Releasable GLP-1 conjugates

Abstract

To provide compounds that undergo hydrolysis under physiological conditions to release a GLP polypeptide or analog thereof and are useful in the treatment of disorders that can be beneficially treated with the GLP polypeptide or analog thereof.SOLUTION: Provided is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where D is a residue of a GLP-polypeptide or an analog thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] Claiming priority This application is a continuation of U.S. Provisional Patent Application No. 62 / 730,341, filed September 12, 2018. No. 62 / 730,935, filed September 13, 2018; and and priority to U.S. Provisional Patent Application No. 62 / 771,972, filed November 27, 2018. No. 6,399,433, filed on Oct. 23, 2003, and the entire contents of which are incorporated herein by reference.

[0002] This document describes aliphatic polymers (e.g., polyethylene glycol) that are directly or indirectly Glucagon-like peptide (GL) bound to P), e.g., glucagon-like peptide 1 (GLP-1) polypeptide or an analog thereof ( For example, conjugates of GLP-1 analogs, The analogue of can be released from the conjugate in vivo. These are referred to herein as "releasable GLP-1 conjugates." Methods and materials for making and using such releasable GLP-1 conjugates are provided. Further includes: [Background technology]

[0003] The World Health Organization reports that 200 million adults had diabetes, compared with 108 million in 1980. In 2014, the number was estimated at over 400 million (1). 90% of these people had type 2 diabetes. This is not only related to population growth, but also to the fact that the age-standardized diabetes population It has increased from 4.7% to 8.5% of adults. Most of this is in developing countries, including China and India. It is associated with rising wealth in emerging countries and is linked to weight gain and other medical problems such as cardiovascular disease. This is due to a diet that leads to diabetes (e.g., consumption of sugary drinks) Cardiovascular complications are the leading cause of morbidity and mortality in this population (2). New treatments for diabetes are needed to combat the disease and its complications.

[0004] In general, diabetes and insulin treatment can be associated with weight gain, but glucagon-like peptide GLP-1 receptor (GLP-1R) agonists are often associated with weight loss. This has led to the use of GLP-1R agonists for the treatment of weight gain as well as the treatment of diabetes. There has been growing interest in using at least one GLP-1R agonist (liraglutide) ) are approved for the treatment of both type 2 diabetes and obesity. In 2016, one in 10 people (more than 2 billion) could be considered obese or severely overweight (7). In 2019, more than 340 million children and adolescents (ages 5-19) will be overweight or obese. Obesity can often be treated with dietary modification, but there are some acute The condition can rapidly progress to diabetes and serious illness and is not benefiting from medically assisted treatment. You can benefit.

[0005] The pharmacokinetic properties of proteins can be improved by the incorporation of certain polymers, e.g., polyethylene glycol (P EG) (Fee and Van Alstine,Chemical Engineering Science,61 :924-934(2006). Several approaches to PEGylation of biologically active molecules have been proposed. However, in some cases, PEG (a hydrophilic polymer) The presence of ) significantly blocks the surface area of ​​the conjugate, reducing its solubility and other constraints. (Fee and Van Alstine, Biol. Conjugate Chemistry, 2004(15), 1304-1313). This could have adverse effects and any increase in circulating lifetime resulting from PEGylation, non-specific protein This may offset the reduced lipid degradation or other enhanced properties. One example of LP-1 is Lee et al., Bioconjugate Che m., 2006(16), 377-382. In this example, the authors via the reactive amino group at the amino terminus of the polypeptide (natural proteolysis occurs, and such PEG inhibition of such proteolysis is beneficial) and PEGylation via various lysine residues G2000 can be covalently attached to GLP-1. PEG-lysine modified GLP-1 The conjugate had insulinotropic activity similar to that of native GLP-1, but the PEG- Amino-terminal modified GLP-1 conjugates showed reduced potency. Methods for designing, preparing, and using such conjugates are provided herein. . Summary of the Invention

[0006] Indirectly (e.g., linked to an aliphatic polymer (e.g., polyethylene glycol, PEG) Glucagon-like peptide (glucagon-like peptide) bound to the tide, GLP), e.g., glucagon-like peptide 1 (GLP-1) polypeptide or Conjugates of analogs thereof (e.g., GLP-1 analogs) are provided herein, The GLP polypeptide or analogue thereof may be released from the conjugate in vivo. In some embodiments, the GLP polypeptide or analog thereof is a GLP-1 polypeptide. Such conjugates are referred to herein as "releasable This document describes such releasable GLP-1 conjugates. The present invention further includes methods and materials for making and using the ducts.

