 1, 2, or 3) or FL5 (where p is 2, 3, or 4), Each FF is independently selected from FF10, FF12, FF116, FF134, FF163, FF193, FF203, FF221, FF222, and FF224, and FF12 and FF222 have either (S,R) or (S,S) stereochemistry. Each Z1c is conjugated either directly or indirectly to one or more lysine side chains of X1 or the N-terminal amine group of X1 via FL3 or FL5. X1 is insulin having optionally 0 to 4 residues that are replaced, inserted, or mutated by the polypeptide drug substance and / or lysine, with lysine being directly or indirectly conjugated to Z1c.

[0318] In some embodiments, Z1c is FF224, n' is 0, and Z1a is an amine-containing amino acid.

[0319] In some embodiments, Z1c is directly covalently bonded to X1 via a linker, and the linker independently contains γ-glutamic acid, β-alanine, and

[0320] [ka] formula FL3 (wherein p is 1, 2, or 3), and

[0321] [ka] formula FL5 (where p is 2, 3, or 4) is selected.

[0322] In some embodiments, the compound further comprises an active pharmaceutical ingredient directly or indirectly covalently bonded to the compound.

[0323] In some embodiments, compounds of formula I are selected from Examples 315, 318, 320, 605-608, 610-612, 589-595, 562-574, and 803-914.

[0324] In some embodiments, X1 is insulin having optionally 0 to 4 residues that are replaced, inserted, or mutated by a polypeptide drug substance and / or lysine, with each lysine conjugated to Z1c.

[0325] In some embodiments, one or more amines are independently acetylated and / or independently alkylated.

[0326] In some embodiments, X1 comprises a polypeptide drug substance, and the covalent bond to X1 is to the amino group of one or more lysine residues and / or to the N-terminal amino group of X1.

[0327] In some embodiments, each R1 of FF1 to FF231 is independently C1 to C 22 Alkyl alkyl groups, C1-C 22 Acyl group, (C3-C8) cycloalkyl group, C1-C 22 Selected from haloalkyl groups, aryl groups, and heteroaryl groups, each R1 is one or more C1-C1 groups. 22 Alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyls, C1-C 22 It optionally contains an alkyl or aryl group.

[0328] In some embodiments, X4 is -COOH, -(CH2) m COOH, C1~C 22 Alkyl alkyl groups, C1-C 22 Acyl group, (C3-C8) cycloalkyl group, C1-C 22 Selected from haloalkyl groups, aryl groups, and heteroaryl groups, each X4 is one or more C1-C 22 Alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyls, C1-C 22 The formula optionally contains an alkyl or aryl group, where m is 1, 2, 3, 4, or 5.

[0329] In some embodiments, the alkyl group of Y9 is C1~C 22 It is alkyl. In some embodiments, Y9 is CH3.

[0330] In some embodiments, at least one primary or secondary amine from FF1 to FF223 and FF225 to FF231 is covalently bonded to B6.

[0331] In some embodiments, the amine of the compound is conjugated to an aromatic boron-containing group via an amide bond.

[0332] In some embodiments, the aromatic boron-containing group is selected from phenylboronic acid, boroxol, and phenylboronic acid.

[0333] In some embodiments, the compound is formulated into a solution containing one or more compounds comprising a buffer, stabilizer, vasodilator, preservative, surfactant, salt, sugar, or one or more hydroxyl, alcohol, diol, or phenol. In some embodiments, the solution contains one or more citrate, zinc, and / or cresol.

[0334] In some embodiments, Z1c is conjugated with cysteine.

[0335] In some embodiments, the compound (for example, the compound of formula I) is covalently bonded to a diol, sugar, carbohydrate, or diol-containing molecule, either directly or via a linker.

[0336] In some embodiments, the compound (e.g., the compound of formula I) is covalently bound to an antibody, albumin or a fragment thereof, or covalently bound directly or via a linker to a molecule that can bind to at least one protein present in human plasma. In at least one embodiment, the disclosure provides a method for administering the compounds disclosed herein to human subjects as therapeutic or prophylactic agents.

[0337] In some embodiments, the compounds disclosed herein are used as intermediate compounds for the production of any of the compounds disclosed herein.

[0338] In some embodiments, the compounds disclosed herein include at least one Z1c. In at least some embodiments, Z1c is a boron-containing compound. In some embodiments, a subset of the boron-containing compounds is selected from non-aromatic and / or aromatic boron-containing groups. In some embodiments, Z1c is an aromatic boron-containing group. In at least one embodiment, the compounds of the disclosure include at least one Z1c selected from FF1-FF18, FF35, FF56-FF62, FF65-FF67, FF70-FF72, FF75-FF77, FF80-FF81, FF84, FF88, FF92, FF101-FF102, FF107-FF136, FF193-194, FF203, and FF225-231.

[0339] In at least some embodiments, Z1c is selected from FF1 to FF231. In some embodiments, the compound has at least one chiral center and includes at least one Z1c selected from FF1, FF2, FF5, FF9, FF11-FF13, FF15-FF24, FF27, FF31, FF34-FF36, FF38, FF39, FF43-FF58, FF60-FF70, FF72-FF75, FF77-FF80, FF82-FF84, FF86-FF212, FF216-FF220, FF222, FF223, FF227, FF229, FF230, FF231, and combinations thereof.

[0340] In some embodiments, the compound comprises at least one FF12 and / or FF116. In some embodiments, the stereochemistry of FF12 and FF116 is independently selected from (S,S), (S,R), (R,R), and (R,S).

[0341] In some embodiments, X1 comprises human insulin or a human insulin analog comprising A and B chains, wherein the C-terminus of the A chain of the human insulin analog is optionally extended with up to 20 polypeptide residues, and / or the N-terminus of the B chain of the human insulin analog is optionally extended with up to 10 polypeptide residues. In some embodiments, 1 to 6 residues of the insulin A chain and / or insulin B chain are deleted or mutated.

[0342] In some embodiments, X1 comprises at least one lysine having an amine side chain, and Z1c is directly covalently bonded to the amine side chain. In some embodiments, the compounds of the present disclosure comprises at least one Z1a comprising one or more amino acids having an amine side chain, the one or more amino acids being selected from lysine, diaminopropionic acid, diaminobutyric acid, and ornithine, and Z1c is directly or indirectly covalently bonded to the amine side chain.

[0343] In some embodiments, the compounds of the present disclosure may comprise one or more isotopes selected from deuterium, tritium, carbon-13, carbon-14, and iodine-124. In at least one embodiment, the compound comprises deuterium.

[0344] In some embodiments, X1 comprises a drug substance covalently bonded to at least one Z1c via an acid-containing linker. In some embodiments, the compositions of the present disclosure comprise at least one compound disclosed herein (e.g., a compound comprising X1 of formula I and one or more Z1c), or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt or hydrate, or an isotopic derivative formulated together with one or more pharmaceutically acceptable carriers.

[0345] In some embodiments, the Disclosure also provides compositions or mixtures comprising at least one of the compounds disclosed herein for use as a pharmaceutical for the treatment of diabetes, for the control of blood glucose levels, or for controlling the release of a drug based on physiological levels of low molecular weight or sugar-containing diols.

[0346] Some embodiments disclosed herein are methods for administering the compounds disclosed herein to human subjects as therapeutic or prophylactic agents.

[0347] In some embodiments, the disclosure provides a method for producing the compounds disclosed herein, comprising at least one alkylation and / or amidation step.

[0348] In some embodiments, the Disclosure provides a method of treating a subject by administering a device or formulation containing a compound disclosed herein, such as in Examples 1 to 915. For example, the device may be a fixed-dose syringe, a microdosing syringe, or an internal or external patch.

[0349] In some embodiments, the present disclosure provides a method for treating or preventing diabetes mellitus, impaired glucose tolerance, hyperglycemia, or metabolic syndrome (metabolic syndrome X, insulin resistance syndrome), comprising administering a therapeutically effective amount of a compound disclosed herein to a subject in need thereof.

[0350] In at least some embodiments, the disclosure covers compounds of formulas FF1 to FF231, or their tautomers, stereoisomers or mixtures of stereoisomers, or pharmaceutically acceptable salts, hydrates, or isotopic derivatives. In at least some embodiments, the disclosure covers compounds selected from formulas FF1 to FF48, FF49 to FF88, FF89 to FF112, FF113 to FF136, FF137 to FF160, FF161 to FF164, FF165 to FF166, FF167 to FF192, FF193 to FF209, and FF210 to FF231.

[0351] In some embodiments, this disclosure applies to compounds selected from formulas FF1 to FF48. In the formula, X is selected from maleimide, amine, OH, and halogen. i is 1, 2, 3, 4, 5, 6, or 7. j is 1, 2, 3, 4, 5, 6, or 7. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group.

[0352] In some embodiments, the present disclosure applies to compounds selected from formulas FF49 to FF88. In the formula, X is selected from maleimide, amine, OH, and halogen. i is 1, 2, 3, 4, 5, 6, or 7. j is 1, 2, 3, 4, 5, 6, or 7. R1a is selected from COOH, CH3, H, and OH. R2, R3, R4, and R5 are each independently selected from CH3, H, OH, and COOH, and at least one of R2, R3, R4, and R5 is CH3 or OH. B1 and B2 may be the same or different, and each is an aromatic boron-containing group independently.

[0353] In some embodiments, the present disclosure applies to compounds selected from formulas FF89 to FF112. In the formula, X is selected from maleimide, amine, OH, and halogen. i is 1, 2, 3, 4, 5, 6, or 7. B1, B2, and B3 may be the same or different, and each independently represents an aromatic boron-containing group, a carboxylic acid derivative, or H, and at least two of B1, B2, and B3 in each FF structure are independently aromatic boron-containing groups.

[0354] In some embodiments, this disclosure applies to compounds selected from formulas FF113 to FF136. In the formula, X is selected from maleimide, amine, OH, and halogen. i is 0, 1, 2, 3, 4, 5, 6, or 7. j is 0, 1, 2, 3, 4, 5, 6, or 7. k is 0, 1, 2, 3, 4, 5, 6, or 7. m is 0, 1, 2, 3, 4, 5, 6, or 7. i+j+k+m is greater than 0. Each R1 is independently selected from H, alkyl groups, acyl groups, cycloalkyl groups, haloalkyl groups, aryl groups, and heteroaryl groups, and each R1 optionally contains one or more alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyls, alkyls, or aryl groups. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group, a compound, a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt.

[0355] In some embodiments, this disclosure applies to compounds selected from formulas FF137 to FF160. In the formula, X is selected from maleimide, amine, OH, and halogen. i is 0, 1, 2, 3, 4, 5, 6, or 7. j is 0, 1, 2, 3, 4, 5, 6, or 7. k is 0, 1, 2, 3, 4, 5, 6, or 7. m is 0, 1, 2, 3, 4, 5, 6, or 7. i+j+k+m is greater than 0. Each R1 is independently selected from H, alkyl groups, acyl groups, cycloalkyl groups, haloalkyl groups, aryl groups, and heteroaryl groups, and each R1 optionally contains one or more alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyls, alkyls, or aryl groups. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group.

[0356] In some embodiments, this disclosure applies to compounds selected from formulas FF161 to FF164. In the formula, X is selected from maleimide, amine, OH, and halogen. i is 1, 2, 3, 4, or 5 (for example, 1, 2, 3, or 5), j is 1, 2, 3, 4, or 5 (for example, 1, 2, 3, or 5), For different values ​​of j, each R6, R7, R8, and R9 independently corresponds to H, CF3, CH3, CHF2, and (CH2). m Selected from CH3, where m is 1, 2, 3, 4, or 5. Y3, Y4, Y5, Y6, and Y7 are each independently selected from H, CH2-X4, and equations IV-1 to IV-135 (as previously defined). X4 is -COOH, -(CH2) m Selected from COOH, alkyl groups, acyl groups, cycloalkyl groups, haloalkyl groups, aryl groups, and heteroaryl groups, each optionally containing one or more alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyls, alkyls, or aryl groups, where m is 1, 2, 3, 4, or 5. At least one of Y5, Y6, and Y7 in equations FF162 and FF163 is not H, At least one of Y7, R8, and R9 in FF164 is not H, Xa represents CH=O, CHF2, CF3, CH2F, COOH, CH2OH, CH2NO2, CH2NH2, CH3, C(CH3)3, CH(CH3)2, CH((CH2)3CH3)2, or CH(CH2CH3)2. Xb represents O, NH, CH2, or S. Xc represents CH or N, Each R 10 These are independently H, F, Cl, Br, CH3, CF3, CH=O, OH, COOH, and (CH2) n Selected from CH3, m is 1, 2, 3, 4, or 5, and n is 1, 2, 3, 4, or 5. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group. In some embodiments, when j is 4, in the case of FF163, X is not NH2.

[0357] In some embodiments, this disclosure applies to compounds selected from formulas FF165 to FF166. In the formula, X is selected from maleimide, amine, OH, and halogen. m is 1, 2, 3, 4, 5, 6, or 7. n is 1, 2, 3, 4, 5, 6, or 7. X5 is S, O, or NH. Each R1 independently contains H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, m is 1, 2, 3, 4, 5, 6, or 7.

[0358] In some embodiments, this disclosure applies to compounds selected from formulas FF167 to FF192. In the formula, X is selected from maleimide, amine, OH, and halogen. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group.

[0359] In some embodiments, the present disclosure applies to compounds selected from formulas FF193 to FF209. In the formulas, R in FF208 and FF209 is an alkyl, aryl, or halide covalently bonded to the amino group of the side chain of FF208 or FF209 via at least one CH2 group. R1 and R2 are independently selected from H, CH3, alkyl, and formulas IV-1 to IV-135. i is 1, 2, 3, 4, or 5. j is 1, 2, 3, 4, or 5. In the formula, X is selected from maleimide, amine, OH, and halogen. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group.

[0360] In some embodiments, the present disclosure applies to compounds selected from formulas FF210 to FF224. In the formulas, R11 in FF210 to FF212 is independently selected from formulas IV-1 to IV-135, and R12 is selected from amine, hydroxyl, alkyl, and halide groups. Each R13 is independently selected from H, CH3, alkyl, aryl, and formulas IV-1 to IV-135, and R14 is independently selected from H, CH3, alkyl, aryl, and heteroaryl, where X is independently selected from maleimide, amine, OH, and halogen. X'' is an amine, i is 1, 2, 3, 4, or 5. j is 1, 2, 3, 4, or 5. B1, B2, B3, B4, B5, and B6 each independently represent an aromatic boron-containing group, and in any compound containing groups B1, B2, and B3, at least two groups are independently aromatic boron-containing groups.

[0361] In some embodiments, the present disclosure applies to compounds selected from formulas FF225 to FF231.

[0362] [ka] In the formula, X is selected from maleimide, amine, OH, and halogen. i is 1, 2, 3, 4, 5, 6, or 7. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group, and B1 and B2 in formulas FF225 to FF231 are not F2 or F6 aromatic boron-containing groups. Formulas F2 and F6 are,

[0363] [ka] And, R1 in 5th place is (C=O)--- *This represents, --- * This represents the connection point to the remaining part of FF225~FF231, 0, 1, or 2 R1 represent F, Cl, CF2, CF3, SF5, OCF3, SO2CH3, and / or SO2CF3, and each of the remaining R1 represents H. Y8 is O, i is 1, Each of the remaining R1s is H, Y8 is O, i is 1.

[0364] In at least some embodiments, if X is an amine in any one of the formulas FF1-FF223 and FF225-FF231, then X is optionally acetylated or alkylated.

[0365] In some embodiments, the compound independently comprises at least one of B1, B2, and B3 selected from formulas F1 to F11, or the compound independently comprises at least one of B4, B5, and B6 selected from formulas F1 to F11. In at least some embodiments, B1, B2, and B3 may be the same or different. When B1, B2, and B3 are all present in the compounds of the Disclosure, each is independently an aromatic boron-containing group, a carboxylic acid derivative, or H, provided that in each FF structure containing B1, B2, and B3 groups (i.e., FF1 to FF231), at least two groups are independently aromatic boron-containing groups.

[0366] In some embodiments, for B1, B2, and B3: One R1 is (C=O)--- * , S(=O)(=O)--- * , (CH2) m (C=O)--- * , or (CH2) m --- * This represents, --- * represents the rest of Z1c or the bond site to the compound, and m is 1, 2, 3, 4, 5, 6, or 7. Each of the remaining R1 or R2 can independently be H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, m is 1, 2, 3, 4, 5, 6, or 7.

[0367] In some embodiments, for B4 and B5: In the case of B4, one R1 is (CH2) m ---Represents φ, where φ represents the bond point of X1 to the amine (representing a covalent bond), and in the case of B5, one R1 is (C=O)--- * , S(=O)(=O)--- * , (CH2) m (C=O)--- * , or (CH2) m --- * This represents, --- * represents the bonding site of X1 to the same amine, and m is 1, 2, 3, 4, 5, 6, or 7. Each of the remaining R1 or R2 can independently be H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, m is 1, 2, 3, 4, 5, 6, or 7.

[0368] In some embodiments, for B6: In the case of B6, one R1 is (CH2) m ---Represents φ, where ---φ represents a bond point to the rest of the compound (representing a covalent bond), and m is 1, 2, 3, 4, 5, 6, or 7. Each remaining R1 or R2 is independently H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, m is 1, 2, 3, 4, 5, 6, or 7.

[0369] In some embodiments, Regarding formulas F3 to F4, R w is either O or S, Regarding formulas F5 to F10, If Y8 is O, then i is 1, 2, 3, 4, or 5, or If Y8 is NR, then R is an alkyl group or H, and i is 1, 2, 3, 4, or 5. Y9 is H, CH3, or an alkyl group, however, if Y8 is O, then Y9 is CH3 or an alkyl group. Each Y10 is independently selected from H, CH3, F, CF3, and OCH3, except that at least one Y10 is not H.