[0007] The releasable conjugates provided herein are 3' phosphoconjugates of ribonucleosides. The ester group is unstable in the presence of a free proximal 2' hydroxyl moiety and the 3' phosphotriester group is unstable in the presence of a free proximal 2' hydroxyl moiety. Based on the discovery that the 2' hydroxyl moiety of the ester group can be decomposed after intramolecular nucleophilic attack, The subsequent decomposition reaction is controlled by the attacking nucleophile and the phosphorus atom, This configuration is the most reactive species, and the analogous arabino geometry is virtually unreactive. The conjugates provided herein are conjugates that are or analogs thereof, with little to no trace of pre-existing linkers and polymer systems Little or no GLP-1 polysaccharide synthesis from PEG or similar hydrophilic polymer-containing conjugates. One such example is shown in Scheme 1. 1 as shown below. Scheme 1 [ka]

[0008] In this example, cleavage of the trigger moiety, E, affords a cyclic phosphotriester, a quinone, Formation of a methide, carbon dioxide (CO2), and a GLP-1 polypeptide or analog thereof This results in nucleophilic attack of the free hydroxyl on the phosphorus atom leading to At physiological pH, the phosphodiester is further hydrolyzed to the open 5-membered ring and both isomeric phosphodiesters. Quinone methides can also undergo further hydrolysis (e.g., ester formation) at physiological pH. For example, it can react with water to form 4-(hydroxymethyl)-phenol.

[0009] Such systems have several advantages over alternative conjugates for drug release. For example, the system can be modified so that cleavage can be performed in the manner exemplified above. For example, E is an enzyme-labile group, an acid-labile functional group, or a pH-labile functional group (e.g., salt Additionally, the E group may contain a polymer (e.g., polyethylene glycol). Because the β-E is not directly linked to the β-E molecule, each E can be significantly altered for every conjugate. The need for a base form (underivatized) of any E moiety is obviated and the covalent structure described herein is used. In addition, the use of unsubstituted trigger groups can be used to reduce the amount of free Possibilities for better control of the degradation and release kinetics of prodrugs of biologically active molecules Finally, the releasable conjugates provided herein are substantially synthetic and For example, referring to Scheme 1 above, the 3' hydroxyl of the linker moiety can be In addition to the introduction of phosphotriesters, selective introduction of E moieties to the 2' hydroxyl In fact, the opposite configuration behaves similarly and both regioisomers may be used alone or in combination. or in combination are suitable and useful as releasable conjugates.

[0010] Compounds of formula (I) [ka] or a pharma- ceutically acceptable salt thereof, The aliphatic portion is a polymer, R P , and Polymer-L-(CH2) m - and polymer-L-(CH2-CH2-O) p -( CH2) m -, R P But, with any substitution C 1-6 Alkyl, optionally substituted C 1-3 Alkyl-O- (CH2-CH2-O) p -(CH2) m - and optionally substituted C 3-7 Cycloa Selected from Rukyr, L is a linking group; m and p are each independently an integer from 1 to 10; D comprises a residue of a GLP-1 polypeptide or an analog thereof; Z 1 is O, S, and N(R N ), Z 3 is O and N(R N ) or Z 3 does not exist, A is O or N, and when A is O, R 3 does not exist, R N is H and optionally substituted C 1-6 alkyl, R 3 But H and C 1-6 alkyl; or R 3 and R1 But A and R 1 together with the carbon atom to which it is attached, Forming a 4- to 7-membered aliphatic heterocyclic ring, or R 3 and R 2 But, A, R 1 The carbon atom to which is bonded, and R 2 Carbon atom to which together with the alkyl group to form an optionally substituted 4- to 8-membered aliphatic heterocyclic ring, M A is a self-immolative group having any one of the formulae (a) to (i), [ka] In the formula, x is Z 1 indicates the point of attachment to Z 3 indicates the point of attachment to R 1 and R 2 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 The group consisting of aryl and optionally substituted 5- to 14-membered heteroaryl Selected from or Or, R 1 and R 2 are bonded together with the carbon atom to which they are attached, and optionally Replaced C 3-7 cycloalkyl ring, optionally substituted 4- to 7-membered aliphatic heterocyclic ring, Optionally substituted C 6-10 Aryl or optionally substituted 5-14 membered heteroaryl Form a pool or Or, R 1 and R 2 are linked together to form a ribose ring system, R 7 and R 8 but independently, H and C 1-6 alkyl, Provided herein are compounds or pharma- ceutically acceptable salts thereof, wherein E is a cleavable moiety. It will be offered.

[0011] Also, the compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, The aliphatic portion is a polymer, R P , and Polymer-L-(CH2) m - and polymer-L-(CH2-CH2-O) p -( CH2) m -, R P But, with any substitution C 1-6 Alkyl, optionally substituted C 1-3 Alkyl-O- (CH2-CH2-O) p -(CH2) m - and optionally substituted C 3-7 Cycloa Selected from Rukyr, L is a linking group; m and p are each independently an integer from 1 to 10; D comprises a residue of a biologically active drug; Z 1 is O, S, and N(R N ), Z 3 is O and N(R N ) or Z 3 does not exist, Z 4 is selected from O and S; A is O and N(R N ), R N is H and optionally substituted C 1-4 alkyl, M A is a diradical selected from i. A self-immolative group having any one of the formulae (a) to (i): [ka] And ii. A stable diradical selected from any one of formulas (j) to (l): [ka] In the formula, x is Z 1 indicates the point of attachment to Z 3 indicates the point of attachment to R 1 and R 2 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 The group consisting of aryl and optionally substituted 5- to 14-membered heteroaryl Selected from or Or, R 1 and R 2 are bonded together with the carbon atom to which they are attached, and optionally Replaced C 3-7 cycloalkyl ring, optionally substituted 4- to 7-membered aliphatic heterocyclic ring, Optionally substituted C 6-10 Aryl or optionally substituted 5-14 membered heteroaryl Form a pool or Or, R 1 and R 2 are linked together to form a ribose ring system, R 7 and R 8 are independently H, C 1-6 Alkyl, amino, (C 1-6 Alkyl)a Minho, Ji-(C 1-6 (alkyl)amino, acylamino, and protected amino groups. R, Also provided herein are compounds, or pharma- ceutically acceptable salts thereof, wherein E is a cleavable moiety. It will be offered.

[0012] A compound of formula (I) or formula (II), or a pharma- ceutically acceptable salt thereof, Further provided herein is a pharmaceutical composition comprising an acceptable carrier.

[0013] The present disclosure also provides a method of treating a disease or condition in a subject in need of treatment. The method includes administering to the subject a therapeutically effective amount of a compound of formula (I) or formula (II), or a pharmaceutical formulation thereof. The method includes administering a therapeutically acceptable salt thereof, or a pharmaceutical composition as described herein. In some embodiments, the disease or condition is selected from diabetes and obesity.

[0014] The present disclosure also provides a compound of the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein an aliphatic moiety, R 1 , R 2 , A, E, and D are described herein.

[0015] Unless otherwise defined, all technical and scientific terms used herein are defined by the It has the same meaning as commonly understood by one of ordinary skill in the art to which the application pertains. are described herein for use in this application and are known in the art. The materials, methods, and examples are provided by way of example only. All publications mentioned herein are illustrative and not intended to be limiting. All materials, patent applications, patents, sequences, database entries, and other references are incorporated by reference. In the event of a conflict, the present specification, including definitions, will control. It shall be so.

[0016] Other features and advantages of the present application will become apparent from the following detailed description and drawings, as well as the claims. It will become clear from [Brief description of the drawings]