[0370] In some embodiments, regarding formulas F5 to F10, If Y8 is O, then i is 2, 3, 4, or 5. Y9 is H, CH3, or an alkyl group, however, if Y8 is O, then Y9 is CH3 or an alkyl group. Each Y10 is CH3. In some embodiments, the compound is N-(3-(3-borono-5-nitrobenzamide)propyl)-N-(3-borono-5-nitrobenzoyl)glycine (DS01), N-(4-((4-(3-Borono-5-nitrobenzamide)cyclohexyl)methyl)cyclohexyl)-N-(3-Borono-5-nitrobenzoyl)glycine (DS02), N-(4-((3-Borono-5-nitrobenzamide)methyl)benzyl)-N-(3-Borono-5-nitrobenzoyl)glycine (DS03), N-(3-((3-Borono-5-nitrobenzamide)methyl)benzyl)-N-(3-Borono-5-nitrobenzoyl)glycine (DS04), N-(4-(3-borono-5-nitrobenzamide)butyl)-N-(3-borono-5-nitrobenzoyl)glycine (DS05), N-(3-(3-borono-5-fluorobenzamide)propyl)-N-(3-borono-5-fluorobenzoyl)glycine (DS06), N-(3-(3-Borono-5-fluorobenzamide)-2,2-dimethylpropyl)-N-(3-Borono-5-fluorobenzoyl)glycine (DS07), Bis(3-(3-Borono-5-Fluorobenzamide)propyl)glycine (DS08), N-(4-((3-Borono-5-fluorobenzamide)methyl)benzyl)-N-(3-Borono-5-fluorobenzoyl)glycine (DS09), N-(3-((3-Borono-5-fluorobenzamide)methyl)benzyl)-N-(3-Borono-5-fluorobenzoyl)glycine (DS10), N-(2-(3-borono-5-fluorobenzamide)cyclohexyl)-N-(3-borono-5-fluorobenzoyl)glycine (DS11), N-(3-(3-borono-4-fluorobenzamide)propyl)-N-(3-borono-4-fluorobenzoyl)glycine (DS12), N-(4-((4-(3-Borono-4-fluorobenzamide)cyclohexyl)methyl)cyclohexyl)-N-(3-Borono-4-fluorobenzoyl)glycine (DS13), N-(3-(3-Borono-4-fluorobenzamide)-2,2-dimethylpropyl)-N-(3-Borono-4-fluorobenzoyl)glycine (DS14), N-(4-((3-Borono-4-fluorobenzamide)methyl)benzyl)-N-(3-Borono-4-fluorobenzoyl)glycine (DS15), N-(3-((3-Borono-4-fluorobenzamide)methyl)benzyl)-N-(3-Borono-4-fluorobenzoyl)glycine (DS16), N-((1S,2R)-2-(3-Borono-4-fluorobenzamide)cyclohexyl)-N-(3-Borono-4-fluorobenzoyl)glycine (DS17), N-((1S,2S)-2-(3-Borono-4-fluorobenzamide)cyclohexyl)-N-(3-Borono-4-fluorobenzoyl)glycine (DS18), N-(3-(3-Borono-5-bromobenzamide)propyl)-N-(3-Borono-5-bromobenzoyl)glycine (DS19), N-(4-((4-(3-Borono-5-bromobenzamide)cyclohexyl)methyl)cyclohexyl)-N-(3-Borono-5-bromobenzoyl)glycine (DS20), Bis(3-(3-Borono-5-bromobenzamide)propyl)glycine (DS21), N-(4-((3-Borono-5-bromobenzamide)methyl)benzyl)-N-(3-Borono-5-bromobenzoyl)glycine (DS22), N-(3-((3-Borono-5-bromobenzamide)methyl)benzyl)-N-(3-Borono-5-bromobenzoyl)glycine (DS23), N-(2-(3-Borono-5-bromobenzamide)cyclohexyl)-N-(3-Borono-5-bromobenzoyl)glycine (DS24), N-(3-(4-Borono-3-fluorobenzamide)propyl)-N-(4-Borono-3-fluorobenzoyl)glycine (DS25), N-(4-((4-(4-Borono-3-fluorobenzamide)cyclohexyl)methyl)cyclohexyl)-N-(4-Borono-3-fluorobenzoyl)glycine (DS26), N-(3-(4-Borono-3-fluorobenzamide)-2,2-dimethylpropyl)-N-(4-Borono-3-fluorobenzoyl)glycine (DS27), Bis(3-(4-Borono-3-Fluorobenzamide)propyl)glycine (DS28), N-(4-((4-Borono-3-fluorobenzamide)methyl)benzyl)-N-(4-Borono-3-fluorobenzoyl)glycine (DS29), N-(3-((4-Borono-3-fluorobenzamide)methyl)benzyl)-N-(4-Borono-3-fluorobenzoyl)glycine (DS30), N-((1S,2R)-2-(4-Borono-3-fluorobenzamide)cyclohexyl)-N-(4-Borono-3-fluorobenzoyl)glycine (DS31), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)propyl)glycine (DS32), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(5-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pentyl)glycine (DS33), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-2,2-dimethylpropyl)glycine (DS34), Bis(3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)propyl)glycine (DS35), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(3-((1-hydroxy-1,3-dihydrobenzo[c][1,2]]oxabolol-6-carboxamide)methyl)benzyl)glycine (DS36), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-((1S,2R)-2-(1-hydroxy-1,3-dihydrobenzo[c]][1,2]oxabolol-6-carboxamide)cyclohexyl)glycine (DS37), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)butyl)glycine (DS38), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-((1S,2S)-2-(1-hydroxy-1,3-dihydrobenzo[c]][1,2]oxabolol-6-carboxamide)cyclohexyl)glycine (DS39), (R)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)propyl)glycine (DS40), (S)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)propyl)glycine (DS41), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)cyclohexyl)glycine (DS42), N-(3-(4-Borono-3,5-difluorobenzamide)propyl)-N-(4-Borono-3,5-difluorobenzoyl)glycine (DS43), N-(3-(4-Borono-2-fluorobenzamide)propyl)-N-(4-Borono-2-fluorobenzoyl)glycine (DS44), N-(2-(N-ethyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)ethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c]][1,2]oxabolol-6-carbonyl)glycine (DS45), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(2-(1-hydroxy-N-(2-hydroxyethyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)ethyl)glycine (DS46), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(5-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)hexyl)glycine (DS47), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(4-((4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)cyclohexyl)methyl)cyclohexyl)glycine (DS48), ((2S,4S)-1-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pyrrolidine-2-carbonyl)glycine (DS49), ((2S,4S)-4-(3-Borono-4-fluorobenzamide)-1-(3-Borono-4-fluorobenzoyl)pyrrolidine-2-carbonyl)glycine (DS50), ((2S,4S)-4-(3-Borono-5-nitrobenzamide)-1-(3-Borono-5-nitrobenzoyl)pyrrolidine-2-carbonyl)glycine (DS51), ((2S,4S)-4-(5-Borono-2-fluorobenzamide)-1-(5-Borono-2-fluorobenzoyl)pyrrolidine-2-carbonyl)glycine (DS52), (S)-(1,4-bis(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)piperazine-2-carbonyl)glycine (DS53), (S)-N-(3-amino-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-3-oxopropyl)-N-benzyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS54), (S)-N-(3-amino-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-3-oxopropyl)-1-hydroxy-N-(4-(trifluoromethyl)benzyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS55), (S)-N-(3-amino-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-3-oxopropyl)-N-ethyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS56), (S)-N-(3-amino-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-3-oxopropyl)-1-hydroxy-N-propyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS57), (S)-N-(3-amino-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-3-oxopropyl)-1-hydroxy-N-isobutyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS58), (S)-N-(3-amino-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-3-oxopropyl)-1-hydroxy-N-((5-(thiophen-2-yl)pyridine-2-yl)methyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS59), (S)-N-(3-amino-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-3-oxopropyl)-1-hydroxy-N-isopentyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS60), (S)-N-(3-amino-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-3-oxopropyl)-1-hydroxy-N-(quinoline-5-ylmethyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS61), (S)-N-(3-amino-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-3-oxopropyl)-1-hydroxy-N-(2-(trifluoromethoxy)benzyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS62), (S)-N-(3-amino-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-3-oxopropyl)-1-hydroxy-N-(4-(methylsulfonyl)benzyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS63), (3-((2S,4S)-4-(5-Borono-2-(methylsulfonyl)benzamide)-2-carbamoylpyrrolidine-1-carbonyl)-4-(methylsulfonyl)phenyl)boronic acid (DS64), (4-(((3S,5S)-1-(4-Borono-2,6-difluorobenzoyl)-5-carbamoylpyrrolidine-3-yl)carbamoyl)-3,5-difluorophenyl)boronic acid (DS65), (R,E)-4,5-bis(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)penta-2-enoic acid (DS66), (2S,4S)-1-(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-4-(1-hydroxy-4-(trifluoromethyl))-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pyrrolidine-2-carboxamide (DS67), N,N'-((2S,3S)-1-amino-1-oxobutan-2,3-diyl)bis(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)(DS68), (R)-3,4-bis(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)butanoic acid (DS69), 3-((2S,4S)-1-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-4-(1-hydroxy-1,3-dihydrobenzo[c]][1,2]oxabolol-6-carboxamide)pyrrolidine-2-carboxamide)propanoic acid (DS70), (S)-3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-5-carboxamide)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]]oxabolol-6-carboxamide)butanoic acid (DS71), (R)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-5-carboxamide)-5-(1-hydroxy-1,3-dihydrobenzo[c][1,2]]oxabolol-6-carboxamide)pentanoic acid (DS72), (2S,4R)-1-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pyrrolidine-2-carboxylic acid (DS73), (2S,4R)-1-(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-4-(1-hydroxy-4-(trifluoromethyl))-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pyrrolidine-2-carboxylic acid (DS74), (2S,3S)-3-(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-2-(1-hydroxy-7-(trifluoromethyl))-1,3-dihydrobenzo[c][1,2]oxabolol-5-carboxamide)butanoic acid (DS75), (R)-5-(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-4-(1-hydroxy-7-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxabolol-5-carboxamide)pentanoic acid (DS76), ((2S,4S)-1-(5-Borono-2-nitrobenzoyl)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pyrrolidine-2-carbonyl)glycine (DS77), ((2S,4S)-1-(5-Borono-2-(methylsulfonyl)benzoyl)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pyrrolidine-2-carbonyl)glycine (DS78), ((2S,4S)-1-(3-Borono-2,6-difluorobenzoyl)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pyrrolidine-2-carbonyl)glycine (DS79), (S)-(3-((3-Borono-4-fluorobenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-5-nitrophenyl)boronic acid (DS80), (S)-(3-((4-Borono-3,5-difluorobenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-5-nitrophenyl)boronic acid (DS81), (S)-(3-((3-Boronobenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-5-nitrophenyl)boronic acid (DS82), (S)-(3-((4-Borono-2-methoxybenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-5-nitrophenyl)boronic acid (DS83), (S)-(3-((4-Borono-2-(trifluoromethyl)benzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-5-nitrophenyl)boronic acid (DS84), (S)-(5-((3-Borono-N-(5,6-diamino-6-oxohexyl)-4-fluorobenzamide)methyl)-2-fluorophenyl)boronic acid (DS85), (S)-(5-((4-Borono-3,5-difluorobenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-2-fluorophenyl)boronic acid (DS86), (S)-(3-((3-Borono-N-(5,6-diamino-6-oxohexyl)-4-fluorobenzamide)methyl)phenyl)boronic acid (DS87), (S)-(5-((4-Borono-2-methoxybenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-2-fluorophenyl)boronic acid (DS88), (S)-(5-((4-Borono-3-(trifluoromethyl)benzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-2-fluorophenyl)boronic acid (DS89), (S)-(4-((3-Borono-4-fluorobenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-2-fluorophenyl)boronic acid (DS90), (S)-(4-((4-Borono-3,5-difluorobenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-2-fluorophenyl)boronic acid (DS91), (S)-(4-((3-Boronobenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-2-fluorophenyl)boronic acid (DS92), (S)-(4-((4-Borono-2-methoxybenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-2-fluorophenyl)boronic acid (DS93), (S)-(4-((4-Borono-2-(trifluoromethyl)benzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-2-fluorophenyl)boronic acid (DS94), (S)-(5-((3-Borono-5-bromo-N-(5,6-diamino-6-oxohexyl)benzamide)methyl)-2-fluorophenyl)boronic acid (DS95), (S)-(3-((4-Borono-3,5-difluorobenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-5-bromophenyl)boronic acid (DS96), (S)-(3-((3-Borono-5-bromo-N-(5,6-diamino-6-oxohexyl)benzamide)methyl)phenyl)boronic acid (DS97), (S)-(3-((3-Borono-5-bromo-N-(5,6-diamino-6-oxohexyl)benzamide)methyl)-5-methoxyphenyl)boronic acid (DS98), (S)-(3-((4-Borono-2-(trifluoromethyl)benzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-5-bromophenyl)boronic acid (DS99), (S)-(3-((3-Borono-4-fluorobenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-5-fluorophenyl)boronic acid (DS100), (S)-(3-((4-Borono-3-methoxybenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-5-fluorophenyl)boronic acid (DS101), (S)-(3-((4-Borono-2-(trifluoromethyl)benzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-5-fluorophenyl)boronic acid (DS102), (S)-(4-((N-(5,6-diamino-6-oxohexyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)methyl)-2-fluorophenyl)boronic acid (DS103), (S)-(4-((N-(5,6-diamino-6-oxohexyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)methyl)-2,6-difluorophenyl)boronic acid (DS104), (S)-(3-((N-(5,6-diamino-6-oxohexyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)methyl)phenyl)boronic acid (DS105), (S)-(4-((N-(5,6-diamino-6-oxohexyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)methyl)-3-methoxyphenyl)boronic acid (DS106), (S)-N-(5,6-diamino-6-oxohexyl)-1-hydroxy-N-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-yl)methyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS107), (S)-N-(4-amino-3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-4-oxobutyl)-1-hydroxy-N-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-yl)methyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS108), (S)-N-(6-amino-5-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-6-oxohexyl)-1-hydroxy-N-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-yl)methyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS109), (2S,4S)-1-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pyrrolidine-2-carboxylic acid (DS110), (2S,3S)-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-5-carboxamide)-3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]]oxabolol-6-carboxamide)butanoic acid (DS111), and (2S,4R)-1-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-4-(1-hydroxy-1,3-dihydrobenzo[c]][1,2]oxabolol-6-carboxamide)pyrrolidine-2-carboxylic acid (DS112), N-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(2-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)ethyl)glycine (DS113), N-(1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxavorinine-7-carbonyl)-N-(2-(1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxavorinine-7-carboxamide)ethyl)glycine (DS114), N-(2-(2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-7-yl)acetamide)ethyl)-N-(2-(1-hydroxy-1,3-dihydrobenzo[c]][1,2]oxabolol-7-yl)acetyl)glycine (DS115), N-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-7-carbonyl)-N-(2-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-7-carboxamide)ethyl)glycine (DS116), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-3-carbonyl)-N-(2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-3-carboxamide)ethyl)glycine (DS117), 3,5-Bis((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)methyl)benzoic acid (DS118), 3,5-Bis((1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxavorinine-7-carboxamide)methyl)benzoic acid (DS119), 3,5-Bis((2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-7-yl)acetamide)methyl)benzoic acid (DS120), 3,5-Bis((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-7-carboxamide)methyl)benzoic acid (DS121), 3,5-Bis((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-3-carboxamide)methyl)benzoic acid (DS122), (S)-3-(2,3-bis(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)propanamide)propanoic acid (DS123), (S)-3-(2,3-bis(1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxavorinin-7-carboxamide)propanamide)propanoic acid (DS124), (S)-3-(2,3-bis(2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-7-yl)acetamide)propanamide)propanoic acid (DS125), (S)-3-(2,3-bis(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-7-carboxamide)propanamide)propanoic acid (DS126), 3-((2S)-2,3-bis(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-3-carboxamide)propanamide)propanoic acid (DS127), (3,5-Bis((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)methyl)benzoyl)glutamic acid (DS128), (3,5-Bis((1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxavorinin-7-carboxamide)methyl)benzoyl)glutamic acid (DS129), (3,5-Bis((2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-7-yl)acetamide)methyl)benzoyl)glutamic acid (DS130), (3,5-Bis((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-7-carboxamide)methyl)benzoyl)glutamic acid (DS131), (3,5-Bis((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-3-carboxamide)methyl)benzoyl)glutamic acid (DS132), 4-(3,4-bis(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pyrrolidine-1-yl)-4-oxobutanoic acid (DS133), 4-(3,4-bis(1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxavorinin-7-carboxamide)pyrrolidine-1-yl)-4-oxobutanoic acid (DS134), 4-(3,4-bis(2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-7-yl)acetamide)pyrrolidine-1-yl)-4-oxobutanoic acid (DS135), 4-(3,4-bis(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-7-carboxamide)pyrrolidine-1-yl)-4-oxobutanoic acid (DS136), 4-(3,4-bis(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-3-carboxamide)pyrrolidine-1-yl)-4-oxobutanoic acid (DS137), ((S)-2,3-bis(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)propanoyl)-L-glutamic acid (DS138), ((S)-2,3-bis(1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxavorinin-7-carboxamide)propanoyl)-L-glutamic acid (DS139), ((S)-2,3-bis(2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-7-yl)acetamide)propanoyl)-L-glutamic acid (DS140), ((S)-2,3-bis(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-7-carboxamide)propanoyl)-L-glutamic acid (DS141), ((2S)-2,3-bis(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-3-carboxamide)propanoyl)-L-glutamic acid (DS142), (4-(3,4-bis(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pyrrolidine-1-yl)-4-oxobutanoyl)-L-glutamic acid (DS143), (4-(3,4-bis(1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxavorinin-7-carboxamide)pyrrolidine-1-yl)-4-oxobutanoyl)-L-glutamic acid (DS144), (4-(3,4-bis(2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-7-yl)acetamide)pyrrolidine-1-yl)-4-oxobutanoyl)-L-glutamic acid (DS145), (4-(3,4-bis(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-7-carboxamide)pyrrolidine-1-yl)-4-oxobutanoyl)-L-glutamic acid (DS146), (4-(3,4-bis(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-3-carboxamide)pyrrolidine-1-yl)-4-oxobutanoyl)-L-glutamic acid (DS147), (S)-2,3-bis(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)propanoic acid (DS148), (S)-2,3-bis(1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxavorinin-7-carboxamide)propanoic acid (DS149), (S)-2,3-bis(2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-7-yl)acetamide)propanoic acid (DS150), (S)-2,3-bis(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-7-carboxamide)propanoic acid (DS151), and (2S)-2,3-bis(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-3-carboxamide)propanoic acid (DS152) is selected. In some embodiments, the compound of formula (I) is

[0371] [ka] Selected from.

[0372] In some embodiments, the compound of formula I is

[0373] [ka]

[0374] [ka] Selected from.

[0375] In some embodiments, the compound is

[0376] [ka] Selected from.

[0377] In some embodiments, the compound of formula I is

[0378] [ka] Selected from.

[0379] In some embodiments, the compound is defined as p'=1, m'=0, o'=1, n'=0, and q'=1.

[0380] [ka] That is the case.

[0381] In some embodiments, the compound is such that p'=1 and 2, m'=0 and 1, o'=1 and 1, n'=0, and q'=2 and 1.

[0382] [ka] That is the case.

[0383] In some embodiments, the disclosure relates to compounds comprising one or more diboronates (where the compound is represented by formula IB), stereoisomers or mixtures of stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0384] [ka] During the ceremony, Each Z1b is an independent linker portion, and each n' is 0, 1, 2, 3, 4, or 5. X1 comprises an active pharmaceutical ingredient or polypeptide, Each Z1c is covalently bonded to the amine of X1, either directly or via one or more Z1b. a) At least one Z1c is independently selected from diboronates, and the diboronates are independently selected from formulas FF12A, FF12B, FF12C, FF12D, FF116A, FF116B, FF116C, FF116D, FF225, and FF227. b) Each additional Z1c is optionally and independently selected from diboronates, sugar moieties, diol-containing moieties, and polyol-containing moieties, and the diboronates are independently selected from formulas FF12A, FF12B, FF12C, FF12D, FF116A, FF116B, FF116C, FF116D, FF225, and FF227. Each q' is 1, 2, 3, 4, or 5, and if q' is 2 or greater, the corresponding Z1c and Z1b are selected independently and may be the same or different. Formulas FF12A, FF12B, FF12C, FF12D, FF116A, FF116B, FF116C, FF116D, FF225, and FF227 are:

[0385] [ka] And, In the formula, X represents the covalent bond site of Z1b to the amine, or, if n' is 0, the covalent bond site of X1 to the amine. i is 1, 2, 3, 4, 5, 6, or 7. B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group. If each Z1c is selected from formulas FF225 and FF227, then at least one of B1 and B2 is formula F7. Equation F7 is,

[0386] [ka] And, During the ceremony, One R1 is (C=O)--- * This represents, --- * This represents the connection point to the rest of Z1c, The remaining R1 cells are, independently, H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, where m is 1, 2, 3, 4, 5, 6, or 7. Y8 is O or NR, and R is an alkyl group (e.g., C1-C6 alkyl group) or H. Each Y10 is independently selected from H, CH3, F, and CF3, and for at least one F7, at least one Y10 is not H.

[0387] In some embodiments, each Z1b is independently a linker portion, and each n' is 0, 1, 2, The values ​​are 3, 4, or 5, and at least one n' is 1, 2, 3, 4, or 5. In some embodiments, each n' is 1, 2, 3, 4, or 5. In some embodiments, each n' is 2, 3, or 4.

[0388] In some embodiments, the compound is The compound is selected from the compound represented by formula IB, its stereoisomers, mixtures of its stereoisomers, and pharmaceutically acceptable salts thereof, provided that the compound is not any of Examples 1-880 disclosed in PCT / US2021 / 059802.

[0389] In some embodiments, the compound is represented by formula IB, or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0390] [ka] During the ceremony, Each n' is 0, 1, 2, or 3, and at least one n' is 1, 2, or 3. Each q is 1, 2, 3, or 4. Each Z1b is independently a linker moiety, and each Z1c is covalently bonded to the amine of X1 either directly or via one or more of the Z1b, provided that Z1b is not a diol-containing moiety. One or more positions in a compound may contain isotopes.

[0391] In some embodiments, each Z1c is covalently bonded to the amine of X1 via one or more Z1b, and each Z1b is independently selected from the formulas FL3, FL5, FL5A, FL5B, FL65A, FL65B, FL69, FL69A, FL69B, FL70, FL70A, and FL70B. FL3, FL5, FL5A, FL5B, FL65A, FL65B, FL69, FL69A, FL69B, FL70, FL70A, and FL70B are,

[0392] [ka] And, During the ceremony, R'' represents a direct or indirect covalent bond to Z1c. Z'' represents a direct or indirect covalent bond to X1, A' is H and C1~C 20 Selected from alkyl, and A'' is a C2-C group optionally terminated with an acid group. 20 It is an acyl group, C2~C 20 One or more carbon atoms of the acyl group may be optionally and independently replaced by a group selected from C(=O), O, NH, NH2, S, S(O), SO2, phenyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heteroaryl, or 6-membered heteroaryl, C2~C 20Acyl groups, NH, NH2, SO2, phenyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heteroaryl, and 6-membered heteroaryl each independently have 0, 1, 2, 3, or 4 R groups. x It has been replaced with, R x These are selected from C1-C5 alkyl groups, halogens (e.g., F, Cl, Br, I), C1-C5 haloalkyl groups, carboxylic acids, hydroxyls, -O-C1-C5 alkyl groups, -S(=O)2NH2, NH2, 5-membered heterocyclines, 6-membered heterocyclines, 5-membered heteroaryl groups, phenyl groups, and 6-membered heteroaryl groups. p is 1, 2, 3, 4, or 5. q is 1, 2, 3, 4, or 5. Any primary amine is optionally acetylated or alkylated.

[0393] In some embodiments, A' is H. In some embodiments, A' is C1~C 20 It is an alkyl group. In some embodiments, the alkyl group is C1-C 18 It is an alkyl group. In some embodiments, the alkyl group is C1-C 16 It is an alkyl group. In some embodiments, the alkyl group is C1-C 14 It is an alkyl group. In some embodiments, the alkyl group is C1-C 12 It is an alkyl group. In some embodiments, the alkyl group is C1-C 10It is an alkyl group. In some embodiments, the alkyl group is a C1-C8 alkyl group. In some embodiments, the alkyl group is a C1-C6 alkyl group. In some embodiments, the alkyl group is a C1-C4 alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. In some embodiments, "alkyl" is a linear hydrocarbon. In some embodiments, "alkyl" is a branched-chain hydrocarbon.

[0394] In some embodiments, each Z1b is independently

[0395] [ka] Selected from, During the ceremony, p is 1, 2, 3, 4, or 5.

[0396] In some embodiments, each Z1b is independently

[0397] [ka] Selected from.

[0398] In some embodiments, each A'' is independently

[0399] [ka]

[0400] [ka] Selected from.

[0401] In some embodiments, each A'' is independently selected from AB-1, AB-2, AB-3, AB-4, AB-5, AB-7, AB-8, AB-9, AB-10, AB-11, AB-12, AB-13, AB-14, AB-15, AB-16, AB-17, AB-18, AB-19, AB-20, AB-21, AB-22, AB-23, AB-24, AB-25, AB-26, AB-27, AB-28, AB-29, AB-30, AB-31, AB-32, AB-33, AB-34, AB-35, AB-36, AB-37, AB-38, and AB-39. In some embodiments, each A'' is independently selected from AB-1, AB-2, AB-3, AB-4, AB-5, AB-7, AB-8, AB-9, AB-10, AB-11, AB-12, AB-13, and AB-14. In some embodiments, each A'' is independently selected from formulas AB-15, AB-16, AB-17, AB-18, AB-19, AB-20, AB-21, AB-22, AB-23, AB-24, AB-25, AB-26, AB-27, and AB-28.

[0402] In some embodiments, B1 and B2 are independently selected from formulas F2 and F7. Formulas F2 and F7 are,

[0403] [ka] And, During the ceremony, One R1 is (C=O)--- * This represents, --- * This represents the connection point to the rest of Z1c, The remaining R1 cells are, independently, H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) m Selected from CH3 and OCF3, where m is 1, 2, 3, 4, 5, 6, or 7. Y8 is either O, or Y8 is NR, where R is an alkyl group (e.g., C1-C6 alkyl group) or H. Each Y10 is independently selected from H, CH3, F, and CF3, and for at least one F7, at least one Y10 is not H. In some embodiments, the 5' position R1 is (C=O)--- * This represents, --- * This represents the connection point to the rest of Z1c.

[0404] In some embodiments, B1 and B2 are independently represented by formula F2, Equation F2 is,

[0405] [ka] And, During the ceremony, R1 in 5th place is (C=O)--- * This represents, --- * This represents the connection point to the rest of Z1c, Each of the remaining R1s is independently selected from H, F, Cl, Br, OH, CF3, CHF2, NO2, CH3, OCH3, and OCF3.

[0406] In some embodiments, B1 and B2 independently represent formula F7.

[0407] [ka] During the ceremony, R1 in 5th place is (C=O)--- * This represents, ---* This represents the connection point to the rest of Z1c, Each of the remaining R1s is independently selected from H, F, Cl, Br, OH, CF3, CHF2, NO2, CH3, OCH3, and OCF3. Y8 is O or NR, and R is an alkyl group (e.g., C1-C6 alkyl group) or H. Each Y10 is independently selected from H, CH3, F, and CF3, and for at least one F7, at least one Y10 is not H.

[0408] In some embodiments, B1 and B2 independently represent formula F7A.

[0409] [ka] During the ceremony, R1 in 5th place is (C=O)--- * This represents, --- * This represents the connection point to the rest of Z1c, Each of the remaining R1s is independently selected from H, F, Cl, Br, OH, CF3, CHF2, NO2, CH3, OCH3, and OCF3.

[0410] In some embodiments, at least one diboronate is F7, Y8 is O, and each Y10 is CH3. In some embodiments, each of the remaining R1s is independently selected from (a) H, CF3, and F, or (b) the remaining two R1s are H and the remaining one R1 is CF3 or F. In some embodiments, at least one R1 in B1 or B2 is F or CF3. In some embodiments, each of the remaining R1s is H.

[0411] In some embodiments, the compound is represented by formula IE, or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0412] [ka] During the ceremony, q' is 2, 3, or 4. Each corresponding Z1c and Z1b1 is selected independently and may be the same or different. Each Z1b1 is either a combination or selected from FL70, FL70A, and FL70B. Each Z1b2 is FL3, Each Z1c is covalently bonded to Z1b1 via an amine at the β or gamma position of the Z1b1 skeleton. At least one Z1c is covalently bonded to at least one Z1b1 selected from FL70, FL70A, and FL70B.

[0413] In some embodiments, the compound is represented by formula IE, or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0414] [ka] During the ceremony, q' is 2, 3, or 4. Each corresponding Z1c and Z1b1 is selected independently and may be the same or different. Each Z1b1 is either a combination or selected from FL70, FL70A, and FL70B. Each Z1b2 is selected from FL5, FL5A, and FL5B. Each Z1c is covalently bonded to Z1b1 via the beta or gamma position of the Z1b1 skeleton. At least one Z1c is covalently bonded to at least one Z1b1 selected from FL70, FL70A, and FL70B.

[0415] In some embodiments, at least one Z1c is conjugated to an amine at the β position of the Z1b skeleton.

[0416] In some embodiments, the compound is represented by formula IE, or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0417] [ka] During the ceremony, q' is 2, 3, or 4. Each corresponding Z1c and Z1b1 is selected independently and may be the same or different. Each Z1b1 is either a combination or selected from FL69, FL69A, and FL69B. Each Z1b2 is either FL3 or FL5B. Each Z1c is covalently bonded to Z1b1 via the amine at the alpha position of the Z1b1 skeleton. At least one Z1c is covalently bonded to at least one Z1b1 selected from FL69, FL69A, and FL69B.

[0418] In some embodiments, the compound is represented by formula IE, or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0419] [ka] During the ceremony, q' is 2, 3, or 4. Each corresponding Z1c is selected independently and may be the same or different. Each Z1b1 is a bond, Each Z1b2 is FL3, Each Z1c is covalently bonded to Z1b2 via the amine at the β position of the Z1b2 skeleton.

[0420] In some embodiments, the polypeptide comprises an insulin receptor agonist having A and B chains. In some embodiments, In some embodiments, each Z1c is selected from formulas FFL-1 to FFL-68, where formulas FFL-1 to FFL-68 are,

[0421] [ka]

[0422] [ka]

[0423] [ka]

[0424] [ka]

[0425] [ka] or its stereoisomer, In the formula, X represents the covalent bond site of X1 to the amine.

[0426] In some embodiments, B1 and B2 are independently selected from formulas F2 and F7, each of the remaining R1 is independently selected from H, CF3, and F, each Z1c is covalently bonded to the amine of X1 via one or more of Z1b, and each of Z1c and one or more Z1b are combined to be selected from formulas FFL2-5, 9-12, 16, 20, 21, 27, 32, 34, 35, 37-40, 44-47, 51, 55, 56, 62, 66, and 67, or their stereoisomers, where X represents a covalent bond site to the amine of X1.

[0427] In some embodiments, B1 and B2 are independently selected from formula F2, where each of the remaining R1s is independently selected from H, CF3, and F, and each Z1c is covalently bonded to the amine of X1 via one or more of Z1b, where each of Z1c and one or more Z1b, in combination, is selected from formulas FFL2-5, 9-12, 16, 20, 21, 27, 32, 34, 35, 37-40, 44-47, 51, 55, 56, 62, 66, and 67, or their stereoisomers, where X represents a covalent bond site to the amine of X1.

[0428] In some embodiments, B1 and B2 are independently selected from formula F7A, where each remaining R1 is independently selected from H, CF3, and F, and each Z1c is covalently bonded to the amine of X1 via one or more of Z1b, where each of Z1c and one or more Z1b, in combination, is selected from formulas FFL2-5, 9-12, 16, 20, 21, 27, 32, 34, 35, 37-40, 44-47, 51, 55, 56, 62, 66, and 67, or their stereoisomers, where X represents a covalent bond site to the amine of X1.

[0429] In some embodiments, the compound (e.g., formula I or formula IB) has an affinity to bind to one or more glycated proteins or glycosylated proteins and / or sugar moieties or sugars or polysaccharides on the cell surface.

[0430] In some embodiments, q' is at least 2, and at least one of Z1c is a sugar moiety, a diol-containing moiety, and a polyol-containing moiety. In some embodiments, the sugar moiety is selected from STR1, STR2, STR3, STR4, and STR5.

[0431] [ka] During the ceremony, One R1''' represents a connection point to Z1b, Each of the remaining R1''' is independently -H, -OR 3 , -N(R 3)2, -SR 3 -OH, -OCH3, -OR 5 NHC(O)CH3, -CH2R 3 , -C(O)NHOH, -NHC(O)CH3, -CH2OH, -CH2OR 5 -NH2, -CH2R 4 ,-R 6 , and -R 7 Selected from, in STR1, STR2, and STR4, at least one of the remaining R1''' is OH, Each R 3 These are independently -H, acetyl, phosphate, and -R 2 , -SO2R 2 ,-S(O)R 2 , -P(O)(OR 2 )2, -C(O)R 2 , -CO2R 2 , and -C(O)N(R 2 ) Selected from 2, Each R 2 These are independently -H, C 1~6 A 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms selected from aliphatic rings, phenyl rings, nitrogen, oxygen, and sulfur; a 4-7 member heterocyclic ring having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur; and selected from alkyl groups (e.g., C1-C6 alkyl groups). Each R 4 These are independently -H, -OH, and -OR 3 , -N(R 3 )2, -OR 5 , and -SR 3 Selected from, Each R 5 These are independently selected from monosaccharides, disaccharides, trisaccharides, pentoses, and hexoses. Each R 6 These are independently -NCOCH2- and -(OCH2CH2) n -, -OC 1~9 Alkylene group and substituted C 1~9 Selected from alkylene groups, one or more methylene groups are -O-, -(CH2) n -, -OCH2-, -N(R 2 )C(O)-, -N(R2 )C(O)N(R 2 )-, -SO2-, -SO2N(R 2 )-,-N(R 2 )SO2-, -S-, -N(R 2 )-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R 2 )-, or -N(R 2 )SO2N(R 2 ) is arbitrarily replaced by, and index n is 1, 2, 3, 4, 5, 6, 7, or 8, Each R 7 Independently, -N(R 2 )2, -F, -Cl, -Br, -I, -SH, -OR 2 , -SR 2 -NH2, -N3,

[0432]

number

[0433] In some embodiments, X1 includes a polypeptide human hormone, an insulin receptor agonist, an endocrine hormone, insulin, human insulin, glucagon, amylin, relaxin, GLP-1, GIP, oxytomodulin, somatostatin, a gastric suppressor polypeptide, a glucose-dependent insulin-secreting polypeptide, a hybrid peptide comprising sequences derived from two or more human polypeptide hormones, or an analogue thereof.