[0017] [Figure 1] 1 is a table showing the observed isoforms of liraglutide after digestion with the proteolytic enzyme dipeptidyl peptidase IV DPP-IV. [Diagram 2] 1 shows the spectra of 2.67 μM liraglutide and compound 7 after digestion with 50 mU / mL DPP-IV in 10 mM Na2HPO4 pH 7.6 at 37° C. for 15 hours. [Diagram 3] 1 shows exemplary data of extracted ion chromatogram (EIC) traces of full size liraglutide and liraglutide fragments in a sample liraglutide after digestion with DPP-IV for 96 hours at 37° C. and pH 7.4. [Figure 4] 1 is a line graph of the concentration of liraglutide in arbitrary units for liraglutide and compound 7 after digestion with 50 mU / mL DPP-IV in 10 mM Na2HPO4 pH 7.4 at 37° C. [Diagram 5] 1 is a line graph of the concentration of liraglutide fragments shown in arbitrary units for liraglutide after digestion with 50 mU / mL DPP-IV in 10 mM Na2HPO4 pH 7.4 at 37° C. [Figure 6] 1 is a line graph of the concentration of liraglutide fragments in arbitrary units for compound 7 after digestion with 50 mU / mL DPP-IV in 10 mM Na2HPO4 pH 7.4 at 37° C. [Figure 7] 1 is a line graph of the concentration of the sum of all observed liraglutide fragments in arbitrary units for liraglutide and compound 7 after digestion with 50 mU / mL DPP-IV in 10 mM Na2HPO4 pH 7.4 at 37° C. [Figure 8]Non-limiting examples of GLP-1 analogs are provided. [Figure 9] 1 is a graph plotting the amount of liraglutide biological activity detected for the indicated amounts of liraglutide (SEQ ID NO:3) and compound 7. [Figure 10] 1 is a graph plotting the amount of liraglutide biological activity released from Compound 7 upon incubation in rat plasma for the indicated times. [Figure 11] Contains a graph plotting the amount of liraglutide (ng / mL) detected in pooled samples collected at the indicated times from rats administered liraglutide (SEQ ID NO:3, Group 1) or Compound 7 (Group 2). [Figure 12] FIG. 1 contains a graph plotting the amount of active liraglutide (nmol / L) detected in samples collected at the indicated times from rats administered liraglutide (SEQ ID NO:3, Group 1) or Compound 7 (Group 2). The half-life of each is provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] definition "C n-m The term "alkyl" refers to a straight chain alkyl group (e.g., methyl, ethyl, pyryl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.) and Contains branched chain alkyl groups (e.g., isopropyl, tert-butyl, isobutyl, etc.) In certain embodiments, a straight or branched chain alkyl has 12 or fewer carbon atoms in its backbone. (For example, in a linear chain, C 1-12 ;C for branched chains 3-12 ). For example, C 1-1 The term 2 includes alkyl groups containing 1 to 12 carbon atoms.

[0019] As used herein, "C n-m The term "alkylene" may be used alone or in combination with other Used in combination with the term aryl, arylalkyl, or arylalkyl, to refer to a divalent alkyl linking group having n to m carbon atoms. Examples of alkylene groups include ethane-1,1-diyl, ethane-1,2-diyl, and propane-1,1-diyl. -1,1,-diyl, propane-1,3-diyl, propane-1,2-diyl, butane- 1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methyl-propane Pan-1,3-diyl and the like. In the above, the alkylene portion is 2-6, 2-4, 2-3, 1-6, 1-4, or 1-2. Contains carbon atoms.

[0020] As used herein, "C n-m "Alkenyl" means a group consisting of one or more double carbon-carbon bonds. The alkyl group has n to m carbon atoms. Examples of the alkenyl group include ethene. n-propenyl, isopropenyl, n-butenyl, sec-butenyl, etc. In some embodiments, the alkenyl moiety has 2 to 6 alkyl groups, but is not limited to these. Contains 2 to 4 or 2 to 3 carbon atoms. n-m The term "alkenylene" , refers to a divalent alkenyl linking group.

[0021] As used herein, "C n-m The term "alkoxy" may be used alone or in combination with other and refers to a group of formula -O-alkyl, where the alkyl group has n to m alkyl groups. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g. , n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and te rt-butoxy). In some embodiments, , the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0022] As used herein, "C n-m The term "alkylamino" refers to a group of the formula -NH(a) In some embodiments, the alkyl group has n to m carbon atoms. In the alkyl group, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of the amino group include N-methylamino, N-ethylamino, and N-propylamino ( For example, N-(n-propyl)amino and N-isopropylamino), N-butylamino N-(n-butyl)amino and N-(tert-butyl)amino, for example. These include, but are not limited to:

[0023] As used herein, "di(C n-m The term "amino" refers to a group of the formula N(alkyl)2, wherein each of the two alkyl groups independently represents n to m In some embodiments, each alkyl group independently has 1 to 6, 1 having up to 4, or 1 to 3 carbon atoms.