[0434] In some embodiments, X1 comprises insulin having an A chain and a B chain, wherein the A chain optionally comprises a sequence selected from SEQ ID NOs: 1, 25, 24051, and 24052, and the B chain optionally comprises a sequence selected from SEQ ID NOs: 24060, 24061, 24062, 24063, 24064, and 25000-25397.

[0435] In some embodiments, X1 comprises insulin having an A chain and a B chain, the A chain comprising a sequence selected from SEQ ID NOs: 1, 24051, and 24052. The B chain contains sequences selected from SEQ ID NOs: 24063, 25095, 25228, 25229, 25232, 25236, 25305, 25308, 25312, and 25380-25397. Each Z1b is independently selected from FL3, FL5, FL5A, FL5B, FL65A, FL65B, FL69A, and FL69B. Each Z1c is independently selected from FF12A, FF12B, FF12C, FF12D, FF116A, FF116B, FF116C, FF116D, and FF227, and each Z1c is covalently bound to a lysine residue of X1 via one or more Z1b. B1 and B2 are independently equation F2 or equation F7, respectively.

[0436] In some embodiments, each B1 and B2 is independently selected from F2 and F7 and covalently bonded to Z1c using an amide bond. Each Z1b is independently selected from (i) FL3 (wherein p is 1, 2, or 3), (ii) FL5B (wherein p is 2, 3, or 4), (iii) FL65A, and (iv) FL69A (wherein p is 2, 3, or 4). Each Z1c is independently selected from FF12A, FF116A, and FF227, and each Z1c is covalently bound to a lysine residue of X1 via one or more Z1b. X1 comprises a polypeptide containing an insulin receptor agonist having an A chain and a B chain, wherein the A chain comprises a sequence selected from SEQ ID NOs: 1, 24051, and 24052, and the B chain comprises a sequence selected from SEQ ID NOs: 24063, 25095, 25228, 25229, 25232, 25236, 25305, 25308, 25312, and 25380-25397, and at least two lysines of X1 are each independently conjugated to Z1b.

[0437] In some embodiments, at least one Z1c is FF227, and i is 1.

[0438] In some embodiments, provided herein are compounds selected from the group comprising polypeptides having an A chain and a B chain, wherein the A chain comprises a sequence selected from 1, 24051, and 24052, and the B chain comprises a sequence selected from SEQ ID NOs: 24063, 25228, 25229, 25232, 25305, 25308, 25312, 25236, 25095, and 25380-25397.

[0439] In some embodiments, X1 is insulin further comprising 1 to 5 residues that are replaced, inserted, added, or mutated by an amino acid having a free amine conjugated to Z1c via one or more of the Z1b residues.

[0440] In some embodiments, at least one Z1c is conjugated via one or more Z1b to the free amine side chain of the amino acid X1 that is replaced, inserted, or mutated on insulin.

[0441] In some embodiments, the compound is represented by formula IF, or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt. Z1c-Linker (Formula IF) The Z1c-linker is

[0442] [ka]

[0443] [ka]

[0444] [ka]

[0445] [ka]

[0446] [ka] Selected from, where X is selected from a leaving group, NH2, and H, B1 and B2 may be the same or different, and each independently represents an aromatic boron-containing group.

[0447] In some embodiments, the compound represented by formula IF independently comprises at least one B1 or B2 selected from formulas F2 and F7. Formulas F2 and F7 are,

[0448] [ka] And, During the ceremony, R1 in 5th place is (C=O)--- * This represents, --- * This represents the connection point to the rest of Z1c, The remaining R1 cells are, independently, H, F, Cl, Br, OH, CH2-NH2, NH2, (C=O)-NH2, CH=O, SO2CH3, SO2CF3, CF3, CHF2, NO2, CH3, OCH3, O(CH2) m CH3, -(SO2)NH-CH3, -(SO2)NH(CH2) mSelected from CH3 and OCF3, where m is 1, 2, 3, 4, 5, 6, or 7. Y8 is either O, or Y8 is NR, where R is an alkyl group (e.g., C1-C6 alkyl group) or H. Each Y10 is independently selected from H, CH3, F, and CF3, and for at least one F7, at least one Y10 is not H.

[0449] In some embodiments, the Z1c linker (i.e., formula IF) is,

[0450] [ka]

[0451] [ka]

[0452] [ka]

[0453] [ka]

[0454] [ka]

[0455] [ka]

[0456] [ka]

[0457] [ka]

[0458] [ka]

[0459] [ka]

[0460] [ka]

[0461] [ka]

[0462] [ka]

[0463] [ka]

[0464] [ka] or selected from their stereoisomers or mixtures of stereoisomers, pharmaceutically acceptable salts, and combinations thereof, In the formulas, X is either a leaving group or represents a direct covalent bond site to X1 in formula I or formula IB.

[0465] In some embodiments, when X is a leaving group, X is selected from N-oxysuccinimide, 2,3,5,6-tetrafluorophenoxy (TFP), pentafluorophenoxy (Pfp), OH, halogen, maleimidoalkylamino, maleimidoamide polyethylene glycolamino, and maleimidopolyethylene glycolamino. In some embodiments, X is selected from N-oxysuccinimide and OH. In some embodiments, X is OH. In some embodiments, X is N-oxysuccinimide. In some embodiments, maleimidopolyethylene glycolamino is selected from Mal-PEG2-amine, Mal-PEG4-amine, and Mal-PEG5-amine, or pharmaceutically acceptable salts thereof. In some embodiments, maleimidoalkylamino is selected from Mal-C6-amine and N-(2-aminoethyl)maleimide, or pharmaceutically acceptable salts thereof. In some embodiments, the maleimidoamide polyethylene glycol amino is selected from Mal-amide-PEG9-amine, Mal-amide-PEG11-amine, Mal-amide-PEG23-amine, 4-Mal-methylcyclohexanecarboxamide-methyl-[1,2,3]triazole-PEG8-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the Z1c-linker is

[0466] [ka]

[0467] [ka]

[0468] [ka]

[0469] [ka]

[0470]

change

[0471]

change

[0472]

change

[0473]

change

[0474]

change

[0475]

change

[0476]

change

[0477]

change

[0478]

change

[0479]

change

[0480]

change

[0481] [ka]

[0482] [ka]

[0483] [ka]

[0484] [ka]

[0485] [ka]

[0486] [ka]

[0487] [ka]

[0488] [ka]

[0489] [ka]

[0490] [ka]

[0491] [ka]

[0492] [ka]

[0493] [ka]

[0494] [ka] The stereoisomers or mixtures of stereoisomers, pharmaceutically acceptable salts, and combinations thereof are selected.

[0495] In at least one embodiment, the compounds of the present disclosure may be used as intermediates in the manufacture of active pharmaceutical ingredients or as therapeutic agents for prophylactic compounds.

[0496] In another embodiment, the disclosure includes a human insulin analog comprising an A chain and a B chain, wherein the sequence of the A chain is X aa’ X bb’ X cc’ X dd’ X ee’ X ff’ X gg’ VEQCCX hh’ X ii’ ICSLYQLENYCNX jj’ X kk’ X ll’ X mm’ X nn’ X oo’ X pp’ (Sequence ID 24015) is included, and the sequence of the B strand is, (i)X aa X bb X cc X dd KXee X ff X gg X hh X ii X jj KX kk X ll X mm X nn QHLCGSHLVEALYLVCX oo X pp X qq GFFYTX rr X ss X tt X uu X vv X ww (Sequence ID 24016) (X aa’ , X bb’ , X cc’ , X dd’ , X ee’ , X ff’ , X gg’ , X hh’ , X ii’ , X jj’ , X kk’ , X ll’ , X mm’ , X nn’ , X oo’ , X pp’ , X aa , X bb , X cc , X dd , X ee , X ff , X gg , X hh , X ii , X jj , X kk , X ll , X mm , X nn , X oo , X pp , X qq , X rr , X ss , X tt , X uu , X ...

Claims

1. A compound comprising one or more diboronates of the following formula, or a stereoisomer thereof or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, Each Z1b is an independent linker portion, and each n' is 0, 1, 2, 3, 4, or 5, with at least one n' being 1, 2, 3, 4, or 5. X1 comprises an active pharmaceutical ingredient or polypeptide, Each Z1c is covalently bonded to the amine of X1 either directly or via one or more Z1b. c) At least one Z1c is independently selected from diboronates, and the diboronate is independently selected from formulas FF12A, FF12B, FF12C, FF12D, FF116A, FF116B, FF116C, FF116D, FF225, and FF227. d) Each additional Z1c is arbitrarily and independently selected from diboronate, sugar moiety, diol-containing moiety, and polyol-containing moiety, and the diboronate is independently selected from formulas FF12A, FF12B, FF12C, FF12D, FF116A, FF116B, FF116C, FF116D, FF225, and FF227, If each q' is 1, 2, 3, 4, or 5, and q' is 2 or greater, then the corresponding Z1c and Z1b are selected independently and may be the same or different. Formulas FF12A, FF12B, FF12C, FF12D, FF116A, FF116B, FF116C, FF116D, FF225, and FF227 are, 【Chemistry 2】 And, In the formula, X represents the covalent bond site of Z1b to the amine, or, if n' is 0, the covalent bond site of X1 to the amine. i is 1, 2, 3, 4, 5, 6, or 7, B １ and B ２ However, they may be the same or different, and each independently represents an aromatic boron-containing group. If each Z1c is selected from formulas FF225 and FF227, then B １ and B ２ At least one of them is equation F7, Equation F7 is, 【Transformation 3】 And, During the ceremony, One R １ However, (C=O) --- ＊ This represents, --- ＊ However, this represents the connection point to the remaining part of Z1c, Each remaining R １ is independently H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ , (C=O)-NH ２ , CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ CH ３ OCH ３ O(CH ２ ) ｍ CH ３ -(SO ２ )NH-CH ３ -(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ is selected from, m is 1, 2, 3, 4, 5, 6, or 7, Y8 is O or NR, and R is C １ ~C ６ It is an alkyl group or H, Each Y10 independently controls H and CH ３ , F, and CF ３ A compound, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt, selected from, wherein for at least one F7, at least one Y10 is not H.

2. Each n' is 0, 1, 2, or 3, and at least one n' is 1, 2, or 3. Each q is 1, 2, 3, or 4. Each Z1b is independently a linker portion, and each Z1c is covalently bonded to the amine of X1 either directly or via one or more of the Z1b, provided that the Z1b is not a diol-containing portion. The compound according to claim 1, or a stereoisomer thereof or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein one or more positions of the compound may contain an isotope.

3. Each Z1c is covalently bonded to the amine of X1 via one or more of the Z1b, and each Z1b is independently selected from formulas FL3, FL5, FL5A, FL5B, FL65A, FL65B, FL69, FL69A, FL69B, FL70, FL70A, and FL70B. FL3, FL5, FL5A, FL5B, FL65A, FL65B, FL69, FL69A, FL69B, FL70, FL70A, and FL70B are, 【Chemistry 4】 And, During the ceremony, R'' represents a direct or indirect covalent bond to Z1c, Z'' represents a direct or indirect covalent bond to X1, A' is H and C １ ~C ２０ Selected from alkyl groups, A'' is a C which is optionally terminated with an acid group. ２ ~C ２０ It is an acyl group, and the C ２ ~C ２０ One or more carbon atoms of the acyl group are arbitrarily and independently C(=O), O, NH, NH ２ ,S,S(O),SO ２ , replaced by a group selected from phenyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heteroaryl, and 6-membered heteroaryl, the C ２ ~C ２０ Acyl group, NH, NH ２ SO ２ Phenyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heteroaryl, and 6-membered heteroaryl each independently have 0, 1, 2, 3, or 4 R ｘ It has been replaced with, R ｘ However, C １ ~C ５ Alkyl, halogen, C １ ~C ５ Haloalkyl, carboxylic acid, hydroxyl, -O-C １ ~C ５ Alkyl, -S (=O) ２ NH ２ NH ２ Selected from 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heteroaryl, phenyl, and 6-membered heteroaryl, p is 1, 2, 3, 4, or 5, q is 1, 2, 3, 4, or 5. A compound according to claim 1 or 2, wherein any primary amine is optionally acetylated or alkylated, or a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

4. Each Z1b operates independently. 【Transformation 5】 Selected from, During the ceremony, The compound according to claim 3, wherein p is 1, 2, 3, 4, or 5.

5. Each Z1b operates independently. 【Transformation 6】 A compound according to claim 3 or 4, selected from the above, or a pharmaceutically acceptable salt thereof.

6. Each A'' is independent, 【Transformation 7】 【Transformation 8】 A compound according to any one of claims 3 to 5, selected from, or a pharmaceutically acceptable salt thereof.

7. B １ and B ２ However, independently selected from formulas F2 and F7, Formulas F2 and F7 are, 【Chemistry 9】 And, During the ceremony, One R １ However, (C=O) --- ＊ This represents, --- ＊ However, this represents the connection point to the remaining part of Z1c, The remaining rounds １ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, Y8 is either O, or Y8 is NR and R is C １ ~C ６ It is an alkyl group or H, Each Y10 is independently H, CH ３ , F, and CF ３ selected from, and for at least one F7, at least one Y10 is not H. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

8. 5th place R １ However, (C=O) --- ＊ This represents, --- ＊ The compound according to claim 7, or a pharmaceutically acceptable salt thereof, which represents a bonding site to the remaining portion of Z1c.

9. B １ and B ２ However, independently, it is expressed by equation F2, Equation F2 is, 【Chemistry 10】 And, During the ceremony, R at the 5'-position １ represents (C=O)--- ＊ and--- ＊ represents the bonding point to the remaining part of Z1c The remaining rounds １ However, independently, H, F, Cl, Br, OH, CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , and OCF ３ A compound according to claim 7, or a pharmaceutically acceptable salt thereof, selected from the above.

10. B １ and B ２ However, independently, it is equation F7, 【Chemistry 11】 During the ceremony, 5th place R １ However, (C=O) --- ＊ This represents, --- ＊ However, this represents the connection point to the remaining part of Z1c, The remaining rounds １ These are independently H, F, Cl, Br, OH, CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , and OCF ３ Selected from, Y8 is O or NR, and R is C １ ~C ６ It is an alkyl group or H, Each Y10 independently controls H and CH ３ , F, and CF ３ A compound according to claim 7, or a pharmaceutically acceptable salt thereof, selected from, wherein for at least one F7, at least one Y10 is not H.

11. B １ and B ２ However, independently, it is formula F7A, 【Chemistry 12】 During the ceremony, 5th place R １ However, (C=O) --- ＊ This represents, --- ＊ However, this represents the connection point to the remaining part of Z1c, The remaining rounds １ However, independently, H, F, Cl, Br, OH, CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , and OCF ３ A compound according to claim 7 or 10, selected from, or a pharmaceutically acceptable salt thereof.

12. at least one B １ or B ２ A compound according to any one of claims 1 to 8, wherein F7 is O, Y8 is O, and each Y10 is CH3, or a pharmaceutically acceptable salt thereof.

13. The remaining rounds １ However, independently, H, CF ３ , and F are selected, and the remaining two R are optionally １ However, H is the remaining one R １ However, CF ３ A compound according to any one of claims 7 to 11, or F, or a pharmaceutically acceptable salt thereof.

14. B １ or B ２ at least one R １ However, F or CF ３ The compound according to any one of claims 7 to 11, or a pharmaceutically acceptable salt thereof.

15. The remaining rounds １ A compound according to any one of claims 7 to 11, wherein H is present, or a pharmaceutically acceptable salt thereof.

16. The following formula is available: 【Chemistry 13】 During the ceremony, q' is 2, 3, or 4, Each corresponding Z1c and Z1b1 is selected independently and may be the same or different. Each Z1b1 is either a combination or selected from FL70, FL70A, and FL70B, and FL70, FL70A, and FL70B are 【Chemistry 14】 And, In the formula, R'', Z'', A', A'', p, and q are as defined in claim 3, Each Z1b2 is FL3, and FL3 is 【Chemistry 15】 And R'', Z'', and p are as defined in claim 3, Each Z1c is covalently bonded to Z1b1 via an amine at the beta or gamma position of the Z1b1 skeleton. The compound according to claim 3, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein at least one Z1c is covalently bonded to at least one Z1b1 selected from FL70, FL70A, and FL70B.

17. The following formula is available: 【Chemistry 16】 During the ceremony, q' is 2, 3, or 4, Each corresponding Z1c and Z1b1 is selected independently and may be the same or different. Each Z1b1 is either a combination or selected from FL70, FL70A, and FL70B, and FL70, FL70A, and FL70B are 【Chemistry 17】 And, In the formula, R'', Z'', A', A'', p, and q are as defined in claim 3, Each Z1b2 is selected from FL5, FL5A, and FL5B, and FL5, FL5A, and FL5B are, [Chemistry 18] Thus, R'', Z'', and p are as defined in claim 3, Each Z1c is covalently bonded to Z1b1 via an amine at the beta or gamma position of the Z1b1 skeleton. The compound according to claim 3, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein at least one Z1c is covalently bonded to at least one Z1b1 selected from FL70, FL70A, and FL70B.

18. The compound according to claim 16 or 17, or a pharmaceutically acceptable salt thereof, wherein at least one Z1c is conjugated to an amine at the beta position of the Z1b1 or Z1b2 skeleton.

19. The following formula is available: 【Chemistry 19】 During the ceremony, q' is 2, 3, or 4, Each corresponding Z1c and Z1b1 is selected independently and may be the same or different. Each Z1b1 is either a combination or selected from FL69, FL69A, and FL69B, and FL69, FL69A, and FL69B are 【Chemistry 20】 Thus, in the formula, R'', Z'', A', A'', and p are as defined in claim 3, Each Z1b2 is either FL3 or FL5B, and FL3 and FL5B are 【Chemistry 21】 Thus, R'', Z'', and p are as defined in claim 3, Each Z1c is covalently bonded to Z1b1 via the amine at the alpha position of the Z1b1 skeleton. The compound according to claim 3, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein at least one Z1c is covalently bonded to at least one Z1b1 selected from FL69, FL69A, and FL69B.

20. The following formula is available: 【Chemistry 22】 During the ceremony, q' is 2, 3, or 4, Each corresponding Z1c is selected independently and may be the same or different. Each Z1b1 is a bond, Each Z1b2 is FL3, and FL3 is 【Chemistry 23】 And R'', Z'', and p are as defined in claim 3, The compound according to claim 3, or a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein each Z1c is covalently bonded to Z1b2 via an amine at the beta position of the skeleton of Z1b2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

21. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein X1 is a polypeptide, and the polypeptide comprises an insulin receptor agonist having an A chain and a B chain.

22. Each Z1c is selected from formulas FFL-1 to FFL-68. Formulas FFL-1 to FFL-68 are, 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 or their stereoisomers, The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X represents a covalent bond site of X1 to an amine.

23. B １ and B ２ However, each is independently selected from formulas F2 and F7, and the remaining R １ However, independently, H, CF ３ Selected from , and F, each Z1c is covalently bonded to the amine of X1 via one or more of the Z1b, and each of the Z1c and the one or more Z1b combine to form formula FFL2-5, 9-12, 16, 20, 21, 27, 32, 34, 35, 37-40, 44-47, 51, 55, 56, 62, 66, and 67; 【Transformation 30】 【Chemistry 31】 Or selected from those stereoisomers, The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein X represents a covalent bond site of X1 to an amine.

24. B １ and B ２ However, each is independent of equation F2, and the remaining R １ However, independently, H, CF ３ Selected from , and F, where each Z1c is covalently bonded to the amine of X1 via one or more of the Z1b, and each of the Z1c and the one or more Z1b together form the formula FFL2-5, 9-12, 16, 20, 21, 27, 32, 34, 35, 37-40, 44-47, 51, 55, 56, 62, 66, and 67; 【Chemistry 32】 【Transformation 33】 Or selected from those stereoisomers, The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein X represents a covalent bond site of X1 to an amine.

25. B １ and B ２ However, each is independent of the equation F7A, and the remaining R １ However, independently, H, CF ３ Selected from , and F, where each Z1c is covalently bonded to the amine of X1 via one or more of the Z1b, and each of the Z1c and the one or more Z1b together form the formula FFL2-5, 9-12, 16, 20, 21, 27, 32, 34, 35, 37-40, 44-47, 51, 55, 56, 62, 66, and 67; 【Transformation 34】 【Chemistry 35】 Or selected from those stereoisomers, The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein X represents a covalent bond site of X1 to an amine.

26. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound has an affinity for binding to one or more glycated proteins or glycosylated proteins and / or sugar moieties, sugars, or polysaccharides on the surface of a cell.

27. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein q' is at least 2, and at least one of the Z1c is a sugar moiety, a diol-containing moiety, and a polyol-containing moiety.

28. The aforementioned Z1c is selected from formulas STR1, STR2, STR3, STR4, and STR5. 【number】 During the ceremony, One R １ ''' represents the connection point to Z1b, R １ Each carbon atom bonded to ''' independently has (R) or (S) stereochemistry, The remaining rounds １ ''' independently, -H, -OR ３ , -N(R ３ ) ２ , -SR ３ -OH, -OCH ３ , -OR ５ NHC(O)CH ３ ien-CH ２ R ３ , -C(O)NHOH, -NHC(O)CH ３ ien-CH ２ OH, -CH ２ OR ５ , -NH ２ ien-CH ２ R ４ , -R ６ , and -R ７ Selected from, in STR1, STR2, and STR4, the remaining R １ At least one of them is OH, Each R ３ However, independently, -H, acetyl, phosphate, and -R ２ , -SO ２ R ２ , -S(O)R ２ , -P(O)(OR ２ ) ２ , -C(O)R ２ , -CO ２ R ２ , and -C(O)N(R ２ ) ２ Selected from, Each R ２ However, independently, -H, C １～６ A 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms selected from an aliphatic ring, a phenyl ring, nitrogen, oxygen, and sulfur; a 4-7 member heterocyclic ring having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur; and C １ ~C ６ Selected from alkyl groups, Each R ４ However, independently, -H, -OH, -OR ３ , -N(R ３ ) ２ , -OR ５ , and -SR ３ Selected from, Each R ５ However, they are independently selected from monosaccharides, disaccharides, trisaccharides, pentoses, and hexoses. Each R ６ However, independently, -NCOCH ２ -, - (OCH ２ CH ２ ) ｎ -, -O-C １～９ Alkylene group and substituted C １～９ Selected alkylene groups, with one or more methylene groups -O-, -(CH ２ ) ｎ -, -OCH ２ -, -N(R ２ )C(O)-,-N(R ２ ) C(O)N(R ２ ) -, -SO ２ -, -SO ２ N(R) ２ )-,-N(R ２ ) SO ２ -, -S-, -N(R ２ )-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R ２ )-, or -N(R ２ ) SO ２ N(R) ２ ) is arbitrarily replaced by, and index n is 1, 2, 3, 4, 5, 6, 7, or 8, Each R ７ However, independently, -N(R ２ ) ２ , -F, -Cl, -Br, -I, -SH, -OR ２ , -SR ２ , -NH ２ , -N ３ , [Math 1] -CO ２ R ２ , -C(O)R ２ , -OSO ２ R ２ -N(R) ２ ) ２ , -OR ２ , -SR ２ , and -CH ３ ien-CH ２ NH ２ Selected from, The compound according to claim 27, or a pharmaceutically acceptable salt thereof, wherein the structures STR1, STR2, STR3, STR4, and STR5 optionally comprise one or more acetyl, acetylene, acetonide, and / or pinacol protecting groups.

29. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X1 comprises a polypeptide human hormone, an insulin receptor agonist, an endocrine hormone, insulin, human insulin, glucagon, amylin, relaxin, GLP-1, GIP, oxytomodulin, somatostatin, a gastric suppressor polypeptide, a glucose-dependent insulin-secreting polypeptide, a hybrid peptide comprising sequences derived from two or more human polypeptide hormones, or an analog thereof.

30. A compound according to any one of claims 1 to 2 and 19 to 29, or a pharmaceutically acceptable salt thereof, wherein X1 comprises insulin having an A chain and a B chain, optionally the A chain comprising a sequence selected from SEQ ID NOs: 1, 25, 24051, and 24052, and optionally the B chain comprising a sequence selected from SEQ ID NOs: 24060, 24061, 24062, 24063, 24064, and 25000 to 25397.

31. X1 comprises insulin having an A chain and a B chain, wherein the A chain comprises a sequence selected from SEQ ID NOs: 1, 24051, and 24052. The B chain includes a sequence selected from sequence numbers 24063, 25095, 25228, 25229, 25232, 25236, 25305, 25308, 25312, and 25380-25397. Each Z1b is independently selected from FL3, FL5, FL5A, FL5B, FL65A, FL65B, FL69A, and FL69B. Each Z1c is independently selected from FF12A, FF12B, FF12C, FF12D, FF116A, FF116B, FF116C, FF116D, and FF227, and each Z1c is covalently bonded to a lysine residue of X1 via one or more of the Z1b. B １ and B ２ The compound according to claim 30, or a pharmaceutically acceptable salt thereof, wherein each is independently formula F2 or formula F7.

32. Each B １ and B ２ However, independently selected from F2 and F7, they are covalently bonded to Z1c using amide bonds. Each Z1b is independently selected from (i) FL3 (wherein p is 1, 2, or 3), (ii) FL5B (wherein p is 2, 3, or 4), (iii) FL65A, and (iv) FL69A (wherein p is 2, 3, or 4), Each Z1c is independently selected from FF12A, FF116A, and FF227, and each Z1c is covalently bonded to a lysine residue of X1 via one or more of the Z1b. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X1 comprises a polypeptide having an A chain and a B chain, the A chain comprising a sequence selected from SEQ ID NOs: 1, 24051, and 24052, the B chain comprising a sequence selected from SEQ ID NOs: 24063, 25095, 25228, 25229, 25232, 25236, 25305, 25308, 25312, and 25380-25397, and at least two lysines of X1 are each independently conjugated to Z1b.

33. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein at least one Z1c is FF227 and i is 1.

34. The aforementioned compound, Example 1A: 【Chemistry 37】 Example 2A: 【Transformation 38】 Example 3A: 【Chemistry 39】 Example 4A: 【Chemistry 40】 Example 5A: 【Chemistry 41】 Example 6A: 【Chemistry 42】 Example 7A: 【Chemistry 43】 Example 8A: 【Chemistry 44】 Example 9A: 【Chemistry 45】 Example 10A: 【Chemistry 46】 Example 11A: 【Chemistry 47】 Example 12A: 【Chemistry 48】 Example 13A: 【Chemistry 49】 Example 14A: [Transformation 50] Example 15A: 【Chemistry 51】 Example 16A: 【Chemistry 52】 Example 17A: 【Chemistry 53】 Example 18A: 【Chemistry 54】 Example 19A: 【Transformation 55】 Example 20A: 【Transformation 56】 Example 21A: 【Chemistry 57】 Example 22A: 【Chemistry 58】 Example 23A: 【Chemistry 59】 Example 24A: 【Transformation 60】 Example 25A: 【Chemistry 61】 Example 26A: 【Transformation 62】 Example 27A: 【Transformation 63】 Example 28A: 【Chemistry 64】 Example 29A: 【Transformation 65】 Example 30A: 【Chemical Formula 66】 Example 31A: 【Transformation 67】 Example 32A: 【Transformation 68】 Example 33A: 【Transformation 69】 Example 34A: 【Transformation 70】 Example 35A: 【Chemistry 71】 Example 36A: 【Chemistry 72】 Example 37A: 【Transformation 73】 Example 38A: 【Chemistry 74】 Example 39A: 【Chemistry 75】 Example 40A: 【Transformation 76】 Example 41A: 【Chemical 77】 Example 42A: 【Transformation 78】 Example 43A: 【Transformation 79】 Example 44A: 【Chemistry 80】 Example 45A: 【Chemistry 81】 Example 46A: 【Chemistry 82】 Example 47A: 【Chemistry 83】 Example 48A: 【Chemical 84】 Example 49A: 【Chemical 85】 Example 50A: 【Chemical 86】 Example 51A: 【Transformation 87】 Example 52A: 【Chemical 88】 Example 53A: 【Chemical 89】 Example 54A: 【Chemistry 90】 Example 55A: 【Chemistry 91】 Example 56A: 【Chemistry 92】 Example 57A: 【Chemistry 93】 Example 58A: 【Chemical 94】 Example 59A: 【Chemical 95】 Example 60A: 【Chemistry 96】 Example 61A: 【Chemistry 97】 Example 62A: 【Chem.98】 Example 63A: 【Chem.99】 Example 64A: 【Chemistry 100】 Example 65A: 【Chemistry 101】 Example 66A: 【Chemical Engineering 102】 Example 67A: 【Chemistry 103】 Example 68A: 【Chemical 104】 Example 69A: 【Chemistry 105】 Example 70A: 【Chemistry 106】 Example 71A: 【Chemistry 107】 Example 72A: 【Chemistry 108】 Example 73A: 【Chemistry 109】 Example 74A: 【Chemical 110】 Example 75A: 【Chemistry 111】 Example 76A: 【Chemistry 112】 Example 77A: 【Chemistry 113】 Example 78A: 【Chemistry 114】 Example 79A: 【Chemical 115】 Example 80A: 【Chemistry 116】 Example 81A: 【Chemistry 117】 Example 82A: 【Chemistry 118】 Example 83A: 【Chemical 119】 Example 84A: 【Chemical 120】 Example 85A: 【Chemistry 121】 A compound selected from, according to claim 1 or 2, or The pharmaceutically acceptable salts, their isotopes, and their combinations.

35. A compound selected from the group consisting of polypeptides comprising an A chain and a B chain, wherein the A chain comprises a sequence selected from 1, 24051, and 24052, and the B chain comprises a sequence selected from SEQ ID NOs: 24063, 25228, 25229, 25232, 25305, 25308, 25312, 25236, 25095, and 25380-25397.

36. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

37. The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein X1 further comprises 1 to 5 residues that are replaced, inserted, added, or mutated by an amino acid having a free amine conjugated to Z1c via one or more of the Z1b residues, the insulin.

38. A compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein at least one Z1c is conjugated via one or more of the Z1b to a free amine side chain of an amino acid X1 that is replaced, inserted, or mutated on insulin.

39. A compound of the following formula, or its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, Z1c-Linker The aforementioned Z1c-linker, 【Chemistry 122】 【Chemical 123】 【Chemistry 124】 【Chemistry 125】 【Chemistry 126】 Selected from, where X is a leaving group, NH ２ Selected from , and H, B １ and B ２ However, the compounds, stereoisomers or mixtures thereof, or pharmaceutically acceptable salts, which may be identical or different, each independently represent an aromatic boron-containing group.

40. Independently, at least one B selected from formulas F2 and F7 １ or B ２ Including formulas F2 and F7, 【Chemistry 127】 And, During the ceremony, 5th place R １ However, (C=O) --- ＊ This represents, --- ＊ However, this represents the connection point to the remaining part of Z1c, The remaining rounds １ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３、 - (SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, Y8 is either O, or Y8 is NR and R is C １ ~C ６ It is an alkyl group or H, Each Y10 independently controls H and CH ３ , F, and CF ３ A compound according to claim 39, or a pharmaceutically acceptable salt thereof, selected from, wherein for at least one F7, at least one Y10 is not H.

41. The aforementioned Z1c-linker, 【Chemistry 128】 【Chemistry 129】 【Chemistry 130】 【Chemistry 131】 【Chemistry 132】 【Chemistry 133】 【Chemistry 134】 【Chemistry 135】 【Transformation 136】 【Chemistry 137】 【Chemistry 138】 【Chemistry 139】 [Chemical 140] 【Chemistry 141】 【Chemistry 142】 or selected from their stereoisomers or mixtures of stereoisomers, pharmaceutically acceptable salts, and combinations thereof, The compound according to claim 39, wherein X is a leaving group in the formula.

42. The compound according to claim 41, or a pharmaceutically acceptable salt thereof, wherein X is selected from N-oxysuccinimide, 2,3,5,6-tetrafluorophenoxy (TFP), pentafluorophenoxy (Pfp), OH, halogen, maleimidoalkylamino, maleimidoamide polyethylene glycolamino, and maleimidopolyethylene glycolamino.

43. The aforementioned compound, 【Chemistry 143】 【Chemistry 144】 【Chemistry 145】 【Chemistry 146】 【Chemistry 147】 【Chemistry 148】 【Chemistry 149】 [Chemical 150] 【Chemistry 151】 【Chemistry 152】 【Chemistry 153】 【Chemistry 154】 【Chemistry 155】 【Chemistry 156】 【Chemistry 157】 The compound according to claim 42, or selected from stereoisomers thereof, mixtures of stereoisomers, pharmaceutically acceptable salts, and combinations thereof.

44. A polypeptide comprising an A chain and a B chain, wherein the A chain comprises a sequence selected from 1, 24051, and 24052, and the B chain comprises a sequence selected from 25000 to 25397.

45. The polypeptide according to claim 44, wherein the A chain comprises a sequence selected from 1, 24051, and 24052, and the B chain comprises a sequence selected from 24063, 25228, 25229, 25000, 25001, 25006-25009, 25076, 25077, 25082-25085, 25228, 25229, 25232, 25234-25237, 25304, 25305, 25308, and 25310-25313.

46. The polypeptide according to claim 44, wherein the A chain comprises a sequence selected from 1 and 24051, and the B chain comprises a sequence selected from 24063, 25228, 25229, 25011, 25012, 25017-25020, 25087, 25088, 25093-25096, 25229, 25239, 25232, 25240, 25245-25248, 25305, 25308, 25315, 25316, and 25321-25324.

47. The polypeptide according to claim 44, wherein the A chain comprises a sequence selected from 1 and 24051, and the B chain comprises a sequence selected from 24063, 25228, 25229, 25232, 25234-25237, 25304, 25305, 25308, and 25310-25313.

48. A compound having agonist activity against an insulin receptor, comprising at least one aromatic boron-containing group having agonist activity against an insulin receptor, or a pharmaceutically acceptable salt thereof, wherein the compound has a first EC50 activity for activating the insulin receptor at a first glucose concentration and a second EC50 activity for activating the insulin receptor at a second glucose concentration, the first glucose concentration being 5.6 mM, and When the second glucose concentration is 16.7 mM, the compound has an insulin receptor agonist potency ratio of approximately 1.2 to approximately 20, approximately 1.5 to approximately 15, approximately 2 to approximately 14, approximately 2.5 to approximately 13, approximately 2.5 to approximately 12, approximately 2.5 to approximately 11, approximately 2.5 to approximately 10, approximately 2.5 to approximately 9, approximately 2.5 to approximately 8, approximately 2.5 to approximately 7, approximately 2.5 to approximately 6, approximately 2.5 to approximately 5, or approximately 2.5 to approximately 4.5 for the first EC50 to the second EC50, or a pharmaceutically acceptable salt thereof.

49. A compound having agonist activity against glucose, comprising at least one aromatic boron-containing group having binding affinity to glucose, or a pharmaceutically acceptable salt thereof, administered to a first rat group at a dose of 30 nmol / kg at a first glucose infusion rate to provide a blood glucose concentration of 100 mg / dL, and to a second rat group at a second glucose infusion rate to provide a blood glucose concentration of 200 mg / dL. A compound, or a pharmaceutically acceptable salt thereof, that, when given, provides relative glucose injection rate differences (mg / kg / min.min) of about 1 to about 2500, about 1 to about 2000, about 1 to about 1500, about 100 to about 1500, and about 1000 to about 1500, and relative glucose injection rate ratios of about 0.1 to about 5, about 0.2 to about 4.5, about 0.5 to about 4, about 0.5 to about 3.5, about 1 to about 3.5, about 1.5 to about 3.5, or about 2 to about 3.

50. The compound according to claim 48 or 49, or a pharmaceutically acceptable salt thereof, wherein the at least one aromatic boron-containing group is bonded to an FF skeleton, and the FF skeleton is selected from formulas FF12A, FF12B, FF12C, FF12D, FF116A, FF116B, FF116C, FF116D, FF225, and FF227.

51. The aforementioned at least one aromatic boron-containing group may be the same or different at least one B １ and B ２ A compound according to claim 48 or 49, or a pharmaceutically acceptable salt thereof, comprising the above.

52. B １ and B ２ The compound according to claim 51, or a pharmaceutically acceptable salt thereof, wherein at least one of the is formula F2 or formula F7.

53. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound comprises a diboronate covalently bonded to the amine of X1 and a diol or polyol-containing moiety conjugated to the amine of X1.

54. The compound according to claim 53, or a pharmaceutically acceptable salt thereof, wherein X1 is insulin or an analog thereof comprising A chain and B chain.

55. The compound according to claim 54, or a pharmaceutically acceptable salt thereof, wherein the amine to which the diboronate is covalently bonded is located at or near the C-terminus of the B chain, preferably a B29-lysine or B21-lysine amine, and the amine to which the polyol is conjugated is located at or near the N-terminus of the A chain or the B chain.

56. The compound according to claim 54, or a pharmaceutically acceptable salt thereof, wherein the amine to which the polyol is covalently bonded is located at or near the C-terminus of the B chain, preferably a B29-lysine or B21-lysine amine, and the amine to which the diboronate is conjugated is located at or near the N-terminus of the A chain or B chain.

57. A compound according to any one of claims 1 to 35 and 48 to 56, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

58. A method for treating or preventing diabetes mellitus, impaired glucose tolerance, hyperglycemia, or metabolic syndrome, wherein the method comprises administering a compound according to any one of claims 1 to 35, 37 to 43, and 48 to 56, or a pharmaceutical composition according to claim 36, to a subject in need thereof.

59. A compound according to any one of claims 1 to 35, 37 to 43, and 48 to 56, or a pharmaceutical composition according to claim 36, for use in the treatment or prevention of diabetes, impaired glucose tolerance, hyperglycemia, or metabolic syndrome.

60. Use of a compound according to any one of claims 1 to 35, 37 to 43, and 48 to 56, or a pharmaceutical composition according to claim 36, in the manufacture of a pharmaceutical.

61. A compound according to any one of claims 1 to 35, 37 to 43, and 48 to 56, or a pharmaceutical composition according to claim 36, for use as a therapeutic agent for treating diabetes or obesity, controlling blood glucose levels, or controlling drug release.

62. A method for administering a compound according to any one of claims 1 to 35, 37 to 43, and 48 to 56, or a pharmaceutical composition according to claim 36, wherein the method comprises administering the compound to the subject as a therapeutic or prophylactic agent.

63. A method of treating a subject by administering a device or formulation containing a compound according to any one of claims 1 to 35, 37 to 43, and 48 to 56.

64. Use of any one of the compounds described in claims 1 to 35, 37 to 43, and 48 to 56 as an intermediate in the synthesis of therapeutic agents of active pharmaceutical ingredients or prophylactic compounds.

65. A device or formulation comprising a compound according to any one of claims 1 to 35, 37 to 43, and 48 to 56, or a pharmaceutical composition according to claim 36.

66. A compound comprising at least one diboronate, wherein the diboronate comprises at least two aromatic boron-containing groups, at least one aromatic boron-containing group is covalently bonded to the compound and selected from F3 to F11, and the other aromatic boron-containing group is covalently bonded to the compound and is F1 to F11 or a boronic acid. 【Chemistry 158】 Selected arbitrarily from, At least one R1 in each of F1 to F11 is covalently bonded to the compound, and the remaining R １ and R ２ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, and for formulas F3 to F4, R ｗ However, it is either O or S, Regarding formula F6, If Y8 is O, then i is 1, 2, 3, 4, or 5, or i is 2, 3, 4, or 5 and R is 0, 1, or 2 １ However, F, Cl, CF ２ CF ３ SF ５ OCF ３ SO ２ CH ３ , and / or SO ２ CF ３ To represent, or If Y8 is NR, then R is an alkyl group or H, and i is 1, 2, 3, 4, or 5. Regarding formulas F5 and F7-F10, If Y8 is O, then i is 1, 2, 3, 4, or 5, or If Y8 is NR, then R is an alkyl group or H, and i is 1, 2, 3, 4, or 5. Y9 is CH ３ F, CF ３ CHF ２ , or OCH ３ And each Y10 independently has H, CH ３ F, CF ３ CHF ２ , and OCH ３ A compound selected from, however, in which at least one Y10 is not H.

67. The compound according to claim 66, wherein the compound is a diboron-containing compound.

68. The compound according to claim 66, wherein the compound is a diboron-containing compound.

69. The compound according to claim 66, wherein the at least one aromatic boron-containing group is F7.

70. The at least one aromatic boron-containing group is F7, Y8 is O, and each Y10 is CH ３ The compound according to claim 66.

71. Includes X1 and one or more Z1c, During the ceremony, X1, v. NH ２ Or OH, vi. Active pharmaceutical ingredients containing amines vii. Active pharmaceutical ingredients covalently bonded to an amine-containing linker, or viiii. A compound comprising an amine configured to covalently bond to the active pharmaceutical ingredient, Each Z1c is directly or indirectly covalently bonded to the amine of X1, or to the OH group if X1 is an OH group. Each Z1c operates independently. w) FF1-FF48 (FF1-FF48 is, 【Chemistry 159】 [Chemical 160] 【Chemistry 161】 And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, 5, 6, or 7, j is 1, 2, 3, 4, 5, 6, or 7. B １ and B ２ However, they may be the same or different, and each independently represents an aromatic boron-containing group. x) Formulas FF49 to FF88 (Formulas FF49 to FF88 are, 【Chemistry 162】 【Chemical 163】 And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, 5, 6, or 7, j is 1, 2, 3, 4, 5, 6, or 7. R1a is COOH, CH ３ Selected from H and OH, R2, R3, R4, and R5 each operate independently, CH ３ Selected from H, OH and COOH, and at least one of R2, R3, R4 and R5 is CH ３ or OH, B １ and B ２ However, they may be the same or different, and each is independently an aromatic boron-containing group. y) Models FF89-FF112 (Models FF89-FF112 are, 【Chemistry 164】 And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, 5, 6, or 7, B １ , B ２ and B ３ However, they may be the same or different, and each is independently an aromatic boron-containing group, a carboxylic acid derivative, or H, and in each FF89 to FF112 structure containing B1, B2, and B3 groups, at least two of the B1, B2, and B3 groups are independently aromatic boron-containing groups. z) Formulas FF113 to FF136 (Forms FF113 to FF136 are, 【Chemistry 165】 And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, 5, 6, or 7, j is 1, 2, 3, 4, 5, 6, or 7. k is 1, 2, 3, 4, 5, 6, or 7. m is 1, 2, 3, 4, 5, 6, or 7. Each R1 is independently selected from H, alkyl groups, acyl groups, cycloalkyl groups, haloalkyl groups, aryl groups, and heteroaryl groups, and each R1 optionally contains one or more alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyls, alkyls, or aryl groups. B １ and B ２ However, they may be the same or different, and each independently represents an aromatic boron-containing group. aa) Models FF137 to FF160 (Models FF137 to FF160 are, 【Chemistry 166】 And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, 5, 6, or 7, j is 1, 2, 3, 4, 5, 6, or 7. k is 1, 2, 3, 4, 5, 6, or 7. m is 1, 2, 3, 4, 5, 6, or 7. Each R1 is independently selected from H, alkyl groups, acyl groups, cycloalkyl groups, haloalkyl groups, aryl groups, and heteroaryl groups, and each R1 optionally contains one or more alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyls, alkyls, or aryl groups. B １ and B ２ However, they may be the same or different, and each independently represents an aromatic boron-containing group. bb) Formulas FF161 to FF164 (Forms FF161 to FF164 are, 【Chemistry 167】 And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, or 5. j is 1, 2, 3, 4, or 5. For different values ​​of j, each of R6, R7, R8, and R9 independently determines H, CF ３ ,CH ３ CHF ２ , and (CH ２ ) ｍ CH ３ Selected from, where m is 1, 2, 3, 4, or 5, Y3, Y4, Y5, Y6, and Y7 are each independently H, CH ２ -X4, and selected from formulas IV-1 to IV-135, X4 is -COOH, -(CH ２ ) ｍ Selected from COOH, alkyl groups, acyl groups, cycloalkyl groups, haloalkyl groups, aryl groups, and heteroaryl groups, each X4 optionally contains one or more alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyls, alkyls, or aryl groups, and m is 1, 2, 3, 4, or 5. At least one of Y5, Y6, and Y7 in formulas FF162 and FF163 is not H, and at least one of Y7, R8, and R9 in FF164 is not H. Formulas IV-1 to IV-135 are, 【Chemical 168】 【Chemistry 169】 【Chemistry 170】 And, In the formula, Xa is CH=O, CHF ２ CF ３ ,CH ２ SH, COOH, CH ２ OH, CH ２ NO ２ ,CH ２ NH ２ ,CH ３ , C (CH ３ ) ３ , CH (CH ３ ) ２ , CH((CH ２ ) ３ -CH ３ ) ２ , or CH (CH ２ -CH ３ ) ２ This represents, Xb is O, NH, CH ２ , or represents S, Xc represents CH or N, Each R １０ However, independently, H, F, Cl, Br, CH ３ CF ３ , CH=O, OH, COOH, and (CH ２ ) ｎ CH ３ Selected from, m is 1, 2, 3, 4, or 5, and n is 1, 2, 3, 4, or 5, B １ and B ２ However, they may be the same or different, and each independently represents an aromatic boron-containing group. Formulas IV-1 to IV-135 ＊ However, this represents the connection point to the corresponding equations FF161-164). cc) Model FF165-FF166 (Models FF165-FF166 are, 【Chemistry 171】 And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. m is 1, 2, 3, 4, 5, 6, or 7. n is 1, 2, 3, 4, 5, 6, or 7. X5 is S, O, or NH. Each R １ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7), dd) Formulas FF167 to FF192 (Forms FF167 to FF192 are, 【Chemistry 172】 And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. B １ and B ２ However, they may be the same or different, and each independently represents an aromatic boron-containing group. ee) Models FF193 to FF209 (Models FF193 to FF209 are, 【Chemistry 173】 And, In the formulas, R in FF208 and FF209 is at least one CH group attached to the amino group of the side chain of FF208 or FF209. ２ Alkyl, aryl, or halide molecules covalently bonded via a group, R1 and R2 independently produce H and CH ３ , alkyl, and selected from formulas IV-1 to IV-135, i is 1, 2, 3, 4, or 5. j is 1, 2, 3, 4, or 5. X represents a covalent bond site either directly to the amine of X1, or to an amine directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. B １ and B ２ However, they may be the same or different, and each independently represents an aromatic boron-containing group. ff) Formulas FF210 to FF224 (Forms FF210 to FF224 are, 【Chemistry 174】 And, In the formula, R11 of FF210 to FF212 is selected from formulas IV-1 to IV-135, and R12 is selected from amine, hydroxyl, alkyl, and halide groups. Each R13 independently controls H and CH ３ , alkyl, aryl and selected from formulas IV-1 to IV-135, where R14 is H, CH ３ Selected from alkyl, aryl, and heteroaryl, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. X'' represents the covalent bond site of the compound to the amine--N, and -- represents the CH of the compound. ２ Alternatively, it represents a monocovalent bond to a CH group. i is 1, 2, 3, 4, or 5. j is 1, 2, 3, 4, or 5. B １ , B ２ , B ３ , B ４ , B ５ , and B ６ However, each independently represents an aromatic boron-containing group, B １ , B ２ and B ３ In each FF structure containing the group, at least two of the B1, B2, and B3 groups are independently aromatic boron-containing groups), and gg) Models FF225 to FF231 (Models FF225 to FF231 are, 【Chemistry 175】 And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, 5, 6, or 7, B １ and B ２ However, they may be the same or different, and each independently represents an aromatic boron-containing group. At least one primary or secondary amine from FF1 to FF223 and FF225 to FF231 is optionally B ６ A compound according to any one of claims 66 to 70, selected from (covalently bonded to), or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, hydrate or isotopic derivative.

72. The compound according to claim 71, wherein at least one Z1c is FF227.

73. The compound according to claim 72, wherein at least one Z1c is FF227 and i is 1.

74. The compound according to claim 71, wherein at least one Z1c is selected from FF12 to FF35, FF104 to FF117, FF180 to FF193, and FF196 to FF205.

75. The compound is a molecular conjugate represented by the following formula, or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof. 【Chemistry 176】 During the ceremony, X1, (v) NH ２ Or OH, (vi) polypeptide active pharmaceutical ingredient containing amines, (vii) polypeptide drug substance covalently bonded to an amine-containing linker, or (viiii) comprising an amine configured to covalently bond to a polypeptide drug substance, Each Z1c is independently selected from formulas FF1 to FF231. Each Z1a independently contains 1 to 50 amino acids linked together using amide bonds or peptide bonds. Each Z1b is an independent small molecule linker. Each m' is independently either 0 or 1. Each n' is an independent 0 or positive integer. Each o' is an independent integer greater than or equal to 1. Each p' is a positive integer, If q' is a positive integer of at least one and not more than twice the total number of amine groups in X1, and if any of n', o', p', or q' is two or more, then the corresponding groups Z1a, Z1b, and Z1c are independently selected and may be the same or different. Each Z1c is independently covalently bonded, directly or indirectly, to the amine of Z1a, the amine of Z1b, or X1. The compound according to claim 71, wherein the molecular conjugate may optionally contain one or more isotopes at any position of the molecular conjugate.

76. The aforementioned compound is B １ , B ２ , B ３ , B ４ , B ５ and B ６ It includes at least one base selected from, each independently, 【Chemistry 177】 Selected from, B １ , B ２ , and B ３ in the case of: One R １ However, (C=O) --- ＊ This represents, --- ＊ However, this represents the connection point to the remaining part of Z1c, The remaining rounds １ or R ２ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, B ４ and B ５ in the case of: B ４ In this case, one R １ However, (CH ２ ) ｍ ---Represents φ, and ---φ is the aforementioned Z1 Ｃ This represents the connection point to the remaining part, B ５ In this case, one R １ However, (C=O) --- ＊ , S(=O)(=O)--- ＊ , (CH ２ ) ｍ (C=O) --- ＊ , or (CH ２ ) ｍ --- ＊ This represents, --- ＊ However, the above Z1 Ｃ This represents the connection point to the rest of the part, where m is 1, 2, 3, 4, 5, 6, or 7. The remaining rounds １ or R ２ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, B ６ in the case of: B ６ In this case, one R １ However, (CH ２ ) ｍ ---Represents φ, where ---φ represents the bonding site to the rest of the compound, and m is 1, 2, 3, 4, 5, 6, or 7. The remaining rounds １ or R ２ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, Regarding formula F7, Y8 is O, Each Y10 independently, CH ３ , F, and CF ３ Selected from, Regarding formula F8, Y8 is O, i is 2, 3, 4, or 5, Each Y10 independently controls H and CH ３ , F, and CF ３ Selected from, however, at least one Y10 is not H, The compound according to claim 71, wherein --- represents a bonding site to the remaining portion of Z1c.

77. The aforementioned compound is B １ , B ２ , B ３ , B ４ , B ５ and B ６ It includes at least one base selected from, each independently, 【Chemistry 178】 Selected from the group consisting of, B １ , B ２ , and B ３ in the case of: 5th place R １ However, (C=O) --- ＊ This represents, --- ＊ However, this represents the connection point to the remaining part of Z1c, The remaining rounds １ or R ２ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, B ４ and B ５ in the case of: B ４ In this case, one R １ However, (CH ２ ) ｍ ---Represents φ, and ---φ is the aforementioned Z1 Ｃ This represents the connection point to the remaining part, B ５ In this case, one R １ However, (C=O) --- ＊ , S(=O)(=O)--- ＊ , (CH ２ ) ｍ (C=O) --- ＊ , or (CH ２ ) ｍ --- ＊ This represents, --- ＊ However, the above Z1 Ｃ This represents the connection point to the rest of the part, where m is 1, 2, 3, 4, 5, 6, or 7. The remaining rounds １ or R ２ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, B ６ in the case of: B ６ In this case, one R １ However, (CH ２ ) ｍ ---Represents φ, where ---φ represents the bonding site to the rest of the compound, and m is 1, 2, 3, 4, 5, 6, or 7. The remaining rounds １ or R ２ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, Regarding formula F7A, Y8 is O, Regarding formula F8A, Y8 is O, i is 2, 3, 4, or 5, The compound according to claim 71, wherein --- represents a bonding site to the remaining portion of Z1c.

78. B １ , B ２ , B ３ , B ４ , B ５ and B ６ However, each is independently of equation F7A, 【Chemistry 179】 B １ , B ２ , and B ３ in the case of: 5th place R １ However, (C=O) --- ＊ This represents, --- ＊ However, this represents the connection point to the remaining part of Z1c, The remaining rounds １ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３、 - (SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, B ４ and B ５ in the case of: B ４ In this case, one R １ However, (CH ２ ) ｍ ---Represents φ, and ---φ is the aforementioned Z1 Ｃ This represents the connection point to the remaining part, B ５ In this case, one R １ However, (C=O) --- ＊ , S(=O)(=O)--- ＊ , (CH ２ ) ｍ (C=O) --- ＊ , or (CH ２ ) ｍ --- ＊ This represents, --- ＊ However, the above Z1 Ｃ This represents the connection point to the rest of the part, where m is 1, 2, 3, 4, 5, 6, or 7. The remaining rounds １ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３、 - (SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, B ６ in the case of: B ６ In this case, one R １ However, (CH ２ ) ｍ ---Represents φ, where ---φ represents the bonding site to the rest of the compound, and m is 1, 2, 3, 4, 5, 6, or 7. The remaining rounds １ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３、 - (SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, Y8 is O, The compound according to any one of claims 71 to 77, wherein --- represents a bonding site to the remaining portion of Z1c.

79. At least one Z1c indirectly, via the linker, to the amine of X1, or X1 is NH ２ If so, then NH ２ It is covalently bonded to the OH group if X1 is an OH group, or to the amine of Z1a. The aforementioned linker is given by equation (X'') ｎ１ It is expressed by, in the formula Each n1 is independently selected from 1, 2, 3, 4, and 5. Each X'' v. L- or D-amino acids, wherein the amine functional group of the L- or D-amino acid is directly or indirectly covalently bonded to Z1c, and the acid functional group of the L- or D-amino acid is directly or indirectly conjugated to X1 or Z1a, and vi. Selected independently from formulas FL(IA), FL(IB), FL69, and FL70, Formulas FL(IA) and FL(IB) are, 【Transformation 180】 and its stereoisomers, During the ceremony, G is selected from a 3-6 membered cycloalkyl group, a 3-10 membered heterocyclyl group, a heteroaryl group, and an aryl group, and each group is independently optionally substituted with 1 to 3 groups selected from hydroxy, amino, halogen, cycloalkyl, alkoxy, and alkyl groups. E is an alkylene group that is either absent or may be substituted with 1 to 3 groups independently selected from halogen, hydroxyl, and amino. Q is either absent or selected from hydrogen, alkyl, halo, cyano, alkoxy, carboxylic acid, amino, hydroxy, amide, haloalkyl, cycloalkyl, heterocyclic, heteroaryl, and aryl, and each of the alkyl, alkoxy, cycloalkyl, heterocyclic, heteroaryl, and aryl groups is independently and optionally substituted with 1 to 5 groups selected from alkyl, amino, amide, halo, hydroxy, cyano, haloalkyl, and alkoxy. Q' is selected from hydrogen, alkyl, and acyl groups. Q and Q', together with the carbon and nitrogen atoms to which they are bonded, optionally form a 4-membered heterocycline, a 5-membered heterocycline, a 6-membered heterocycline, a 9-membered bicyclic heterocycline, or a 10-membered bicyclic heterocycline, and each of these 4-membered heterocyclines, 5-membered heterocyclines, 6-membered heterocyclines, 9-membered bicyclic heterocyclines, and 10-membered bicyclic heterocyclines are independently optionally substituted with 1 to 5 groups selected from alkyl, amino, halo, hydroxy, cyano, amide, haloalkyl, and alkoxy groups. p is 0, 1, 2, 3, 4, or 5, q is 0, 1, 2, 3, 4, or 5, R'' represents a direct or indirect covalent bond to Z1c, Z- represents a direct or indirect covalent bond to X1 or Z1a, Any primary amine is optionally acetylated or alkylated. Models FL69 and FL70 are, 【Chemistry 181】 and its stereoisomers, During the ceremony, R'' represents a direct or indirect covalent bond to Z1c, Z'' represents a direct or indirect covalent bond to X1 or Z1a, A' is selected from H, alkyl, saturated fatty acids, unsaturated fatty acids, cycloalkyl, haloalkyl, aryl, and heteroaryl. A'' is, (i) Bile acids conjugated directly or indirectly via their acidic groups to an amine in FL69 or FL70, or (ii) C which is optionally terminated by an acid group ２ ~C ２０ Acyl group, the C ２ ~C ２０ One or more carbon atoms of the acyl group are arbitrarily and independently C(=O), O, NH, NH ２ ,S,S(O),SO ２ , replaced by a group selected from phenyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heteroaryl, and 6-membered heteroaryl, the C ２ ~C ２０ Acyl group, NH, NH ２ SO ２ , phenyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heteroaryl, and 6-membered heteroaryl each independently have 0, 1, 2, 3, or 4 R atoms ｘ It is replaced with C ２ ~C ２０ It is an acyl group, R ｘ However, C １ ~C ５ Alkyl, halogen, C １ ~C ５ Haloalkyl, carboxylic acid, hydroxyl, -O-C １ ~C ５ Alkyl, NH ２ , and selected from substituted or unsubstituted 5-membered heterocyclyls, 6-membered heterocyclyls, 5-membered heteroaryls, and 6-membered heteroaryls, p is 1, 2, 3, 4, or 5, q is 1, 2, 3, 4, or 5. The compound according to any one of claims 71 to 75, wherein any primary amine is optionally acetylated or alkylated.

80. Each A'' is independent, 【Chemistry 182】 【Chemistry 183】 A compound according to claim 79, selected from the above.

81. The compound comprises at least one Z1b selected from formulas IIa to IIai and formulas IIIa to IIIai, Equations IIa to IIai are, 【Chemistry 184】 And, During the ceremony, r is 0, 1, 2, 3, 4, or 5, s is 0, 1, 2, 3, 4, or 5, W is CH ２ --- or (C=O) --- represents a covalent bond to X1, Each V １ However, independently, NH---†, CH ２ ---† and (C=O)---† are selected, and each V ２ However, N---†, where ---† is a covalent bond to consecutive Z1b, Z1a, or Z1c, provided that V １ However, when connected to Z1c, it is NH---†, and the covalent bond between the Z1a unit and the Z1b unit each independently contains an amine bond or an amide bond, and when n'=0 and m'=1, Z1a is directly conjugated to X1 by an amine bond or an amide bond. Equations IIIa to IIIai are, 【Chemistry 185】 And, During the ceremony, r is 1, 2, 3, 4, or 5. s is 1, 2, 3, 4, or 5. Each V １ However, independently, NH---†, CH ２ ---† and (C=O)---† are selected, and each V ２ However, N---†, and ---† is covalently bonded to consecutive Z1b, Z1a, or Z1c, provided that V １ The compound according to claim 71 or 75, wherein when connected to Z1c, it is NH---†, and the covalent bond between the Z1a unit and the Z1b unit each independently contains an amine bond or an amide bond, and when n'=0 and m'=1, Z1a is directly conjugated to X1 by an amine bond or an amide bond.

82. The above at least one Z1c is (i) Equation FL1 to FL19: 【Chemistry 186】 (In the formulas, in formulas FL1 to FL19, Z'' represents the connection point with respect to X1, R'' represents the connection point to Z1c, p is 1, 2, 3, 4, or 5, q is 1, 2, 3, 4, or 5. r is 1, 2, 3, 4, or 5. (Any primary amine is optionally acetylated or alkylated) and (ii) The compound according to claim 75, indirectly covalently bonded via a linker selected from L- or D-amino acids (where the acidic functional group of the amino acid is conjugated to X1) that include at least one amine group directly conjugated to Z1c.

83. n' is 1, and each of the Z1b independently gives (i) equations FL1 to FL19: 【Chemistry 187】 (In the formulas, in formulas FL1 to FL19, Z'' represents the connection point with respect to X1, R'' represents the connection point to Z1c, p is 1, 2, 3, 4, or 5, q is 1, 2, 3, 4, or 5. r is 1, 2, 3, 4, or 5. Any primary amine is optionally acetylated or alkylated), and (ii) The compound according to claim 75, selected from L- or D-amino acids (where the acidic functional group of the amino acid is conjugated to X1) that include at least one amine group directly conjugated to Z1c.

84. The compound according to claim 71 or 75, wherein the compound comprises an active pharmaceutical ingredient comprising a human polypeptide hormone from the human pancreas, insulin, glucagon, GLP-1, somatostatin, gastric suppressor polypeptide, glucose-dependent insulin-secreting polypeptide, a hybrid peptide comprising sequences from two or more human polypeptide hormones, or analogs thereof.

85. X1 comprises human insulin or a human insulin analog comprising an A chain and a B chain, wherein the A chain comprises a sequence selected from SEQ ID NOs: 1 and 3-33, and the B chain comprises a sequence selected from SEQ ID NOs: 2 and 34-74, 24047, and 24048. Each Z1c is independently selected from FF1, FF10, FF12, FF14, FF15, FF114, FF115, FF116, FF163, FF193, FF194, FF203, FF221-FF231 and is covalently coupled to Z1a and / or Z1b or X1, either directly or indirectly via a linker. Each Z1a is either not present independently, or independently present as K, GK, KGSH (SEQ ID NO: 24049), KGSHK (SEQ ID NO: 4238), KNSTK (SEQ ID NO: 5085), GKASHK (SEQ ID NO: 12414), GKEEEK (SEQ ID NO: 12677), GKEEHK (SEQ ID NO: 12680), GKGHSK (SEQ ID NO: 13120), GKGSH (SEQ ID NO: 24050), GKGSHK (SEQ ID NO: 13198), GKGSTK (SEQ ID NO: 1320) 5) A sequence selected from GKHENK (SEQ ID NO: 13271), GKNSHK (SEQ ID NO: 13982), GKNSTK (SEQ ID NO: 13989), GKQSSK (SEQ ID NO: 14380), GKYQFK (SEQ ID NO: 15128), GKGSKK (SEQ ID NO: 24045), GKKPGKK (SEQ ID NO: 24046), GKGPSK (SEQ ID NO: 24044), GKPSHKP (SEQ ID NO: 24043), and GSHKGSHK (SEQ ID NO: 24042), Each of the linkers is selected from FL1, FL3, FL4, and FL5. Each m' is independently either 0 or 1. Each n' is independently 0, 1, 2, or 3. Each o' is independently 1, 2, 3, 4, or 5. Each p' is 1, 2, 3, 4, or 5. If q' is 1, 2, 3, or 4, and any of n', o', p', or q' is 2 or more, then the corresponding bases Z1a, Z1b, and Z1c are independently selected and may be the same or different. The compound according to claim 71 or 75, wherein each Z1c is independently and directly or indirectly covalently bonded to the amine of Z1a, the amine of Z1b, or X1.

86. X1 comprises the human insulin or human insulin analog comprising A chain and B chain, wherein the A chain comprises SEQ ID NO: 1, and the B chain is selected from SEQ ID NOs: 2, 36, 24047, and 24048. Each Z1c is independently selected from FF1, FF10, FF12, FF14, FF15, FF114, FF115, FF116, FF193, FF194, FF203, and FF221-FF231, and is covalently coupled to Z1a and / or Z1b, or X1, either directly or indirectly via a linker. Each Z1a independently corresponds to K, GK, KGSH (SEQ ID NO: 24049), KGSHK (SEQ ID NO: 4238), KNSTK (SEQ ID NO: 5085), GKASHK (SEQ ID NO: 12414), GKEEEK (SEQ ID NO: 12677), GKEEHK (SEQ ID NO: 12680), GKGHSK (SEQ ID NO: 13120), GKGSH (SEQ ID NO: 24050), GKGSHK (SEQ ID NO: 13198), GKGSTK (SEQ ID NO: 13205), GKHE The sequence includes a sequence selected from NK (SEQ ID NO: 13271), GKNSHK (SEQ ID NO: 13982), GKNSTK (SEQ ID NO: 13989), GKQSSK (SEQ ID NO: 14380), GKYQFK (SEQ ID NO: 15128), GKGSKK (SEQ ID NO: 24045), GKKPGKK (SEQ ID NO: 24046), GKGPSK (SEQ ID NO: 24044), GKPSHKP (SEQ ID NO: 24043), and GSHKGSHK (SEQ ID NO: 24042). Each of the linkers either does not exist independently, or is independently selected from FL3 and FL5. Each m' is independently either 0 or 1. Each n' is independently either 0 or 2. Each o' is independently 1, 2, or 3. Each p' is 1, 2, or 3. If q' is 1, 2, or 3, and any of n', o', p', or q' is 2 or more, then the corresponding bases Z1a, Z1b, and Z1c are independently selected and may be the same or different. The compound according to claim 71 or 75, wherein each Z1c is independently covalently bonded directly or indirectly to the amine of Z1a, the amine of Z1b, or X1.

87. The compound according to claim 71 or 75, wherein each of the Z1a is independently absent or independently comprises a sequence selected from K, GK, KGSH (SEQ ID NO: 24049), GKGSH (SEQ ID NO: 24050), KGSHK (SEQ ID NO: 4238), and GKGSHK (SEQ ID NO: 13198).

88. Each of the Z1c is independently selected from FF1, FF10, FF12, FF14, FF15, FF114, FF115, FF116, and FF221 to FF231, and the B １ and B ２ However, the compound according to claim 71 or 75, independently selected from formulas F1 and F2.

89. B １ and B ２ However, the compound according to any one of claims 71 and 75-76, independently selected from F2 and F7.

90. B １ or B ２ at least one R １ However, F or CF ３ The compound according to any one of claims 76 to 78.

91. The compound according to claim 71 or 75, wherein Z1b is independently non-existent FL3 or FL5.

92. The compound according to claim 71 or 75, wherein each of the Z1c is independently selected from FF10, FF12, FF116, FF221, FF222, and FF224 to FF231.

93. Each B １ and B ２ However, independently selected from F2 and F7, they are covalently bonded to Z1c using amide bonds. Each Z1b is independently a non-existent FL3 (where p is 1, 2, or 3) or FL5 (where p is 2, 3, or 4), Each FF is independently selected from FF10, FF12, FF116, FF134, FF163, FF193, FF203, FF221, FF222 and FF224-FF231, and each FF12 and FF222 has either (S,R) or (S,S) stereochemistry. Each Z1c is conjugated directly or indirectly to one or more lysine side chains of X1 or the N-terminal amine group of X1 via FL3 or FL5. The compound according to claim 76, wherein X1 is insulin having 0 to 4 residues which are replaced, inserted, or mutated by a polypeptide drug substance and / or lysine, and the lysine is directly or indirectly conjugated to Z1c, respectively.

94. The compound according to claim 71 or 75, wherein Z1c is FF224, n' is 0, and Z1a is an amine-containing amino acid.

95. The aforementioned compound, 【Chemical 188】 A compound according to any one of claims 71 to 94, selected from the above.

96. The aforementioned compound, 【Chemical 189】 【Chemistry 190】 A compound according to any one of claims 71 to 94, selected from the above.

97. The aforementioned compound, 【Chemistry 191】 A compound according to claim 96, selected from the above.

98. Z1c is directly covalently bonded to X1 via a linker, and the linker independently contains gamma-glutamic acid, beta-alanine, and 【Chemistry 192】 Formula FL3 (wherein p is 1, 2, or 3), and 【Chemistry 193】 Formula FL5 The compound according to claim 71 or 75, selected from (wherein p is 2, 3, or 4).

99. X1 is OH or NH ２ The compound according to claim 71 or 75, further comprising an active pharmaceutical ingredient in which the compound is directly or indirectly covalently bonded.

100. A tautomer, stereoisomer, or mixture of stereoisomers of a compound according to claims 66 to 71, or a pharmaceutically acceptable salt, hydrate, or isotopic derivative thereof.

101. A compound comprising X1 and one or more Z1c, or a tautomer thereof, stereoisomer, or mixture of stereoisomers, or a pharmaceutically acceptable salt, hydrate, or isotope derivative thereof, During the ceremony, X1, (ix)NH ２ Or OH, (x) Active pharmaceutical ingredient containing amines, (xi) A drug substance covalently bonded to an amine-containing linker, or (xi) comprising an amine configured to covalently bond to the active pharmaceutical ingredient, Each Z1c is directly or indirectly covalently bonded to the amine of X1, or to the OH group if X1 is an OH group. Each Z1c operates independently. w) FF1-FF48 (FF1-FF48 is, 【Chemistry 194】 【Chemistry 195】 【Chemistry 196】 And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, 5, 6, or 7, j is 1, 2, 3, 4, 5, 6, or 7. B １ and B ２ However, they may be the same or different, and each independently represents an aromatic boron-containing group. x) Formulas FF49 to FF88 (Formulas FF49 to FF88 are, 【Chemistry 197】 【Chemistry 198】 And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, 5, 6, or 7, j is 1, 2, 3, 4, 5, 6, or 7. R1a is COOH, CH ３ Selected from H and OH, R2, R3, R4, and R5 each operate independently, CH ３ Selected from H, OH and COOH, and at least one of R2, R3, R4 and R5 is CH ３ or OH, B １ and B ２ However, they may be the same or different, and each is independently an aromatic boron-containing group. y) Models FF89-FF112 (Models FF89-FF112 are, 【Chemistry 199】 And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, 5, 6, or 7, B １ , B ２ and B ３ However, they may be the same or different, and each is independently an aromatic boron-containing group, a carboxylic acid derivative, or H, and in each FF89 to FF112 structure containing B1, B2, and B3 groups, at least two of the B1, B2, and B3 groups are independently aromatic boron-containing groups. z) Formulas FF113 to FF136 (Forms FF113 to FF136 are, 【Chemistry 200】 And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, 5, 6, or 7, j is 1, 2, 3, 4, 5, 6, or 7. k is 1, 2, 3, 4, 5, 6, or 7. m is 1, 2, 3, 4, 5, 6, or 7. Each R1 is independently selected from H, alkyl groups, acyl groups, cycloalkyl groups, haloalkyl groups, aryl groups, and heteroaryl groups, and each R1 optionally contains one or more alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyls, alkyls, or aryl groups. B １ and B ２ However, they may be the same or different, and each independently represents an aromatic boron-containing group. aa) Models FF137 to FF160 (Models FF137 to FF160 are, 【Chemical Engineering 201】 And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, 5, 6, or 7, j is 1, 2, 3, 4, 5, 6, or 7. k is 1, 2, 3, 4, 5, 6, or 7. m is 1, 2, 3, 4, 5, 6, or 7. Each R1 is independently selected from H, alkyl groups, acyl groups, cycloalkyl groups, haloalkyl groups, aryl groups, and heteroaryl groups, and each R1 optionally contains one or more alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyls, alkyls, or aryl groups. B １ and B ２ However, they may be the same or different, and each independently represents an aromatic boron-containing group. bb) Formulas FF161 to FF164 (Forms FF161 to FF164 are, 【Chemical Engineering 202】 And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, or 5. j is 1, 2, 3, 4, or 5. For different values ​​of j, each of R6, R7, R8, and R9 independently determines H, CF ３ ,CH ３ CHF ２ , and (CH ２ ) ｍ CH ３ Selected from, where m is 1, 2, 3, 4, or 5, Y3, Y4, Y5, Y6, and Y7 are each independently H, CH ２ -X4, and selected from formulas IV-1 to IV-135, X4 is -COOH, -(CH ２ ) ｍ Selected from COOH, alkyl groups, acyl groups, cycloalkyl groups, haloalkyl groups, aryl groups, and heteroaryl groups, each X4 optionally contains one or more alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyls, alkyls, or aryl groups, and m is 1, 2, 3, 4, or 5. At least one of Y5, Y6, and Y7 in formulas FF162 and FF163 is not H, and at least one of Y7, R8, and R9 in FF164 is not H. Formulas IV-1 to IV-135 are, 【Chemical 203】 【Chemical 204】 【Chemical 205】 And, In the formula, Xa is CH=O, CHF ２ CF ３ ,CH ２ SH, COOH, CH ２ OH, CH ２ NO ２ ,CH ２ NH ２ ,CH ３ , C (CH ３ ) ３ , CH (CH ３ ) ２ , CH((CH ２ ) ３ -CH ３ ) ２ , or CH (CH ２ -CH ３ ) ２ This represents, Xb is O, NH, CH ２ , or represents S, Xc represents CH or N, Each R １０ However, independently, H, F, Cl, Br, CH ３ CF ３ , CH=O, OH, COOH, and (CH ２ ) ｎ CH ３ Selected from, m is 1, 2, 3, 4, or 5, and n is 1, 2, 3, 4, or 5, B １ and B ２ However, they may be the same or different, and each independently represents an aromatic boron-containing group. Formulas IV-1 to IV-135 ＊ However, this represents the connection point to the corresponding equations FF161-164). cc) Model FF165-FF166 (Models FF165-FF166 are, 【Chemical 206】 And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. m is 1, 2, 3, 4, 5, 6, or 7. n is 1, 2, 3, 4, 5, 6, or 7. X5 is S, O, or NH. Each R １ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7), dd) Formulas FF167 to FF192 (Forms FF167 to FF192 are, 【Chemical 207】 And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. B １ and B ２ However, they may be the same or different, and each independently represents an aromatic boron-containing group. ee) Models FF193 to FF209 (Models FF193 to FF209 are, 【Chemical 208】 And, In the formula, R in FF208 and FF209 is at least one CH group attached to the amino group of the side chain of FF208 or FF209. ２ Alkyl, aryl, or halide molecules covalently bonded via a group, R1 and R2 independently produce H and CH ３ , alkyl, and selected from formulas IV-1 to IV-135, i is 1, 2, 3, 4, or 5. j is 1, 2, 3, 4, or 5. X represents a covalent bond site either directly to the amine of X1, or to an amine directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. B １ and B ２ However, they may be the same or different, and each independently represents an aromatic boron-containing group. ff) Formulas FF210 to FF224 (Forms FF210 to FF224 are, 【Chemical Engineering 209】 And, In the formula, R11 of FF210 to FF212 is selected from formulas IV-1 to IV-135, and R12 is selected from amine, hydroxyl, alkyl, and halide groups. Each R13 independently controls H and CH ３ , alkyl, aryl and selected from formulas IV-1 to IV-135, where R14 is H, CH ３ Selected from alkyl, aryl, and heteroaryl, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. X'' represents the covalent bond site of the compound to the amine--N, and -- represents the CH of the compound. ２ Alternatively, it represents a monocovalent bond to a CH group. i is 1, 2, 3, 4, or 5. j is 1, 2, 3, 4, or 5. B １ 、B ２ 、B ３ 、B ４ 、B ５ 、and B ６ each independently represents an aromatic boron-containing group, and B １ 、B ２ and B ３ in each FF structure containing a group, at least two of the B1, B2 and B3 groups are independently aromatic boron-containing groups), and gg) Models FF225 to FF231 (Models FF225 to FF231 are, 【Chemical 210】 And, In the formula, X represents a covalent bond site that is directly attached to the amine of X1, or to an amine that is directly or indirectly covalently bonded to X1, or, if X1 is an OH group, to an OH group. i is 1, 2, 3, 4, 5, 6, or 7, B １ and B ２ However, they may be the same or different, and each independently represents an aromatic boron-containing group, and B of formulas FF225 to FF231 １ and B ２ However, it is not a boronic acid or an F2 or F6 aromatic boron-containing group, Formulas F2 and F6 are, 【Chemistry 211】 And, R in 4th or 5th place １ However, (C=O) --- ＊ This represents, --- ＊ However, this represents the connection point to the remaining part of Z1c, 0, 1, or 2 R １ However, F, Cl, CF ２ CF ３ SF ５ OCF ３ SO ２ CH ３ , and / or SO ２ CF ３ This represents the remaining R １ However, it represents H, Y8 is O, i is 1, At least one primary or secondary amine from FF1 to FF223 and FF225 to FF231 is optionally B ６ A compound selected from (covalently bonded to), or a tautomer, stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, hydrate or isotopic derivative thereof.

102. The compound is a molecular conjugate represented by the following formula, or a stereoisomer thereof, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof. 【Chemical Engineering 212】 During the ceremony, X1, (v) NH ２ Or OH, (vi) polypeptide active pharmaceutical ingredient containing amines, (vii) polypeptide drug substance covalently bonded to an amine-containing linker, or (viiii) comprising an amine configured to covalently bond to a polypeptide drug substance, Each Z1c is independently selected from formulas FF1 to FF231. Each Z1a independently contains 1 to 50 amino acids linked together using amide bonds or peptide bonds. Each Z1b is an independent small molecule linker. Each m' is independently either 0 or 1. Each n' is an independent 0 or positive integer. Each o' is an independent integer greater than or equal to 1. Each p' is a positive integer, If q' is a positive integer of at least one and not more than twice the total number of amine groups in X1, and if any of n', o', p', or q' is two or more, then the corresponding groups Z1a, Z1b, and Z1c are independently selected and may be the same or different. Each Z1c is independently covalently bonded, directly or indirectly, to the amine of Z1a, the amine of Z1b, or X1. The compound according to claim 101, wherein the molecular conjugate may optionally contain one or more isotopes at any position of the molecular conjugate.