[0024] As used herein, the term "thio" refers to a group of the formula SH.

[0025] As used herein, the term "amino" refers to a group of formula -NH2.

[0026] As used herein, the term "carboxy" or "carboxyl" refers to - Refers to the C(O)OH group.

[0027] As used herein, "halo" or "halogen" refers to F, Cl, Br, or In some embodiments, halo is F, Cl, or Br. In embodiments, halo is F or Cl.

[0028] The term "n-membered", where n is an integer, typically refers to a ring formation. Describes the number of ring-forming atoms in a moiety where the number of atoms is n. For example, piperidinyl is is an example of a 6-membered heterocycloalkyl ring, and pyrazolyl is an example of a 5-membered heteroaryl ring. Pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydropyridyl is an example of a 6-membered heteroaryl ring. Rho-naphthalene is an example of a 10-membered cycloalkyl group.

[0029] As used herein, "cycloalkyl" refers to a cyclized alkyl and / or aryl group. Cycloalkyl groups refer to non-aromatic cyclic hydrocarbons, including aryl groups. Cycloalkyl groups can be monocyclic or polycyclic (e.g., For example, fused rings can include groups having 2, 3, or 4 fused rings, as well as spiro rings. The ring carbon atoms of a chloroalkyl group may be oxo or sulfido (e.g., C(O) or The definition of cycloalkyl includes non-aromatic One or more aromatic rings fused to (i.e., having a bond in common with) a cyclic hydrocarbon Moieties having, for example, benzo or thienyl derivatives such as cyclopentane, cyclohexane, etc. Cycloalkyl groups containing fused aromatic rings are also contemplated as long as the ring-forming atoms of the fused aromatic rings are not substituted. The cycloalkyl group may be bonded through any ring-forming atom, including 3, 4, 5, 6, 7 The ring may have 1, 8, 9, 10, 11, or 12 ring-forming atoms. In embodiments, the cycloalkyl is a 3-12 membered monocyclic or bicyclic cycloalkyl. In some embodiments, cycloalkyl is C3-7 It is a monocyclic cycloalkyl. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclopropyl. Cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadiene norbornyl, cycloheptatrienyl, norbornyl, norpinyl, nor Norcarnyl, cyclooctyl, cyclooctenyl, etc. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cycloalkyl, cyclopropyl, cyclobutyl, cycloalkyl, cyclopropyl, cyclobutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopropyl ... pentyl, cyclohexyl, cyclooctyl, or cyclooctenyl. In this embodiment, cycloalkyl is a cyclooctyl fused to one or two benzene rings. In some embodiments, the cycloalkyl is a 3-8 membered or 3-7 membered ring. Monocyclic cycloalkyl groups, such as C 3-8 or C 3-7 cycloalkyl). In some embodiments, the cycloalkyl is an 8-12 membered bicyclic cycloalkyl. In some embodiments, cycloalkyl is an 8-16 membered bicyclic or tricyclic cycloalkyl. Alkyl (e.g., C 8-16 cycloalkyl).

[0030] As used herein, "heteroaryl" refers to an alkyl group selected from sulfur, oxygen, and nitrogen. refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member In some embodiments, the heteroaryl ring is independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroatom ring has 1, 2, 3, or 4 selected heteroatom ring members. Any ring-forming N in the heteroaryl moiety may be an N-oxide. In the form, heteroaryl is 1, 2, or 3 independently selected from nitrogen, sulfur, and oxygen. 5-10 membered monocyclic or bicyclic heteroaryls having 3 or 4 heteroatom ring members In some embodiments, heteroaryl is independently selected from nitrogen, sulfur, and oxygen. 5-6 membered monocyclic heteroaryl rings having 1 or 2 heteroatom ring members selected from the group In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl. A 5-membered heteroaryl ring is a heteroaryl having a ring with 5 ring atoms. wherein one or more (e.g., 1, 2, or 3) ring atoms are selected from the group consisting of N, O, and S. Exemplary 5-membered heteroaryls are thienyl, furyl, pyrrolyl, isopropyl, phenyl ... Midazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl , 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3 -Oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2 ,4-Oxadiazolyl, 1,3,4-Triazolyl, 1,3,4-Thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroaryl ring has six ring atoms. Heteroaryl having one or more (e.g., 1, 2, or 3) rings The atoms are independently selected from N, O, and S. Exemplary 6-membered heteroaryls are Lysyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl. The term "loarylene" refers to a divalent heteroaryl linking group.