103. The aforementioned compound is independently selected from formulas F1 to F11. １ , B ２ and B ３ The compound comprises at least one of the following, or the compound is independently selected from formulas F1 to F11. ４ , B ５ and B ６ Includes at least one of the following: Formulas F1 to F11 are, 【Chemistry 213】 And, B １ , B ２ , and B ３ in the case of: One R １ However, (C=O) --- ＊ , S(=O)(=O)--- ＊ , (CH ２ ) ｍ (C=O) --- ＊ , or (CH ２ ) ｍ --- ＊ This represents, --- ＊ However, this represents the connection point to the remaining part of Z1c, where m is 1, 2, 3, 4, 5, 6, or 7. Each remaining R １ or R ２ is independently H, F, Cl, Br, OH, CH ２ -NH ２ , NH ２ , (C=O)-NH ２ , CH=O, SO ２ CH ３ , SO ２ CF ３ , CF ３ , CHF ２ , NO ２ , CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ , -(SO ２ )NH-CH ３ , -(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ is selected from, m is 1, 2, 3, 4, 5, 6, or 7, B ４ and B ５ in the case of: B ４ In this case, one R １ However, (CH ２ ) ｍ ---Represents φ, and ---φ is the aforementioned Z1 Ｃ This represents the connection point to the remaining part, B ５ In this case, one R １ However, (C=O) --- ＊ , S(=O)(=O)--- ＊ , (CH ２ ) ｍ (C=O) --- ＊ , or (CH ２ ) ｍ --- ＊ This represents, --- ＊ However, the above Z1 Ｃ This represents the connection point to the rest of the part, where m is 1, 2, 3, 4, 5, 6, or 7. The remaining rounds １ or R ２ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, B ６ in the case of: B ６ In this case, one R １ However, (CH ２ ) ｍ ---Represents φ, where ---φ represents the bonding site to the rest of the compound, and m is 1, 2, 3, 4, 5, 6, or 7. The remaining rounds １ or R ２ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, Regarding formulas F3 to F4, R ｗ However, it is either O or S, Regarding formulas F5 to F10, If Y8 is O, then i is 1, 2, 3, 4, or 5, or If Y8 is NR, then R is an alkyl group or H, and i is 1, 2, 3, 4, or 5. Y9 is H, CH ３ , or alkyl group, however, if Y8 is O, Y9 is CH ３ or alkyl group, Each Y10 independently controls H and CH ３ F, CF ３ , and OCH ３ The compound according to claim 101 or 102, selected from, however, at least one Y10 is not H.

104. The aforementioned compound is B １ , B ２ , B ３ , B ４ , B ５ and B ６ It includes at least one base selected from, each independently selected from F2, F7, F8, and F11, Formulas F2, F7, F8 and F11 are, 【Chemical 214】 And, B １ , B ２ , and B ３ in the case of: One R １ However, (C=O) --- ＊ , or (CH ２ ) ｍ (C=O) --- ＊ This represents, --- ＊ However, this represents the connection point to the remaining part of Z1c, where m is 1, 2, 3, 4, 5, 6, or 7. The remaining rounds １ or R ２ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, B ４ and B ５ in the case of: B ４ In this case, one R １ However, (CH ２ ) ｍ ---Represents φ, and ---φ is the aforementioned Z1 Ｃ This represents the connection point to the remaining part, B ５ In this case, one R １ However, (C=O) --- ＊ , S(=O)(=O)--- ＊ , (CH ２ ) ｍ (C=O) --- ＊ , or (CH ２ ) ｍ --- ＊ This represents, --- ＊ However, the above Z1 Ｃ This represents the connection point to the rest of the part, where m is 1, 2, 3, 4, 5, 6, or 7. The remaining rounds １ or R ２ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, B ６ in the case of: B ６ In this case, one R １ However, (CH ２ ) ｍ ---Represents φ, where ---φ represents the bonding site to the rest of the compound, and m is 1, 2, 3, 4, 5, 6, or 7. The remaining rounds １ or R ２ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, Regarding formula F7, Y8 is O or NR, and R is an alkyl group or H. Each Y10 independently, CH ３ F, CF ３ , and OCH ３ Selected from, Regarding formula F8, If Y8 is O, then i is 1, 2, 3, 4, or 5. If Y8 is NR, then R is an alkyl group or H, and i is 1, 2, 3, 4, or 5. Each Y10 independently controls H and CH ３ F, CF ３ , and OCH ３ Selected from, however, at least one Y10 is not H, The compound according to any one of claims 101 to 103, wherein --- represents a bonding site to the remaining portion of Z1c.

105. The aforementioned compound is B １ , B ２ , B ３ , B ４ , B ５ and B ６ It includes at least one base selected from, each independently, 【Chemical 215】 Selected from the group consisting of, B １ , B ２ , and B ３ in the case of: One R １ However, (C=O) --- ＊ This represents, --- ＊ However, this represents the connection point to the remaining part of Z1c, The remaining rounds １ or R ２ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, B ４ and B ５ in the case of: B ４ In this case, one R １ However, (CH ２ ) ｍ ---Represents φ, and ---φ is the aforementioned Z1 Ｃ This represents the connection point to the remaining part, B ５ In this case, one R １ However, (C=O) --- ＊ , S(=O)(=O)--- ＊ , (CH ２ ) ｍ (C=O) --- ＊ , or (CH ２ ) ｍ --- ＊ This represents, --- ＊ However, the above Z1 Ｃ This represents the connection point to the rest of the part, where m is 1, 2, 3, 4, 5, 6, or 7. The remaining rounds １ or R ２ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, B ６ in the case of: B ６ In this case, one R １ However, (CH ２ ) ｍ ---Represents φ, where ---φ represents the bonding site to the rest of the compound, and m is 1, 2, 3, 4, 5, 6, or 7. The remaining rounds １ or R ２ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, Regarding formula F7, Y8 is O, Each Y10 independently, CH ３ , F, and CF ３ Selected from, Regarding formula F8, Y8 is O, i is 1, 2, 3, 4, or 5. Each Y10 independently controls H and CH ３ , F, and CF ３ Selected from, however, at least one Y10 is not H, The compound according to any one of claims 101 to 104, wherein --- represents a bonding site to the remaining portion of Z1c.

106. The aforementioned compound is B １ , B ２ , B ３ , B ４ , B ５ and B ６ It includes at least one base selected from, each independently, 【Chemical 216】 Selected from, B １ , B ２ , and B ３ in the case of: 5th place R １ However, (C=O) --- ＊ This represents, --- ＊ However, this represents the connection point to the remaining part of Z1c, The remaining rounds １ or R ２ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, B ４ and B ５ in the case of: B ４ In this case, one R １ However, (CH ２ ) ｍ ---Represents φ, and ---φ is the aforementioned Z1 Ｃ This represents the connection point to the remaining part, B ５ In this case, one R １ However, (C=O) --- ＊ , S(=O)(=O)--- ＊ , (CH ２ ) ｍ (C=O) --- ＊ , or (CH ２ ) ｍ --- ＊ This represents, --- ＊ However, the above Z1 Ｃ This represents the connection point to the rest of the part, where m is 1, 2, 3, 4, 5, 6, or 7. The remaining rounds １ or R ２ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, B ６ in the case of: B ６ In this case, one R １ However, (CH ２ ) ｍ ---Represents φ, where ---φ represents the bonding site to the rest of the compound, and m is 1, 2, 3, 4, 5, 6, or 7. The remaining rounds １ or R ２ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, Regarding formula F7A, Y8 is O, Regarding formula F8A, Y8 is O, i is 1, 2, 3, 4, or 5. The compound according to any one of claims 101 to 105, wherein --- represents a bonding site to the remaining portion of Z1c.

107. B １ , B ２ , B ３ , B ４ , B ５ and B ６ However, each is independently of equation F7A, 【Chemical 217】 B １ , B ２ , and B ３ in the case of: 5th place R １ However, (C=O) --- ＊ This represents, --- ＊ However, this represents the connection point to the remaining part of Z1c, The remaining rounds １ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３、 - (SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, B ４ and B ５ in the case of: B ４ In this case, one R １ However, (CH ２ ) ｍ ---Represents φ, and ---φ is the aforementioned Z1 Ｃ This represents the connection point to the remaining part, B ５ In this case, one R １ However, (C=O) --- ＊ , S(=O)(=O)--- ＊ , (CH ２ ) ｍ (C=O) --- ＊ , or (CH ２ ) ｍ --- ＊ This represents, --- ＊ However, the above Z1 Ｃ This represents the connection point to the rest of the part, where m is 1, 2, 3, 4, 5, 6, or 7. The remaining rounds １ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３、 - (SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, B ６ in the case of: B ６ In this case, one R １ However, (CH ２ ) ｍ ---Represents φ, where ---φ represents the bonding site to the rest of the compound, and m is 1, 2, 3, 4, 5, 6, or 7. The remaining rounds １ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３、 - (SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, Y8 is O, The compound according to any one of claims 101 to 106, wherein --- represents a bonding site to the remaining portion of Z1c.

108. At least one Z1c indirectly, via the linker, to the amine of X1, or X1 is NH ２ If so, then NH ２ It is covalently bonded to the OH group if X1 is an OH group, or to the amine of Z1a. The aforementioned linker is given by equation (X'') ｎ１ It is expressed by, in the formula Each n1 is independently selected from 1, 2, 3, 4, and 5. Each X'' independently c) L- or D-amino acids (where the amine functional group of the L- or D-amino acid is directly or indirectly covalently bonded to Z1c, and the acid functional group of the L- or D-amino acid is directly or indirectly conjugated to X1 or Z1a), and d) Selected from formulas FL(IA), FL(IB), FL69, and FL70, Formulas FL(IA) and FL(IB) are, 【Chemistry 218】 and its stereoisomers, During the ceremony, G is selected from a 3-6 membered cycloalkyl group, a 3-10 membered heterocyclyl group, a heteroaryl group, and an aryl group, and each group is independently optionally substituted with 1 to 3 groups selected from hydroxy, amino, halogen, cycloalkyl, alkoxy, and alkyl groups. E is an alkylene group that is either absent or may be substituted with 1 to 3 groups independently selected from halogen, hydroxyl, and amino. Q is either absent or selected from hydrogen, alkyl, halo, cyano, alkoxy, carboxylic acid, amino, hydroxy, amide, haloalkyl, cycloalkyl, heterocyclic, heteroaryl, and aryl, and each of the alkyl, alkoxy, cycloalkyl, heterocyclic, heteroaryl, and aryl groups is independently and optionally substituted with 1 to 5 groups selected from alkyl, amino, amide, halo, hydroxy, cyano, haloalkyl, and alkoxy. Q' is selected from hydrogen, alkyl, and acyl groups. Q and Q', together with the carbon and nitrogen atoms to which they are bonded, optionally form a 4-membered heterocycline, a 5-membered heterocycline, a 6-membered heterocycline, a 9-membered bicyclic heterocycline, or a 10-membered bicyclic heterocycline, and each of these 4-membered heterocyclines, 5-membered heterocyclines, 6-membered heterocyclines, 9-membered bicyclic heterocyclines, and 10-membered bicyclic heterocyclines are independently optionally substituted with 1 to 5 groups selected from alkyl, amino, halo, hydroxy, cyano, amide, haloalkyl, and alkoxy groups. p is 0, 1, 2, 3, 4, or 5, q is 0, 1, 2, 3, 4, or 5, R'' represents a direct or indirect covalent bond to Z1c, Z- represents a direct or indirect covalent bond to X1 or Z1a, Any primary amine is optionally acetylated or alkylated. Models FL69 and FL70 are, 【Chemical 219】 and its stereoisomers, During the ceremony, R'' represents a direct or indirect covalent bond to Z1c, Z'' represents a direct or indirect covalent bond to X1 or Z1a, A' is selected from H, alkyl, saturated fatty acids, unsaturated fatty acids, cycloalkyl, haloalkyl, aryl, and heteroaryl. A'' is, (i) Bile acids conjugated directly or indirectly via their acidic groups to an amine of FL69 or FL70, or (ii) C which is optionally terminated by an acid group ２ ~C ２０ Acyl group, the C ２ ~C ２０ One or more carbon atoms of the acyl group are arbitrarily and independently C(=O), O, NH, NH ２ ,S,S(O),SO ２ , replaced by a group selected from phenyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heteroaryl, and 6-membered heteroaryl, the C ２ ~C ２０ Acyl group, NH, NH ２ SO ２ , phenyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 5-membered heteroaryl, and 6-membered heteroaryl each independently have 0, 1, 2, 3, or 4 R atoms ｘ It is replaced with C ２ ~C ２０ It is an acyl group, R ｘ However, C １ ~C ５ Alkyl, halogen, C １ ~C ５ Haloalkyl, carboxylic acid, hydroxyl, -O-C １ ~C ５ Alkyl, NH ２ , and selected from substituted or unsubstituted 5-membered heterocyclyls, 6-membered heterocyclyls, 5-membered heteroaryls, and 6-membered heteroaryls, p is 1, 2, 3, 4, or 5, q is 1, 2, 3, 4, or 5. The compound according to any one of claims 101 to 107, wherein any primary amine is optionally acetylated or alkylated.

109. Each A'' is independent, 【Chemical 220】 【Chemistry 221】 A compound according to claim 108, selected from the above.

110. The compound comprises at least one Z1b selected from formulas IIa to IIai and formulas IIIa to IIIai, Equations IIa to IIai are, 【Chemistry 222】 【Chemistry 223】 And, During the ceremony, r is 0, 1, 2, 3, 4, or 5, s is 0, 1, 2, 3, 4, or 5, W is CH ２ --- or (C=O) --- represents a covalent bond to X1, Each V １ However, independently, NH---†, CH ２ ---† and (C=O)---† are selected, and each V ２ However, N---†, where ---† is a covalent bond to consecutive Z1b, Z1a, or Z1c, provided that V １ However, when connected to Z1c, it is NH---†, and the covalent bond between the Z1a unit and the Z1b unit each independently contains an amine bond or an amide bond, and when n'=0 and m'=1, Z1a is directly conjugated to X1 by an amine bond or an amide bond. Equations IIIa to IIIai are, 【Chemistry 224】 And, During the ceremony, r is 1, 2, 3, 4, or 5. s is 1, 2, 3, 4, or 5. Each V １ However, independently, NH---†, CH ２ ---† and (C=O)---† are selected, and each V ２ However, N---†, and ---† is covalently bonded to consecutive Z1b, Z1a, or Z1c, provided that V １ The compound according to claim 102, wherein when connected to Z1c, it is NH---†, and the covalent bond between the Z1a unit and the Z1b unit each independently contains an amine bond or an amide bond, and when n'=0 and m'=1, Z1a is directly conjugated to X1 by an amine bond or an amide bond.

111. At least one Z1c is (i) equation FL1 to FL19: 【Chemical 225】 (In the formulas, in formulas FL1 to FL19, Z'' represents the connection point with respect to X1, R'' represents the connection point to Z1c, p is 1, 2, 3, 4, or 5, q is 1, 2, 3, 4, or 5. r is 1, 2, 3, 4, or 5. (Any primary amine is optionally acetylated or alkylated) and (ii) The compound according to claim 101 or 102, indirectly covalently bonded via a linker selected from an L- or D-amino acid (where the acidic functional group of the amino acid is conjugated to X1) that contains at least one amine group directly conjugated to Z1c.

112. n' is 1, and each of the Z1b independently gives (i) equations FL1 to FL19: 【Chemistry 226】 (In the formulas, in formulas FL1 to FL19, Z'' represents the connection point with respect to X1, R'' represents the connection point to Z1c, p is 1, 2, 3, 4, or 5, q is 1, 2, 3, 4, or 5. r is 1, 2, 3, 4, or 5. (Any primary amine is optionally acetylated or alkylated) and (ii) The compound according to claim 102, selected from L- or D-amino acids (where the acidic functional group of the amino acid is conjugated to X1) that include at least one amine group directly conjugated to Z1c.

113. The compound according to claim 101 or 102, wherein the compound comprises an active pharmaceutical ingredient comprising a human polypeptide hormone from the human pancreas, insulin, glucagon, GLP-1, somatostatin, gastric suppressor polypeptide, glucose-dependent insulin-secreting polypeptide, a hybrid peptide comprising sequences from two or more human polypeptide hormones, or analogs thereof.

114. X1 comprises human insulin or a human insulin analog comprising an A chain and a B chain, wherein the A chain comprises a sequence selected from SEQ ID NOs: 1 and 3-33, and the B chain comprises a sequence selected from SEQ ID NOs: 2 and 34-74, 24047, and 24048. Each Z1c is independently selected from FF1, FF10, FF12, FF14, FF15, FF114, FF115, FF116, FF163, FF193, FF194, FF203, FF221-FF231 and is covalently coupled to Z1a and / or Z1b or X1, either directly or indirectly via a linker. Each Z1a is either not present independently, or independently present as K, GK, KGSH (SEQ ID NO: 24049), KGSHK (SEQ ID NO: 4238), KNSTK (SEQ ID NO: 5085), GKASHK (SEQ ID NO: 12414), GKEEEK (SEQ ID NO: 12677), GKEEHK (SEQ ID NO: 12680), GKGHSK (SEQ ID NO: 13120), GKGSH (SEQ ID NO: 24050), GKGSHK (SEQ ID NO: 13198), GKGSTK (SEQ ID NO: 1320) 5) A sequence selected from GKHENK (SEQ ID NO: 13271), GKNSHK (SEQ ID NO: 13982), GKNSTK (SEQ ID NO: 13989), GKQSSK (SEQ ID NO: 14380), GKYQFK (SEQ ID NO: 15128), GKGSKK (SEQ ID NO: 24045), GKKPGKK (SEQ ID NO: 24046), GKGPSK (SEQ ID NO: 24044), GKPSHKP (SEQ ID NO: 24043), and GSHKGSHK (SEQ ID NO: 24042), Each of the linkers is selected from FL1, FL3, FL4, and FL5. Each m' is independently either 0 or 1. Each n' is independently 0, 1, 2, or 3. Each o' is independently 1, 2, 3, 4, or 5. Each p' is 1, 2, 3, 4, or 5. If q' is 1, 2, 3, or 4, and any of n', o', p', or q' is 2 or more, then the corresponding bases Z1a, Z1b, and Z1c are independently selected and may be the same or different. The compound according to claim 101 or 102, wherein each Z1c is independently and directly or indirectly covalently bonded to the amine of Z1a, the amine of Z1b, or X1.

115. X1 comprises the human insulin or human insulin analog comprising A chain and B chain, wherein the A chain comprises SEQ ID NO: 1, and the B chain is selected from SEQ ID NOs: 2, 36, 24047, and 24048. Each Z1c is independently selected from FF1, FF10, FF12, FF14, FF15, FF114, FF115, FF116, FF193, FF194, FF203, and FF221-FF231, and is covalently coupled to Z1a and / or Z1b, or X1, either directly or indirectly via a linker. Each Z1a independently corresponds to K, GK, KGSH (SEQ ID NO: 24049), KGSHK (SEQ ID NO: 4238), KNSTK (SEQ ID NO: 5085), GKASHK (SEQ ID NO: 12414), GKEEEK (SEQ ID NO: 12677), GKEEHK (SEQ ID NO: 12680), GKGHSK (SEQ ID NO: 13120), GKGSH (SEQ ID NO: 24050), GKGSHK (SEQ ID NO: 13198), GKGSTK (SEQ ID NO: 13205), GKHE The sequence includes a sequence selected from NK (SEQ ID NO: 13271), GKNSHK (SEQ ID NO: 13982), GKNSTK (SEQ ID NO: 13989), GKQSSK (SEQ ID NO: 14380), GKYQFK (SEQ ID NO: 15128), GKGSKK (SEQ ID NO: 24045), GKKPGKK (SEQ ID NO: 24046), GKGPSK (SEQ ID NO: 24044), GKPSHKP (SEQ ID NO: 24043), and GSHKGSHK (SEQ ID NO: 24042). Each of the linkers either does not exist independently, or is independently selected from FL3 and FL5. Each m' is independently either 0 or 1. Each n' is independently either 0 or 2. Each o' is independently 1, 2, or 3. Each p' is 1, 2, or 3. If q' is 1, 2, or 3, and any of n', o', p', or q' is 2 or more, then the corresponding bases Z1a, Z1b, and Z1c are independently selected and may be the same or different. The compound according to claim 113 or 114, wherein each Z1c is independently and directly or indirectly covalently bonded to the amine of Z1a, the amine of Z1b, or X1.

116. The compound according to claim 101 or 102, wherein each of the Z1a is independently absent or independently comprises a sequence selected from K, GK, KGSH (SEQ ID NO: 24049), GKGSH (SEQ ID NO: 24050), KGSHK (SEQ ID NO: 4238), and GKGSHK (SEQ ID NO: 13198).

117. Each of the Z1c is independently selected from FF1, FF10, FF12, FF14, FF15, FF114, FF115, FF116, and FF221 to FF231, and the B １ and B ２ The compound according to claim 101 or 102, independently selected from formulas F1 and F2.

118. B １ and B ２ The compound according to claim 103, which is independently selected from F2 and F7.

119. B １ or B ２ at least one R １ However, F or CF ３ The compound according to claim 103.

120. The compound according to claim 111 or 112, wherein Z1b is independently non-existent FL3 or FL5.

121. The compound according to claim 101 or 102, wherein each of the Z1c is independently selected from FF10, FF12, FF116, FF221, FF222, and FF224 to FF231.

122. Each B １ and B ２ However, independently selected from F2 and F7, they are covalently bonded to Z1c using amide bonds. Each Z1b is independently a non-existent FL3 (where p is 1, 2, or 3) or FL5 (where p is 2, 3, or 4), Each FF is independently selected from FF10, FF12, FF116, FF134, FF163, FF193, FF203, FF221, FF222 and FF224-FF231, and each FF12 and FF222 has either (S,R) or (S,S) stereochemistry. Each Z1c is conjugated directly or indirectly to one or more lysine side chains of X1 or the N-terminal amine group of X1 via FL3 or FL5. The compound according to claim 101 or 102, wherein X1 is insulin having optionally 0 to 4 residues that are replaced, inserted, or mutated by a polypeptide drug substance and / or lysine, and the lysine is directly or indirectly conjugated to Z1c, respectively.

123. The compound according to claim 101 or 102, wherein Z1c is FF224, n' is 0, and Z1a is an amine-containing amino acid.

124. The aforementioned compound, 【Chemistry 227】 A compound according to any one of claims 101 to 123, selected from the above.

125. The aforementioned compound, 【Chemistry 228】 【Chemistry 229】 A compound according to any one of claims 101 to 123, selected from the above.

126. The aforementioned compound, 【Chemistry 230】 A compound according to claim 125, selected from the above.

127. The aforementioned Z1c is directly covalently bonded to X1 via a linker, and the linker independently contains gamma-glutamic acid, beta-alanine, and 【Chemistry 231】 Formula FL3 (wherein p is 1, 2, or 3), and 【Chemistry 232】 Formula FL5 The compound according to claim 111 or 112, selected from the formula (wherein p is 2, 3, or 4).

128. X1 is OH or NH ２ The compound according to claim 101 or 102, further comprising an active pharmaceutical ingredient directly or indirectly covalently bonded to the compound.

129. The aforementioned compound, Example 881: 【Chemical 233】 Example 882: 【Chemistry 234】 Example 883: 【Chemical 235】 Example 884: 【Chemistry 236】 Example 885: 【Chemistry 237】 Example 886: 【Chemical 238】 Example 887: 【Chemistry 239】 Example 888: 【Chemistry 240】 Example 889: 【Chemistry 241】 Example 890: 【Chemistry 242】 Example 891: 【Chemistry 243】 Example 892: 【Chemistry 244】 Example 893: 【Chemistry 245】 Example 894: 【Chemistry 246】 Example 895: 【Chemistry 247】 Example 896: 【Chemistry 248】 Example 897: 【Chemistry 249】 Example 898: [Chemical 250] Example 899: 【Chemistry 251】 Example 900: 【Chemistry 252】 Example 901: 【Chemistry 253】 Example 902: 【Chemistry 254】 Example 903: 【Chemistry 255】 Example 904: 【Chemistry 256】 Example 905: 【Chemistry 257】 Example 906: 【Chemistry 258】 Example 907: 【Chemistry 259】 Example 908: 【Chemical 260】 Example 909: 【Chemistry 261】 Example 910: 【Chemistry 262】 Example 911: 【Chemical 263】 Example 912: 【Chemistry 264】 Example 913: 【Chemical 265】 Example 914: 【Chemical 266】 Example 915: 【Chemistry 267】 A compound according to claim 101 or 102, selected from the above.

130. The compound according to claim 101 or 102, wherein X1 is insulin having 0 to 4 residues which are replaced, inserted, or mutated by a polypeptide drug substance and / or lysine, and each of the lysine residues is conjugated to Z1c.

131. The compound according to claim 101 or 102, wherein one or more amines are each independently acetylated and / or independently alkylated.

132. The compound according to claim 101 or 102, wherein X1 comprises a polypeptide active pharmaceutical ingredient, and the covalent bond to X1 is to the amino group of one or more lysine residues and / or to the N-terminal amino group of X1.

133. Each R1 independently, C １ ~C ２２ Alkyl alkyl group, C １ ~C ２２ Acyl group, (C ３ ~C ８ ) Cycloalkyl group, C １ ~C ２２ Selected from haloalkyl groups, aryl groups, and heteroaryl groups, each R1 is one or more C １ ~C ２２ Alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyl, C １ ~C ２２ The compound according to claim 101 or 102, optionally comprising an alkyl or aryl group.

134. X4 is -COOH, -(CH ２ ) ｍ COOH, C １ ~C ２２ Alkyl alkyl group, C １ ~C ２２ Acyl group, (C ３ ~C ８ ) Cycloalkyl group, C １ ~C ２２ Selected from haloalkyl groups, aryl groups, and heteroaryl groups, each X4 has one or more C １ ~C ２２ Alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyl, C １ ~C ２２ The compound according to claim 101 or 102, which optionally contains an alkyl or aryl group, and m is 1, 2, 3, 4, or 5.

135. The alkyl group Y9 is C １ ~C ２２ The compound according to claim 103, wherein it is alkyl.

136. Y9 is CH ３ The compound according to claim 135.

137. The compound according to claim 101, wherein at least one of the primary or secondary amines FF1 to FF223 and FF225 to FF231 is covalently bonded to B6.

138. The compound according to claim 101 or 102, wherein the amine of the compound is conjugated to an aromatic boron-containing group via an amide bond.

139. The compound according to claim 138, wherein the aromatic boron-containing group is selected from phenylboronic acid, boroxol, and phenylboronic acid salt.

140. The compound according to any one of claims 101 to 139, wherein the compound is formulated into a solution containing one or more compounds comprising a buffer, a stabilizer, a vasodilator, a preservative, a surfactant, a salt, a sugar, or one or more compounds comprising hydroxyl, an alcohol, a diol, or a phenol.

141. The compound according to claim 140, wherein the solution comprises one or more of citrate, zinc, and / or cresol.

142. The compound according to claim 101 or 102, wherein the Z1c is conjugated with cysteine.

143. The compound according to claim 101 or 102, wherein the compound is covalently bonded to a diol, sugar, carbohydrate, or diol-containing molecule, either directly or via a linker.

144. The compound according to claim 101 or 102, wherein the compound is covalently bound to an antibody, albumin or a fragment thereof, or is covalently bound directly or via a linker to a molecule that can bind to at least one protein present in human plasma.

145. The aforementioned compound, 【Chemical 268】 【Chemistry 269】 【Chemistry 270】 A compound according to any one of claims 101 to 144, comprising at least one Z1c selected from.

146. The compound according to claim 145, wherein the compound has at least one chiral center and comprises at least one Z1c selected from FF1, FF2, FF5, FF9, FF11-FF13, FF15-FF24, FF27, FF31, FF34-FF36, FF38, FF39, FF43-FF58, FF60-FF70, FF72-FF75, FF77-FF80, FF82-FF84, FF86-FF212, FF216-FF220, FF222, FF223, and combinations thereof.

147. The compound comprises at least one FF12 and / or FF116, The compound according to claim 146, wherein the stereochemistry of FF12 and FF116 is independently selected from (S,S), (S,R), (R,R), and (R,S).

148. The compound according to claim 101 or 102, wherein X1 comprises human insulin or a human insulin analog comprising an A chain and a B chain, wherein the C-terminus of the A chain of the human insulin analog is optionally extended with up to 20 polypeptide residues, and / or the N-terminus of the B chain of the human insulin analog is optionally extended with up to 10 polypeptide residues.

149. The compound according to claim 148, wherein X1 comprises at least one lysine having an amine side chain, and Z1c is directly covalently bonded to the amine side chain.

150. The compound according to claim 101 or 102, comprising an active pharmaceutical ingredient in which X1 is covalently bonded to at least one Z1c via an acid-containing linker.

151. A composition or mixture comprising at least one compound according to any one of claims 101 to 150, for use as a pharmaceutical for the treatment of diabetes, for the control of blood glucose levels, or for controlling the release of a drug based on a physiological level of low molecular weight or sugar-containing diol.

152. A method for administering a compound according to any one of claims 101 to 150 to a human subject as a therapeutic or prophylactic agent.

153. A method for producing the compound according to any one of claims 101 to 150, wherein the method comprises at least one alkylation and / or amidation step.

154. A method for treating a subject by administering a device or formulation containing a compound according to any one of claims 101 to 150 and examples 881 to 915.

155. A method for treating or preventing diabetes mellitus, impaired glucose tolerance, hyperglycemia, or metabolic syndrome, the method comprising administering a therapeutically effective amount of a compound according to any one of claims 101 to 150 or a composition or mixture according to claim 151 to a subject in need thereof.

156. A compound selected from formulas FF1 to FF231, Formulas FF1 to FF48 are, 【Chemistry 271】 【Chemistry 272】 【Chemistry 273】 And, In the formula, X is selected from maleimide, amine, OH, and halogen. i is 1, 2, 3, 4, 5, 6, or 7, j is 1, 2, 3, 4, 5, 6, or 7. B １ and B ２ However, they may be the same or different, and each independently represents an aromatic boron-containing group. Formulas FF49 to FF88 are, 【Chemistry 274】 【Chemistry 275】 And, In the formula, X is selected from maleimide, amine, OH, and halogen. i is 1, 2, 3, 4, 5, 6, or 7, j is 1, 2, 3, 4, 5, 6, or 7. R1a is COOH, CH ３ Selected from H and OH, R2, R3, R4, and R5 each operate independently, CH ３ Selected from H, OH and COOH, and at least one of R2, R3, R4 and R5 is CH ３ or OH, B １ and B ２ However, they may be the same or different, and each is independently an aromatic boron-containing group. Models FF89 to FF112 are, 【Chemistry 276】 And, In the formula, X is selected from maleimide, amine, OH, and halogen. i is 1, 2, 3, 4, 5, 6, or 7, B １ , B ２ and B ３ They may be the same or different, and each independently represents an aromatic boron-containing group, a carboxylic acid derivative, or H, and at least two of B1, B2, and B3 of each FF structure are independently aromatic boron-containing groups. Formulas FF113 to FF136 are, 【Chemistry 277】 And, In the formula, X is selected from maleimide, amine, OH, and halogen. i is 1, 2, 3, 4, 5, 6, or 7, j is 1, 2, 3, 4, 5, 6, or 7. k is 1, 2, 3, 4, 5, 6, or 7. m is 1, 2, 3, 4, 5, 6, or 7. Each R1 is independently selected from H, alkyl groups, acyl groups, cycloalkyl groups, haloalkyl groups, aryl groups, and heteroaryl groups, and each R1 optionally contains one or more alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyls, alkyls, or aryl groups. B １ and B ２ However, they may be the same or different, and each independently represents an aromatic boron-containing group. Formulas FF137 to FF160 are, 【Chemistry 278】 And, In the formula, X is selected from maleimide, amine, OH, and halogen. i is 1, 2, 3, 4, 5, 6, or 7, j is 1, 2, 3, 4, 5, 6, or 7. k is 1, 2, 3, 4, 5, 6, or 7. m is 1, 2, 3, 4, 5, 6, or 7. Each R1 is independently selected from H, alkyl groups, acyl groups, cycloalkyl groups, haloalkyl groups, aryl groups, and heteroaryl groups, and each R1 optionally contains one or more alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyls, alkyls, or aryl groups. B １ and B ２ However, they may be the same or different, and each independently represents an aromatic boron-containing group. Formulas FF161 to FF164 are, 【Chemistry 279】 And, In the formula, X is selected from maleimide, amine, OH, and halogen. i is 1, 2, 3, 4, or 5. j is 1, 2, 3, 4, or 5. For different values ​​of j, each of R6, R7, R8, and R9 independently determines H, CF ３ ,CH ３ CHF ２ , and (CH ２ ) ｍ CH ３ Selected from, where m is 1, 2, 3, 4, or 5, Y3, Y4, Y5, Y6, and Y7 are each independently H, CH ２ -X4, and selected from formulas IV-1 to IV-135, X4 is -COOH, -(CH ２ ) ｍ Selected from COOH, alkyl groups, acyl groups, cycloalkyl groups, haloalkyl groups, aryl groups, and heteroaryl groups, each optionally containing one or more alkyl halides, halides, sulfhydryls, aldehydes, amines, acids, hydroxyls, alkyls, or aryl groups, where m is 1, 2, 3, 4, or 5. In formulas FF162 and FF163, at least one of Y5, Y6, and Y7 is not H, and in FF164, at least one of Y7, R8, and R9 is not H. Formulas IV-1 to IV-135 are, 【Chemistry 280】 【Chemistry 281】 【Chemistry 282】 And, During the ceremony, Xa is CH=O, CHF ２ CF ３ ,CH ２ SH, COOH, CH ２ OH, CH ２ NO ２ ,CH ２ NH ２ ,CH ３ , C (CH ３ ) ３ , CH (CH ３ ) ２ , CH((CH ２ ) ３ CH ３ ) ２ , or CH (CH ２ CH ３ ) ２ This represents, Xb is O, NH, CH ２ , or represents S, Xc represents CH or N, Each R １０ However, independently, H, F, Cl, Br, CH ３ CF ３ , CH=O, OH, COOH, and (CH ２ ) ｎ CH ３ Selected from, m is 1, 2, 3, 4, or 5, and n is 1, 2, 3, 4, or 5, B １ and B ２ However, they may be the same or different, and each independently represents an aromatic boron-containing group. Formulas IV-1 to IV-135 ＊ However, this represents the connection point to the corresponding equations FF161-164, Formulas FF165 to FF166 are, 【Chemistry 283】 And, In the formula, X is selected from maleimide, amine, OH, and halogen. m is 1, 2, 3, 4, 5, 6, or 7. n is 1, 2, 3, 4, 5, 6, or 7. X5 is S, O, or NH. Each R １ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, Formulas FF167 to FF192 are, 【Chemistry 284】 And, In the formula, X is selected from maleimide, amine, OH, and halogen. B １ and B ２ However, they may be the same or different, and each independently represents an aromatic boron-containing group. Models FF193 to FF209 are, 【Chemical 285】 And, In the formula, R in FF208 and FF209 is at least one CH group attached to the amino group of the side chain of FF208 or FF209. ２ Alkyl, aryl, or halide molecules covalently bonded via a group, R1 and R2 independently produce H and CH ３ , alkyl, and selected from formulas IV-1 to IV-135, i is 1, 2, 3, 4, or 5. j is 1, 2, 3, 4, or 5. In the formula, X is selected from maleimide, amine, OH, and halogen. B １ and B ２ However, they may be the same or different, and each independently represents an aromatic boron-containing group. Formulas FF210 to FF224 are, 【Chemistry 286】 And, In the formulas, R11 of FF210 to FF212 is independently selected from formulas IV-1 to IV-135, and R12 is selected from amine, hydroxyl, alkyl, and halide groups. Each R13 independently controls H and CH ３ , alkyl, aryl, and selected from formulas IV-1 to IV-135, where R14 is H, CH ３ Selected from alkyl, aryl, and heteroaryl, In the formula, X is independently selected from maleimide, amine, OH, and halogen. X'' is an amine, i is 1, 2, 3, 4, or 5. j is 1, 2, 3, 4, or 5. and B １ , B ２ , B ３ , B ４ , B ５ , and B ６ However, each independently represents an aromatic boron-containing group, and in each FF structure containing B1, B2, and B3 groups, at least two of the B1, B2, and B3 groups are independently aromatic boron-containing groups. Models FF225 to FF231 are, 【Chemistry 287】 And, In the formula, X is selected from maleimide, amine, OH, and halogen. i is 1, 2, 3, 4, 5, 6, or 7, B １ and B ２ However, they may be the same or different, and each independently represents an aromatic boron-containing group, and B of formulas FF225 to FF231 １ and B ２ However, it is not a boronic acid or an F2 or F6 aromatic boron-containing group, Formulas F2 and F6 are, 【Chemical 288】 And, 5th place R １ However, (C=O) --- ＊ This represents, --- ＊ However, it represents the connection point to the remaining part of FF225-FF231, 0, 1, or 2 R １ However, F, Cl, CF ２ CF ３ SF ５ OCF ３ SO ２ CH ３ , and / or SO ２ CF ３ This represents the remaining R １ However, it represents H, Y8 is O, i is 1, The remaining rounds １ However, it is H, Y8 is O, i is 1, At least one primary or secondary amine from FF1 to FF223 and FF225 to FF231 is optionally B ６ They are covalently bonded, A compound in which X is an amine in any one of the formulas FF1 to FF223 and FF225 to FF231, and X is optionally acetylated or alkylated.

157. The aforementioned compound is independently selected from formulas F1 to F11. １ , B ２ and B ３ The compound comprises at least one of the following, or the compound is independently selected from formulas F1 to F11. ４ , B ５ and B ６ Includes at least one of the following: Formulas F1 to F11 are, 【Chemistry 289】 And, B １ , B ２ , B ３ in the case of: One R １ However, (C=O) --- ＊ , S(=O)(=O)--- ＊ , (CH ２ ) ｍ (C=O) --- ＊ , or (CH ２ ) ｍ --- ＊ This represents, --- ＊ However, this represents the connection point to the remaining part of Z1c, where m is 1, 2, 3, 4, 5, 6, or 7. The remaining rounds １ or R ２ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, B ４ , B ５ in the case of: B ４ In this case, one R １ However, (CH ２ ) ｍ --- Represents φ, where --- φ represents the aforementioned bonding point of X1 to the amine (representing a covalent bond), B ５ In this case, one R １ However, (C=O) --- ＊ , S(=O)(=O)--- ＊ , (CH ２ ) ｍ (C=O) --- ＊ , or (CH ２ ) ｍ --- ＊ This represents, --- ＊ However, this represents the bond site of X1 to the same amine, and m is 1, 2, 3, 4, 5, 6, or 7. The remaining rounds １ or R ２ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, B ６ in the case of: B ６ In this case, one R １ However, (CH ２ ) ｍ --- represents φ, where ---φ represents the bond point to the rest of the compound (representing a covalent bond), and m is 1, 2, 3, 4, 5, 6, or 7. The remaining rounds １ or R ２ However, independently, H, F, Cl, Br, OH, CH ２ -NH ２ NH ２ (C=O)-NH ２ CH=O, SO ２ CH ３ SO ２ CF ３ CF ３ CHF ２ NO ２ ,CH ３ , OCH ３ , O(CH ２ ) ｍ CH ３ ,-(SO ２ ) NH-CH ３ ,-(SO ２ )NH(CH ２ ) ｍ CH ３ , and OCF ３ Selected from, where m is 1, 2, 3, 4, 5, 6, or 7, Regarding formulas F3 to F4, R ｗ However, it is either O or S, Regarding formulas F5 to F10, If Y8 is O, then i is 2, 3, 4, or 5, or If Y8 is NR, then R is an alkyl group or H, and i is 1, 2, 3, 4, or 5. Y9 is H, CH ３ , or an alkyl group, however, if Y8 is O, Y9 is CH ３ Alternatively, it is an alkyl group, and each Y10 is independently H, CH ３ F, CF ３ , and OCH ３ The compound according to claim 156, selected from, provided that at least one Y10 is not H.

158. The aforementioned compound, N-(3-(3-Borono-5-nitrobenzamide)propyl)-N-(3-Borono-5-nitrobenzoyl)glycine (DS01), N-(4-((4-(3-Borono-5-nitrobenzamide)cyclohexyl)methyl)cyclohexyl)-N-(3-Borono-5-nitrobenzoyl)glycine (DS02), N-(4-((3-Borono-5-nitrobenzamide)methyl)benzyl)-N-(3-Borono-5-nitrobenzoyl)glycine (DS03), N-(3-((3-Borono-5-nitrobenzamide)methyl)benzyl)-N-(3-Borono-5-nitrobenzoyl)glycine (DS04), N-(4-(3-Borono-5-nitrobenzamide)butyl)-N-(3-Borono-5-nitrobenzoyl)glycine (DS05), N-(3-(3-borono-5-fluorobenzamide)propyl)-N-(3-borono-5-fluorobenzoyl)glycine (DS06), N-(3-(3-Borono-5-Fluorobenzamide)-2,2-dimethylpropyl)-N-(3-Borono-5-Fluorobenzoyl)glycine (DS07), Bis(3-(3-borono-5-fluorobenzamide)propyl)glycine (DS08), N-(4-((3-Borono-5-Fluorobenzamide)methyl)benzyl)-N-(3-Borono-5-Fluorobenzoyl)glycine (DS09), N-(3-((3-Borono-5-Fluorobenzamide)methyl)benzyl)-N-(3-Borono-5-Fluorobenzoyl)glycine (DS10), N-(2-(3-Borono-5-Fluorobenzamide)cyclohexyl)-N-(3-Borono-5-Fluorobenzoyl)glycine (DS11), N-(3-(3-borono-4-fluorobenzamide)propyl)-N-(3-borono-4-fluorobenzoyl)glycine (DS12), N-(4-((4-(3-Borono-4-Fluorobenzamide)cyclohexyl)methyl)cyclohexyl)-N-(3-Borono-4-Fluorobenzoyl)glycine (DS13), N-(3-(3-Borono-4-Fluorobenzamide)-2,2-dimethylpropyl)-N-(3-Borono-4-Fluorobenzoyl)glycine (DS14), N-(4-((3-Borono-4-Fluorobenzamide)methyl)benzyl)-N-(3-Borono-4-Fluorobenzoyl)glycine (DS15), N-(3-((3-Borono-4-Fluorobenzamide)methyl)benzyl)-N-(3-Borono-4-Fluorobenzoyl)glycine (DS16), N-((1S,2R)-2-(3-Borono-4-Fluorobenzamide)cyclohexyl)-N-(3-Borono-4-Fluorobenzoyl)glycine (DS17), N-((1S,2S)-2-(3-Borono-4-Fluorobenzamide)cyclohexyl)-N-(3-Borono-4-Fluorobenzoyl)glycine (DS18), N-(3-(3-Borono-5-bromobenzamide)propyl)-N-(3-Borono-5-bromobenzoyl)glycine (DS19), N-(4-((4-(3-Borono-5-bromobenzamide)cyclohexyl)methyl)cyclohexyl)-N-(3-Borono-5-bromobenzoyl)glycine (DS20), Bis(3-(3-borono-5-bromobenzamide)propyl)glycine (DS21), N-(4-((3-Borono-5-bromobenzamide)methyl)benzyl)-N-(3-Borono-5-bromobenzoyl)glycine (DS22), N-(3-((3-Borono-5-bromobenzamide)methyl)benzyl)-N-(3-Borono-5-bromobenzoyl)glycine (DS23), N-(2-(3-Borono-5-bromobenzamide)cyclohexyl)-N-(3-Borono-5-bromobenzoyl)glycine (DS24), N-(3-(4-Borono-3-Fluorobenzamide)propyl)-N-(4-Borono-3-Fluorobenzoyl)glycine (DS25), N-(4-((4-(4-Borono-3-fluorobenzamide)cyclohexyl)methyl)cyclohexyl)-N-(4-Borono-3-fluorobenzoyl)glycine (DS26), N-(3-(4-Borono-3-Fluorobenzamide)-2,2-dimethylpropyl)-N-(4-Borono-3-Fluorobenzoyl)glycine (DS27), Bis(3-(4-Borono-3-Fluorobenzamide)propyl)glycine (DS28), N-(4-((4-Borono-3-Fluorobenzamide)methyl)benzyl)-N-(4-Borono-3-Fluorobenzoyl)glycine (DS29), N-(3-((4-Borono-3-Fluorobenzamide)methyl)benzyl)-N-(4-Borono-3-Fluorobenzoyl)glycine (DS30), N-((1S,2R)-2-(4-Borono-3-Fluorobenzamide)cyclohexyl)-N-(4-Borono-3-Fluorobenzoyl)glycine (DS31), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)propyl)glycine (DS32), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(5-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pentyl)glycine (DS33), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-2,2-dimethylpropyl)glycine (DS34), Bis(3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)propyl)glycine (DS35), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(3-((1-hydroxy-1,3-dihydrobenzo[c][1,2]]oxabolol-6-carboxamide)methyl)benzyl)glycine (DS36), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-((1S,2R)-2-(1-hydroxy-1,3-dihydrobenzo[c]][1,2]oxabolol-6-carboxamide)cyclohexyl)glycine (DS37), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)butyl)glycine (DS38), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-((1S,2S)-2-(1-hydroxy-1,3-dihydrobenzo[c]][1,2]oxabolol-6-carboxamide)cyclohexyl)glycine (DS39), (R)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)propyl)glycine (DS40), (S)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)propyl)glycine (DS41), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)cyclohexyl)glycine (DS42), N-(3-(4-borono-3,5-difluorobenzamide)propyl)-N-(4-borono-3,5-difluorobenzoyl)glycine (DS43), N-(3-(4-Borono-2-Fluorobenzamide)propyl)-N-(4-Borono-2-Fluorobenzoyl)glycine (DS44), N-(2-(N-ethyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)ethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)glycine (DS45), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(2-(1-hydroxy-N-(2-hydroxyethyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)ethyl)glycine (DS46), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(5-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)hexyl)glycine (DS47), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(4-((4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)cyclohexyl)methyl)cyclohexyl)glycine (DS48), ((2S,4S)-1-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pyrrolidine-2-carbonyl)glycine (DS49), ((2S,4S)-4-(3-Borono-4-Fluorobenzamide)-1-(3-Borono-4-Fluorobenzoyl)pyrrolidine-2-carbonyl)glycine (DS50), ((2S,4S)-4-(3-Borono-5-nitrobenzamide)-1-(3-Borono-5-nitrobenzoyl)pyrrolidine-2-carbonyl)glycine (DS51), ((2S,4S)-4-(5-Borono-2-Fluorobenzamide)-1-(5-Borono-2-Fluorobenzoyl)pyrrolidine-2-carbonyl)glycine (DS52), (S)-(1,4-bis(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)piperazine-2-carbonyl)glycine (DS53), (S)-N-(3-amino-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-3-oxopropyl)-N-benzyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS54), (S)-N-(3-amino-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-3-oxopropyl)-1-hydroxy-N-(4-(trifluoromethyl)benzyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS55), (S)-N-(3-amino-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-3-oxopropyl)-N-ethyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS56), (S)-N-(3-amino-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-3-oxopropyl)-1-hydroxy-N-propyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS57), (S)-N-(3-amino-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-3-oxopropyl)-1-hydroxy-N-isobutyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS58), (S)-N-(3-amino-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-3-oxopropyl)-1-hydroxy-N-((5-(thiophen-2-yl)pyridine-2-yl)methyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS59), (S)-N-(3-amino-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-3-oxopropyl)-1-hydroxy-N-isopentyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS60), (S)-N-(3-amino-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-3-oxopropyl)-1-hydroxy-N-(quinoline-5-ylmethyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS61), (S)-N-(3-amino-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-3-oxopropyl)-1-hydroxy-N-(2-(trifluoromethoxy)benzyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS62), (S)-N-(3-amino-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-3-oxopropyl)-1-hydroxy-N-(4-(methylsulfonyl)benzyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS63), (3-((2S,4S)-4-(5-Borono-2-(methylsulfonyl)benzamide)-2-carbamoylpyrrolidine-1-carbonyl)-4-(methylsulfonyl)phenyl)boronic acid (DS64), (4-(((3S,5S)-1-(4-Borono-2,6-difluorobenzoyl)-5-carbamoylpyrrolidine-3-yl)carbamoyl)-3,5-difluorophenyl)boronic acid (DS65), (R,E)-4,5-bis(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)penta-2-enoic acid (DS66), (2S,4S)-1-(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-4-(1-hydroxy-4-(trifluoromethyl))-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pyrrolidine-2-carboxamide (DS67), N,N'-((2S,3S)-1-amino-1-oxobutan-2,3-diyl)bis(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)(DS68), (R)-3,4-bis(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)butanoic acid (DS69), 3-((2S,4S)-1-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-4-(1-hydroxy-1,3-dihydrobenzo[c]][1,2]oxabolol-6-carboxamide)pyrrolidine-2-carboxamide)propanoic acid (DS70), (S)-3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-5-carboxamide)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]]oxabolol-6-carboxamide)butanoic acid (DS71), (R)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-5-carboxamide)-5-(1-hydroxy-1,3-dihydrobenzo[c][1,2]]oxabolol-6-carboxamide)pentanoic acid (DS72), (2S,4R)-1-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pyrrolidine-2-carboxylic acid (DS73), (2S,4R)-1-(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-4-(1-hydroxy-4-(trifluoromethyl))-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pyrrolidine-2-carboxylic acid (DS74), (2S,3S)-3-(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-2-(1-hydroxy-7-(trifluoromethyl))-1,3-dihydrobenzo[c][1,2]oxabolol-5-carboxamide)butanoic acid (DS75), (R)-5-(1-hydroxy-4-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-4-(1-hydroxy-7-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxabolol-5-carboxamide)pentanoic acid (DS76), ((2S,4S)-1-(5-Borono-2-nitrobenzoyl)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pyrrolidine-2-carbonyl)glycine (DS77), ((2S,4S)-1-(5-Borono-2-(methylsulfonyl)benzoyl)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pyrrolidine-2-carbonyl)glycine (DS78), ((2S,4S)-1-(3-Borono-2,6-difluorobenzoyl)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pyrrolidine-2-carbonyl)glycine (DS79), (S)-(3-((3-Borono-4-Fluorobenzyl)(5,6-Diamino-6-Oxohexyl)Carbamoyl)-5-Nitrophenyl)Boric Acid (DS80), (S)-(3-((4-Borono-3,5-difluorobenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-5-nitrophenyl)boronic acid (DS81), (S)-(3-((3-Boronobenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-5-nitrophenyl)boronic acid (DS82), (S)-(3-((4-Borono-2-methoxybenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-5-nitrophenyl)boronic acid (DS83), (S)-(3-((4-Borono-2-(trifluoromethyl)benzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-5-nitrophenyl)boronic acid (DS84), (S)-(5-((3-Borono-N-(5,6-diamino-6-oxohexyl)-4-fluorobenzamide)methyl)-2-fluorophenyl)boronic acid (DS85), (S)-(5-((4-Borono-3,5-difluorobenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-2-fluorophenyl)boronic acid (DS86), (S)-(3-((3-Borono-N-(5,6-diamino-6-oxohexyl)-4-fluorobenzamide)methyl)phenyl)boronic acid (DS87), (S)-(5-((4-Borono-2-methoxybenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-2-fluorophenyl)boronic acid (DS88), (S)-(5-((4-Borono-3-(trifluoromethyl)benzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-2-fluorophenyl)boronic acid (DS89), (S)-(4-((3-Borono-4-Fluorobenzyl)(5,6-Diamino-6-Oxohexyl)Carbamoyl)-2-Fluorophenyl)Boric Acid (DS90), (S)-(4-((4-Borono-3,5-difluorobenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-2-fluorophenyl)boronic acid (DS91), (S)-(4-((3-Boronobenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-2-fluorophenyl)boronic acid (DS92), (S)-(4-((4-Borono-2-methoxybenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-2-fluorophenyl)boronic acid (DS93), (S)-(4-((4-Borono-2-(trifluoromethyl)benzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-2-fluorophenyl)boronic acid (DS94), (S)-(5-((3-Borono-5-bromo-N-(5,6-diamino-6-oxohexyl)benzamide)methyl)-2-fluorophenyl)boronic acid (DS95), (S)-(3-((4-Borono-3,5-difluorobenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-5-bromophenyl)boronic acid (DS96), (S)-(3-((3-Borono-5-bromo-N-(5,6-diamino-6-oxohexyl)benzamide)methyl)phenyl)boronic acid (DS97), (S)-(3-((3-Borono-5-bromo-N-(5,6-diamino-6-oxohexyl)benzamide)methyl)-5-methoxyphenyl)boronic acid (DS98), (S)-(3-((4-Borono-2-(trifluoromethyl)benzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-5-bromophenyl)boronic acid (DS99), (S)-(3-((3-Borono-4-Fluorobenzyl)(5,6-Diamino-6-Oxohexyl)Carbamoyl)-5-Fluorophenyl)Boric Acid (DS100), (S)-(3-((4-Borono-3-methoxybenzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-5-fluorophenyl)boronic acid (DS101), (S)-(3-((4-Borono-2-(trifluoromethyl)benzyl)(5,6-diamino-6-oxohexyl)carbamoyl)-5-fluorophenyl)boronic acid (DS102), (S)-(4-((N-(5,6-diamino-6-oxohexyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)methyl)-2-fluorophenyl)boronic acid (DS103), (S)-(4-((N-(5,6-diamino-6-oxohexyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)methyl)-2,6-difluorophenyl)boronic acid (DS104), (S)-(3-((N-(5,6-diamino-6-oxohexyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)methyl)phenyl)boronic acid (DS105), (S)-(4-((N-(5,6-diamino-6-oxohexyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)methyl)-3-methoxyphenyl)boronic acid (DS106), (S)-N-(5,6-diamino-6-oxohexyl)-1-hydroxy-N-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-yl)methyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS107), (S)-N-(4-amino-3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-4-oxobutyl)-1-hydroxy-N-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-yl)methyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS108), (S)-N-(6-amino-5-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)-6-oxohexyl)-1-hydroxy-N-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-yl)methyl)-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide (DS109), (2S,4S)-1-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pyrrolidine-2-carboxylic acid (DS110), (2S,3S)-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-5-carboxamide)-3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]]oxabolol-6-carboxamide)butanoic acid (DS111), (2S,4R)-1-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pyrrolidine-2-carboxylic acid (DS112), N-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carbonyl)-N-(2-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)ethyl)glycine (DS113), N-(1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxavorinine-7-carbonyl)-N-(2-(1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxavorinine-7-carboxamide)ethyl)glycine (DS114), N-(2-(2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-7-yl)acetamide)ethyl)-N-(2-(1-hydroxy-1,3-dihydrobenzo[c]][1,2]oxabolol-7-yl)acetyl)glycine (DS115), N-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-7-carbonyl)-N-(2-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-7-carboxamide)ethyl)glycine (DS116), N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-3-carbonyl)-N-(2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-3-carboxamide)ethyl)glycine (DS117), 3,5-Bis((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)methyl)benzoic acid (DS118), 3,5-Bis((1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxavorinine-7-carboxamide)methyl)benzoic acid (DS119), 3,5-Bis((2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-7-yl)acetamide)methyl)benzoic acid (DS120), 3,5-Bis((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-7-carboxamide)methyl)benzoic acid (DS121), 3,5-Bis((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-3-carboxamide)methyl)benzoic acid (DS122), (S)-3-(2,3-bis(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)propanamide)propanoic acid (DS123), (S)-3-(2,3-bis(1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxavolinine-7-carboxamide)propanamide)propanoic acid (DS124), (S)-3-(2,3-bis(2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-7-yl)acetamide)propanamide)propanoic acid (DS125), (S)-3-(2,3-bis(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-7-carboxamide)propanamide)propanoic acid (DS126), 3-((2S)-2,3-bis(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-3-carboxamide)propanamide)propanoic acid (DS127), (3,5-bis((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)methyl)benzoyl)glutamic acid (DS128), (3,5-bis((1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxavolinine-7-carboxamide)methyl)benzoyl)glutamic acid (DS129), (3,5-bis((2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-7-yl)acetamide)methyl)benzoyl)glutamic acid (DS130), (3,5-bis((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-7-carboxamide)methyl)benzoyl)glutamic acid (DS131), (3,5-bis((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-3-carboxamide)methyl)benzoyl)glutamic acid (DS132), 4-(3,4-bis(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pyrrolidine-1-yl)-4-oxobutanoic acid (DS133), 4-(3,4-bis(1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxavolinin-7-carboxamide)pyrrolidine-1-yl)-4-oxobutanoic acid (DS134), 4-(3,4-bis(2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-7-yl)acetamide)pyrrolidine-1-yl)-4-oxobutanoic acid (DS135), 4-(3,4-bis(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-7-carboxamide)pyrrolidine-1-yl)-4-oxobutanoic acid (DS136), 4-(3,4-bis(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-3-carboxamide)pyrrolidine-1-yl)-4-oxobutanoic acid (DS137), ((S)-2,3-bis(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)propanoyl)-L-glutamic acid (DS138), ((S)-2,3-bis(1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxavolinine-7-carboxamide)propanoyl)-L-glutamic acid (DS139), ((S)-2,3-bis(2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-7-yl)acetamide)propanoyl)-L-glutamic acid (DS140), ((S)-2,3-bis(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-7-carboxamide)propanoyl)-L-glutamic acid (DS141), ((2S)-2,3-bis(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-3-carboxamide)propanoyl)-L-glutamic acid (DS142), (4-(3,4-bis(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-6-carboxamide)pyrrolidine-1-yl)-4-oxobutanoyl)-L-glutamic acid (DS143), (4-(3,4-bis(1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxavolinin-7-carboxamide)pyrrolidine-1-yl)-4-oxobutanoyl)-L-glutamic acid (DS144), (4-(3,4-bis(2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-7-yl)acetamide)pyrrolidine-1-yl)-4-oxobutanoyl)-L-glutamic acid (DS145), (4-(3,4-bis(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-7-carboxamide)pyrrolidine-1-yl)-4-oxobutanoyl)-L-glutamic acid (DS146), (4-(3,4-bis(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-3-carboxamide)pyrrolidine-1-yl)-4-oxobutanoyl)-L-glutamic acid (DS147), (S)-2,3-bis(1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxavolinine-7-carboxamide)propanoic acid (DS149), (S)-2,3-bis(2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-7-yl)acetamide)propanoic acid (DS150), (S)-2,3-bis(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabolol-7-carboxamide)propanoic acid (DS151), and A compound according to claim 156 or 157, selected from (2S)-2,3-bis(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-3-carboxamide)propanoic acid (DS152).