[0031] The term "aromatic" refers to a compound having aromatic character (i.e., a (4n+2) delocalized π( pi) electrons, n being an integer) a carbocyclic or heterocyclic ring having one or more polyunsaturated rings Point to the ring.

[0032] The term "aliphatic" refers to a group of carbon atoms and heteroatoms that form open chains and have aromatic character. Aliphatic compounds are organic compounds (including polymers) that do not contain polyunsaturated rings. It may be linear or cyclic, saturated or unsaturated, straight chain or branched.

[0033] As used herein, the term "polymer" refers to a polymer that is a mixture of multiple repeating subunits. It refers to a macromolecule that contains

[0034] The term "aryl", used alone or in combination with other terms, means a monocyclic or or polycyclic (e.g., having 2, 3, or 4 fused rings). Refers to the group "C n-m The term "aryl" refers to an aryl having n to m ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, anthracenyl, phenanthryl, In some embodiments, the aryl group is an aryl group. has 6 to about 20 carbon atoms, 6 to about 15 carbon atoms, or 6 to about 10 carbon atoms. In some embodiments, the aryl group is phenyl. The term refers to a divalent aryl linking group.

[0035] As used herein, a "heterocycloalkyl" or an "aliphatic heterocycle" refers to an alkyl, aryl, or heterocyclic ring. A non-aromatic monocyclic or refers to a polycyclic heterocycle. Heterocycloalkyl groups are also included in spiro groups. Examples of heterocycloalkyl groups include pyrrolidin-2-one, 1,3- Isoxazolidin-2-one, pyranyl, tetrahydrofuran, oxetanyl, azetidine morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrofuranyl Rothenyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, Pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, The ring carbon atoms and heteroatoms of the heterocycloalkyl group are The molecule may be an oxo or sulfide group (e.g., C(O), S(O), C(S), or S( A heterocycloalkyl group may be optionally substituted with, for example, O. In some embodiments, the heterocycloalkyl group may be bonded through a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. The heterocycloalkyl group contains 0 to 2 double bonds. The definition of heterocycloalkyl includes non-aromatic heterocyclic rings. Has one or more aromatic rings fused to (i.e., have a bond in common with) the aromatic ring Moieties such as benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. Heterocycloalkyl groups containing fused aromatic rings include those in which the ring-forming atoms of the fused aromatic rings are not fused. In some embodiments, the heterocycle may be bonded through any ring-forming atom, including the ring atom. The alkyl group is selected from one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur. and a monocyclic 4- to 6-membered heterocycloalkyl having one or more oxidized ring members. In some embodiments, heterocycloalkyl is selected from the group consisting of nitrogen, oxygen, and sulfur. having 1, 2, 3, or 4 independently selected heteroatoms and one or more oxidized It is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having several ring members. In embodiments, heterocycloalkyl is an 8- to 12-membered heterocycloalkyl, such as In some embodiments, the heterocycloalkyl is a bicyclic heterocycloalkyl. is an 8- to 16-membered heterocycloalkyl (e.g., a bicyclic or tricyclic heterocycloalkyl). In some embodiments, the 8-12 membered bicyclic heterocycloalkyl is 8-12 membered fused heterocycloalkylaryl group or 8-12 membered fused heterocyclo In some embodiments, the heterocycloalkyl is In some embodiments, the bicyclic heterocycloalkyl is a 9-12 membered heterocycloalkyl. The bicyclic heterocycloalkyl is a 9- to 10-membered fused heterocycloalkylaryl group or or a 9- to 10-membered fused heterocycloalkylheteroaryl group. The term "alkylene" refers to a divalent heterocycloalkyl linking group.

[0036] As used herein, the terms "individual" or "patient," which are used interchangeably, , mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, It refers to any animal, including a goat, sheep, horse, or primate, most preferably a human.

[0037] As used herein, the phrase "therapeutically effective amount" refers to the amount that a researcher, veterinarian, physician, or is a biological test performed in a tissue, system, animal, individual, or human that is required by other clinicians. The term "potassium phosphate" refers to the amount of an active compound or pharmaceutical agent that elicits a therapeutic or medical response.