159. The compound according to any one of claims 101 to 150 and 156 to 158, wherein the compound is used as an intermediate in the manufacture of an active pharmaceutical ingredient or as a therapeutic agent for a prophylactic compound.

160. A human insulin analog comprising A chain and B chain, wherein the sequence of the A chain is X ａａ’ X ｂｂ’ X ｃｃ’ X ｄｄ’ X ｅｅ’ X ｆｆ’ X ｇｇ’ VEQCCX ｈｈ’ X ｉｉ’ ICSLYQLENYCNX ｊｊ’ X ｋｋ’ X ｌｌ’ X ｍｍ’ X ｎｎ’ X ｏｏ’ X ｐｐ’ (Sequence ID 24015) and The sequence of the B chain is ()) ａａ ︸ ｂｂ ︸ ｃｃ ︸ ｄｄ ︹ ｅｅ ︸ ｆｆ ︸ ｇｇ ︸ ｈｈ ︸ ｉｉ ︸ ｊｊ ︹ ｋｋ ︸ ｌｌ ︸ ｍｍ ︸ ｎｎ ||||||||||||||____________________________ ｏｏ ︸ ｐｐ ︸ ｑｑ FF) ｒｒ ︸ ｓｓ ︸ ｔｔ ︸ ｕｕ ︸ ｖｖ ︸ ｗｗ (44) (X ａａ’ , X ｂｂ’ , X ｃｃ’ , X ｄｄ’ , X ｅｅ’ , X ｆｆ’ , X ｇｇ’ , X ｈｈ’ , X ｉｉ’ , X ｊｊ’ , X ｋｋ’ , X ｌｌ’ , X ｍｍ’ , X ｎｎ’ , X ｏｏ’ , X ｐｐ’ , X ａａ , X ｂｂ , X ｃｃ , X ｄｄ , X ｅｅ , X ｆｆ , X ｇｇ , X ｈｈ , X ｉｉ , X ｊｊ , X ｋｋ , X ｌｌ , X ｍｍ , X ｎｎ , X ｏｏ , X ｐｐ , X ｑｑ , X ｒｒ , X ｓｓ , X ｔｔ , X ｕｕ , X ｖｖ , and X ｗｗ However, each of these is either absent or selected from amino acid residues A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, Y, and W). (ii) X ａａ X ｂｂ X ｃｃ X ｄｄ KPX ｅｅ X ｆｆ X ｇｇ X ｈｈ X ｉｉ X ｊｊ X ｋｋ X ｌｌ X ｍｍ X ｎｎ QHLCGSHLVEALYLVCX ｏｏ X ｐｐ X ｑｑ GFFYTX ｒｒ X ｓｓ X ｔｔ X ｕｕ X ｖｖ X ｗｗ (SEQ ID NO: 24017) (X ａａ’ , X ｂｂ’ , X ｃｃ’ , X ｄｄ’ , X ｅｅ’ , X ｆｆ’ , X ｇｇ’ , X ｈｈ’ , X ｉｉ’ , X ｊｊ’ , X ｋｋ’ , X ｌｌ’ , X ｍｍ’ , X ｎｎ’ , X ｏｏ’ , X ｐｐ’ , X ａａ , X ｂｂ , X ｃｃ , X ｄｄ , X ｆｆ , X ｇｇ , X ｈｈ , X ｉｉ , X ｊｊ , X ｋｋ , X ｌｌ , X ｍｍ , X ｎｎ , X ｏｏ , X ｐｐ , X ｑｑ , X ｒｒ , X ｓｓ , X ｔｔ , X ｕｕ , X ｖｖ , and X ｗｗ However, each independently is either absent or selected from amino acid residues A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, Y, and W, X ｅｅ (Selected from amino acid residues A, E, F, H, I, K, L, N, P, Q, R, S, T, V, Y, and W) (iii) X ａａ X ｂｂ X ｃｃ X ｄｄ KX ｅｅ X ｆｆ X ｇｇ X ｈｈ X ｉｉ X ｊｊ KX ｋｋ X ｌｌ X ｍｍ X ｎｎ QHLCGSHLVEALYLVCX ｏｏ X ｐｐ X ｑｑ GFFYTX ｒｒ X ｓｓ X ｔｔ X ｕｕ X ｖｖ X ｗｗ (SEQ ID NO: 24018) (X ａａ’ , X ｂｂ’ , X ｃｃ’ , X ｄｄ’ , X ｅｅ’ , X ｆｆ’ , X ｇｇ’ , X ｈｈ’ , X ｉｉ’ , X ｊｊ’ , X ｋｋ’ , X ｌｌ’ , X ｍｍ’ , X ｎｎ’ , X ｏｏ’ , X ｐｐ’ , X ａａ , X ｂｂ , X ｃｃ , X ｄｄ , X ｅｅ , X ｆｆ , X ｇｇ , X ｈｈ , X ｉｉ , X ｊｊ , X ｋｋ , X ｌｌ , X ｍｍ , X ｎｎ , X ｏｏ , X ｐｐ , X ｑｑ , X ｒｒ , X ｓｓ , X ｔｔ , X ｕｕ , X ｖｖ , and X ｗｗ However, each independently is either absent or selected from amino acid residues A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, Y, W, X ｅｅ , X ｆｆ , X ｇｇ , X ｈｈ , X ｉｉ , X ｊｊ At least one of the following exists, X ｅｅ , X ｆｆ , X ｇｇ , X ｈｈ , X ｉｉ , X ｊｊ At least one of them is G. ()) ａａ ︸ ｂｂ ︸ ｃｃ ︸ ｄｄ ︹ ｅｅ ︸ ｆｆ ︸ ｇｇ ︸ ｈｈ ︸ ｉｉ ︸ ｊｊ ︹ ｋｋ ︸ ｌｌ ︸ ｍｍ ︸ ｎｎ ||||||||||||||____________________________ ｏｏ ︸ ｐｐ ︸ ｑｑ FF) ｒｒ ︸ ｓｓ ︸ ｔｔ ︸ ｕｕ ︸ ｖｖ ︸ ｗｗ (4) (X ａａ’ , X ｂｂ’ , X ｃｃ’ , X ｄｄ’ , X ｅｅ’ , X ｆｆ’ , X ｇｇ’ , X ｈｈ’ , X ｉｉ’ , X ｊｊ’ , X ｋｋ’ , X ｌｌ’ , X ｍｍ’ , X ｎｎ’ , X ｏｏ’ , X ｐｐ’ , X ａａ , X ｂｂ , X ｃｃ , X ｄｄ , X ｅｅ , X ｆｆ , X ｇｇ , X ｈｈ , X ｉｉ , X ｊｊ , X ｋｋ , X ｌｌ , X ｍｍ , X ｎｎ , X ｏｏ , X ｐｐ , X ｑｑ , X ｒｒ , X ｓｓ , X ｔｔ , X ｕｕ , X ｖｖ , and X ｗｗ However, each independently is either absent or selected from amino acid residues A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, Y, W, X ｅｅ , X ｆｆ , X ｇｇ , X ｈｈ , X ｉｉ , X ｊｊ At least one of the following exists, X ｅｅ , X ｆｆ , X ｇｇ , X ｈｈ , X ｉｉ , X ｊｊ At least one of them is S), or (v) X ａａ X ｂｂ X ｃｃ X ｄｄ KX ｅｅ X ｆｆ X ｇｇ X ｈｈ X ｉｉ X ｊｊ KX ｋｋ X ｌｌ X ｍｍ X ｎｎ QHLCGSHLVEALYLVCX ｏｏ X ｐｐ X ｑｑ GFFYTX ｒｒ X ｓｓ X ｔｔ X ｕｕ X ｖｖ X ｗｗ (SEQ ID NO: 24020) (X ａａ’ , X ｂｂ’ , X ｃｃ’ , X ｄｄ’ , X ｅｅ’ , X ｆｆ’ , X ｇｇ’ , X ｈｈ’ , X ｉｉ’ , X ｊｊ’ , X ｋｋ’ , X ｌｌ’ , X ｍｍ’ , X ｎｎ’ , X ｏｏ’ , X ｐｐ’ , X ａａ , X ｂｂ , X ｃｃ , X ｄｄ , X ｅｅ , X ｆｆ , X ｇｇ , X ｈｈ , X ｉｉ , X ｊｊ , X ｋｋ , X ｌｌ , X ｍｍ , X ｎｎ , X ｏｏ , X ｐｐ , X ｑｑ , X ｒｒ , X ｓｓ , X ｔｔ , X ｕｕ , X ｖｖ , and X ｗｗ However, each independently is either absent or selected from amino acid residues A, D, E, F, G, H, I, K, L, N, P, Q, R, S, T, V, Y, W, X ｅｅ , X ｆｆ , X ｇｇ , X ｈｈ , X ｉｉ , X ｊｊ At least two of these exist, X ｅｅ , X ｆｆ , X ｇｇ , X ｈｈ , X ｉｉ , X ｊｊ A human insulin analog comprising at least one of which is S and the other is G.

161. The A chain contains a sequence selected from SEQ ID NOs: 1 and 3 to 33, optionally KA, KD, KE, KF, KG, KH, KI, KL, KN, KP, KQ, KR, KS, KT, KY, KAA, KAD, KAE, KAF, KAG, KAH, KAI, KAL, KAN, KAQ, KAR, KAS, KAT, KAY, KDA, KDD, KDE, KDF, KDG, KDH, KDI, KDL, KDN, KDQ, KDR, KDS, KDT, KDY, KEA, KED, KEE, KEF, KEG, KEH, KEI, KEL, KEN, KEQ, KER, KES, KET, KEY, KFA, KFD, KFE, KFF, KFG, KFH, KFI, KFL, KFN, KFQ, KFR, KFS, KFT, KFY, KGA, KGD, KGE, KGF, KGG, KGH, KGI, KGL, KGN, KGQ, KGR, KGS, KGT, KGY, KHA, KHD, KHE, KHF, KHG, KHH, KHI, KHL, KHN, KHQ, KHR, KHS, KHT, KHY, KIA, KID, KIE, KIF, KIG, KIH, KII, KIL, KIN, KIQ, KIR, KIS, KIT, KIY, KLA, KLD, KLE, KLF, KLG, KLH, KLI, KLL, KLN, KLQ, KLR, KLS, KLT, KLY, KNA, KND, KNE, KNF, KNG, KNH, KNI, KNL, KNN, KNQ, KNR, KNS, KNT, KNY, KPA, KPD, KPE, KPF, KPG, KPH, KPI, KPL, KPN, KPQ, KPR, KPS, KPT, KPY, KQA, KQD, KQE, KQF, KQG, KQH, KQI, KQL, KQN, KQQ, KQR, KQS, KQT, KQY, KRA, KRD, KRE, KRF, KRG, KRH, KRI, KRL, KRN, KRQ, KRR, KRS, KRT, KRY, KSA, KSD, KSE, KSF, KSG, KSH, KSI, KSL, KSN, KSQ, KSR, KSS, KST, KSY, KTA, KTD, KTE, KTF, KTG, KTH, KTI, KTL, KTN, KTQ, KTR, KTS, KTT, KTY, KYA, KYD, KYE, KYF, KYG, KYH, KYI, KYL, KYN, KYQ, KYR, KYS, KYT, KYY, SEQ ID NOs: 75 to 24014, KGSH (SEQ ID NO: 24049), GKGSH (SEQ ID NO: 24050), GKGSKK (SEQ ID NO: 24045), GKKPGKK (SEQ ID NO: 24046),The N-terminus and / or C-terminus are affixed by at least one selected from GKGPSK (SEQ ID NO: 24044), GKPSHKP (SEQ ID NO: 24043), and GSHKGSHK (SEQ ID NO: 24042), The B chain contains sequences selected from SEQ ID NOs: 2 and 34-74, 24047, and 24048, and optionally KA, KD, KE, KF, KG, KH, KI, KL, KN, KP, KQ, KR, KS, KT, KY, KAA, KAD, KAE, KAF, KAG, KAH, KAI, KAL, KAN, KAQ, KAR, KAS, KAT, KAY, KDA, KDD, KDE, KDF, KDG, KDH, KDI, KDL, KDN, KDQ, KDR, KDS, KDT, KDY, KEA, KED, KEE, KEF, KEG, KEH, KEI, KEL, KEN, KEQ, KER, KES, KET, KEY, KFA, KFD, KFE, KFF, KFG, KFH, KFI, KFL, KFN, KFQ, KFR, KFS, KFT, KFY, KGA, KGD, KGE, KGF, KGG, KGH, KGI, KGL, KGN, KGQ, KGR, KGS, KGT, KGY, KHA, KHD, KHE, KHF, KHG, KHH, KHI, KHL, KHN, KHQ, KHR, KHS, KHT, KHY, KIA, KID, KIE, KIF, KIG, KIH, KII, KIL, KIN, KIQ, KIR, KIS, KIT, KIY, KLA, KLD, KLE, KLF, KLG, KLH, KLI, KLL, KLN, KLQ, KLr, KLS, KLT, KLY, KNA, KND, KNE, KNF, KNG, KNH, KNI, KNL, KNN, KNQ, KNR, KNS, KNT, KNY, KPA, KPD, KPE, KPF, KPG, KPH, KPI, KPL, KPN, KPQ, KPR, KPS, KPT, KPY, KQA, KQD, KQE, KQF, KQG, KQH, KQI, KQL, KQN, KQQ, KQR, KQS, KQT, KQY, KRA, KRD, KRE, KRF, KRG, KRH, KRI, KRL, KRN, KRQ, KRR, KRS, KRT, KRY, KSA, KSD, KSE, KSF, KSG, KSH, KSI, KSL, KSN, KSQ, KSR, KSS, KST, KSY, KTA, KTD, KTE, KTF, KTG, KTH, KTI, KTL, KTN, KTQ, KTR, KTS, KTT, KTY, KYA, KYD, KYE, KYF, KYG, KYH, KYI, KYL, KYN, KYQ, KYR, KYS, KYT, KYY, SEQ ID NOs: 75-24014, KGSH (SEQ ID NO: 24049), GKGSH (SEQ ID NO: 24050), GKGSKK (SEQ ID NO: 24045).Insulin according to claim 160, wherein the N-terminus and / or C-terminus are appended by at least one selected from GKKPGKK (SEQ ID NO: 24046), GKGPSK (SEQ ID NO: 24044), GKPSHKP (SEQ ID NO: 24043), and GSHKGSHK (SEQ ID NO: 24042).

162. The insulin according to claim 160, wherein there are four or fewer residues added to or deleted from the A chain and / or the B chain.

163. A K residue is present at the N-terminus of the A chain and / or the B chain, and / or three or fewer K residues are present at the N-terminus of the A chain and / or the B chain, and / or (i) The tyrosine in A14 is replaced with glutamic acid and / or (ii) The tyrosine in B16 is replaced with histidine and / or (iii) The phenylalanine in B25 is replaced with histidine and / or One to three residues selected from residues B20, B21, and B22-B29 of the B chain, residue A4 or A8 of the A chain, and any residues of the optionally extended polypeptide are lysine residues, and / or The insulin according to claim 160, wherein there is exactly one K residue within the first 10 residues of the N-terminus of the B chain.

164. A compound according to any one of claims 101 to 150 and 156 to 159, wherein X1 comprises insulin according to any one of claims 160 to 163.

165. The insulin according to any one of claims 160 to 163, wherein the amino groups of the side chains of 1 to 4 lysine residues are each independently covalently bonded as described by the formula of claim 102.

166. The insulin is covalently bonded as described by the formula of claim 102, n' = 0, and the C-terminus of Z1a is directly conjugated to the N-terminus of the B-chain of insulin via a peptide bond. Z1a comprises at least one amino acid selected from K, P, E, G, S, T, A, and R such that the sequence comprises at least one lysine, at least one proline, and at least one amino acid selected from H, R, A, and T. The insulin according to any one of claims 160 to 163, wherein at least one amino group of the lysine side chain of Z1a is covalently bonded as described by the formula.

167. The insulin is covalently bonded as described by the formula of claim 102, Z1a is the array (XA １ A ２ A ３ X) ｍ Contains polypeptides including (SEQ ID NO: 24022), A １ A ２ , and A ３ However, each is independently an L- or D-amino acid. m is an integer in the range of 1 to 4. Each X is either K or KP, The insulin according to any one of claims 160 to 163, wherein at least one epsilonamine group of the lysine side chain of Z1a is covalently bonded as described by the formula.

168. The insulin is covalently bonded as described by the formula of claim 102, Z1a contains a polypeptide comprising a sequence selected from (XA1X)m(GGGGGS)n (SEQ ID NO: 24023), (XA1A2X)m(GGGGGS)n (SEQ ID NO: 24024), (XA1A2A3X)m(GGGGGS)n (SEQ ID NO: 24025), (XA1X)m(GGGGGS)n(XA2X)o (SEQ ID NO: 24026), and (XA1A2X)m(GGGGGS)n(XA3A4X)o (SEQ ID NO: 24027), A １ A ２ A ３ , and A ４ However, each is independently an L- or D-amino acid. m is an integer in the range of 1 to 4. n is an integer in the range of 1 to 4. o is an integer in the range of 1 to 4. Each X is either K or KP, The insulin according to any one of claims 160 to 163, wherein the epsilonamine group of each lysine side chain of at least one lysine side chain of Z1a is further covalently bonded as described by the formula.

169. The insulin is covalently bonded as described by the formula of claim 102, Z1a is the arrangement (GX) ｍ Contains polypeptides including X is KV, m is an integer in the range of 1 to 4. The insulin according to any one of claims 160 to 163, wherein at least one epsilonamine group of the lysine side chain of Z1a is further covalently bonded as described by the formula.

170. The insulin is covalently bonded as described by the formula of claim 102, Z1a contains a polypeptide comprising a sequence selected from (GXA1KGEA2XT)m(GGSGSSS)n(GXGXA3GSSSGSSSXT)o (SEQ ID NO: 24028), (GXA1ESA2LYL)m (SEQ ID NO: 24029), (TXEX)m(GPGS)n (SEQ ID NO: 24030), (GXESA1VA)m(KA2K)n (SEQ ID NO: 24031), (GXEA1A2)m(GGS)n(TYA3XXT)o (SEQ ID NO: 24032), and (TXAXYT)m(TSSSS)n (SEQ ID NO: 24033). Each X is either KV or KP, A １ A ２ A ３ However, each is independently an L- or D-amino acid. m is an integer in the range of 1 to 4. n is an integer in the range of 1 to 4. o is an integer in the range of 1 to 4. The insulin according to any one of claims 160 to 163, wherein at least one epsilonamine group of the lysine side chain of Z1a is further covalently bonded as described by the formula.

171. The insulin is covalently bonded as described by the formula of claim 102, Z1a contains a polypeptide comprising a sequence selected from (TKPYA1KEVETA2GSGS)m(GGGGGS)n (SEQ ID NO: 24034), (YTPLEA1KPYSTSYKPYSEA1L)m(GKPTSLEA2FLVEA2LYTKP)n (SEQ ID NO: 24035), and (GKEALYLTPLESALYKP)m(TKPLEALYLKPEILSLKPESLA)n(GKPGSSSKPDTSSSGTPKTAAGS)o (SEQ ID NO: 24036), A １ and A ２ However, each is independently an L- or D-amino acid. m is an integer in the range of 1 to 4. n is an integer in the range of 1 to 4. The insulin according to any one of claims 160 to 163, wherein at least one epsilonamine group of the lysine side chain of Z1a is further covalently bonded as described by the formula.

172. (i) The A-chain and / or B-chain sequences of the insulin are amended at the N-terminus or C-terminus by KX'K, KX', or X'K, where X' represents a sequence of 2, 3, 4, or 5 residues selected from the wild-type A-chain (SEQ ID NO: 1) and wild-type B-chain (SEQ ID NO: 2), or (ii) X' is a polypeptide of up to 30 residues having amino acids independently selected from K, G, S, E, H, E, N, Q, D, A, P, R, and C, The insulin according to claim 160, wherein in (i) and (ii), each K residue is covalently bonded arbitrarily and independently as described by the formula of claim 102.

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