[0038] As used herein, the term "treat" or "treatment" refers to 1) preventing or inhibiting a disease. Stop: For example, to stop or to stop experiencing the symptoms or symptomology of a disease, condition, or disorder. Preventing a disease, condition, or disorder in an individual exhibiting the disease (i.e., pathology and / or or halt further development of symptomatic symptoms; and / or 2) cause disease remission. For example, experiencing or exhibiting the symptoms or symptomology of a disease, condition, or disorder. ameliorate a disease, condition, disorder, or symptom in an individual reversal of symptoms and / or

[0039] "Protecting group" and "protective group" The term "ve group" refers to the use of one or more subsequent In order to reduce decomposition in the chemical reaction of Suitable protecting groups are well known in the art (e.g., Greene and Wuts,Protective Groups in Organic Synth esis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein by reference in its entirety.

[0040] As used herein, the term "leaving group" refers to a group that, in a chemical reaction, loses bond electrons along with the It refers to a molecule or molecular fragment (e.g., anion) that is displaced as a stable species when released from a surface. Examples of groups include arylsulfonyloxy groups or alkylsulfonyloxy groups, e.g. Examples of anionic leaving groups include mesylate or tosylate groups. Common anionic leaving groups include: Also included are halides such as Cl-, Br-, and I-.

[0041] As used herein, the term "ribose ring system" refers to, for example, the general structure Optionally substituted ribofuranose, arabinofuranose, xylofuranose, or or lyxofuranose ring system. [ka]

[0042] In some embodiments, the ribose ring system is an optionally substituted ribose having the structure: Contains some nucleosides. [ka]

[0043] In another embodiment, the ribose ring system is an optionally substituted lyxonucleases having the structure: Contains some leiosides. [ka]

[0044] In some embodiments, the ribose ring system is an optionally substituted arabinose having the structure: Contains some binonucleosides. [ka]

[0045] In some embodiments, the ribose ring system is an optionally substituted hydroxyl group having the structure: Contains some mononucleosides. [ka]

[0046] In some embodiments, ribonucleosides, arabinonucleosides, xylonucleosides The nucleoside or lyxonucleoside nucleobase is covalently linked to the ribose / lyxose ring at the 1' position. The linked adenine, cytosine, guanine, thymine, or uracil.

[0047] As used herein, the term "self-immolative" refers to the ability of a compound or conjugate to Provides a stable bond formation between two groups, but is unstable upon activation (e.g., nucleophilic attack) , refers to a moiety or residue that leads to rapid cleavage of the moiety or residue and separation of the two groups The chemistry of self-immolative groups is described, for example, in Alouane, A. et al., “Self-immolative groups” olative spacers:kinetic aspects,structure e-property relationships,and applications s”,Angew.Chem.Int.Ed.,2015,54,7492-7509, and Kolakowski, RV et al., “The methylene alkoxy carbamate self-immolative unit:Ut ilization of the targeted delivery of al cohol-containing payloads with antibody- drug conjugates”,Angew.Chem.Int.Ed.,2016 ,55,7948-7951.

[0048] As used herein, the term "optionally substituted" refers to a group of atoms, typically One or more hydrogens on a carbon, oxygen, or nitrogen atom are replaced by a specified substituent. groups (e.g., alkyl groups, cycloalkyl groups, alkylene groups, aryl groups, heteroaryl groups, However, the standard valence of the specified atom must not be exceeded. provided that a stable compound is obtained. When the substituent is C1, C2, or C3, two hydrogens on the atom are replaced. -6 Alkyl, C 1-4 Haloalkyl, C 3-7 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 4-7 membered heterocycloalkyl, substituted 5-14 membered heteroaryl, halo, CN, NO2, OR a , S.R. a , C(O)R a , C( O)NR a R a , C(O)OR a , O.C.(O)R a , O-C(O)NR a R a , N3, NH R a , N.R. a R a , N.R. a C(O)R a , N.R. a C(O)OR a , N.R. a C(O)NR a R a , N.R. a S(O)2R a , S(O)2R a , and S(O)NR a R a Independent from where each R a , H, C 1-6 Alkyl, C 3-7 Cycloalkane Lu, C 6-10Aryl, 4-7 membered heterocycloalkyl, substituted 5-14 membered heterocycloalkyl Aryl, C 1-4 Haloalkyl, C 2-6 Alkenyl, and C 2-6 From alkynyl are independently selected.

[0049] In some embodiments, one or more of the optional substituents is C 1-6 Alkyl, C 1-4 Ha The alkyl group is selected from the group consisting of aryl, arylalkyl, OH, NO2, CN, and acetyl.

[0050] In some embodiments, the optional substituent is SH.

[0051] In some embodiments, the optional substituent is azide (N3).

[0052] In some embodiments, the optional substituent is a group of the formula: [ka]

[0053] In some embodiments, the optional substituent is a maleimide of the formula: [ka]

[0054] In some embodiments, the optional substituent is a cyclooctyne, e.g., a dibenzo Cyclooctyne (DBCO), difluorobenzocyclooctyne (DIFBO), bialiphatic azacyclooctynone (BARAC), dibenzocyclooctyne (DIBO), Fluorinated cyclooctyne (DIFO), monofluorinated cyclooctyne (MOFO), dimethoxane Diazacyclooctyne (DIMAC), or aryl-less octyl cutin (ALO), each of which may be one, two, three, four, or five of the cutins described herein. It is optionally substituted with any of the substituents provided herein.

[0055] In some embodiments, the optional substituents are cyclooctyl groups selected from the group consisting of: It's Chin. [ka]

[0056] As used herein, the term "about" is intended to account for variations due to experimental error. As used herein, the singular forms "a" and "an" refer to and "the" includes plural referents unless the context clearly dictates otherwise.

[0057] compound Compounds of formula (I) In one general aspect, the application relates to a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: The aliphatic portion is a polymer, R P , and Polymer-L-(CH2) m - and polymer-L-(CH2-CH2-O) p -( CH2) m -, R P But, with any substitution C 1-6 Alkyl, optionally substituted C 1-3 Alkyl-O- (CH2-CH2-O) p -(CH2) m - and optionally substituted C 3-7 Cycloa Selected from Rukyr, L is a linking group; m and p are each independently an integer from 1 to 10; D comprises a residue of a GLP-1 polypeptide or an analog thereof; Z 1 is O, S, and N(R N ), Z 3 is O and N(R N ) or Z 3 does not exist, A is O or N, and when A is O, R 3 does not exist, R N is H and optionally substituted C 1-6 alkyl, R 3 But H and C 1-6 alkyl; or R 3 and R 1 But A and R 1 together with the carbon atom to which it is attached, can be optionally substituted Forming a 4- to 7-membered aliphatic heterocyclic ring, or R 3 and R 2 But, A, R 1 The carbon atom to which is bonded, and R 2 Carbon to which together with the atoms form an optionally substituted 4- to 8-membered aliphatic heterocyclic ring, M A is a self-immolative group having any one of the formulae (a) to (i), [ka] In the formula, x is Z 1 indicates the point of attachment to Z 3 indicates the point of attachment to R 1 and R 2 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10aryl, and optionally substituted 5- to 14-membered heteroaryl or selected from the group Or, R 1 and R 2 are bonded together with the carbon atom to which they are attached to any Replaced by C 3-7 Cycloalkyl rings, optionally substituted 4- to 7-membered aliphatic heterocyclic rings , optionally substituted C 6-10 Aryl or optionally substituted 5-14 membered heteroaryl Form a reel or Or, R 1 and R 2 are linked together to form a ribose ring system, R 7 and R 8 but independently, H and C 1-6 alkyl, E is a cleavable moiety.

[0058] In some embodiments of Formula (I), R P , L, m, p, D, Z 1 , Z 3 , A, R N , M A , R 1 , R 2 , R 7 , R 8 and E are as described herein for compounds of formula (I). As stated above, R 3 H and C 1-6 alkyl; or R 3 and R 1 But A and R 1 together with the carbon atom to which it is attached, can be optionally substituted Forming a 4- to 7-membered aliphatic heterocyclic ring, or R 3 and R 2 But, A, R 1 The carbon atom to which is bonded, and R 2 Carbon to which Together with the atoms, form an optionally substituted 4- to 8-membered aliphatic heterocyclic ring.

[0059] In some embodiments of Formula (I), A is N. In other embodiments, A is O. be.

[0060] In some embodiments of Formula (I), A is NR 3 It is.

[0061] In some embodiments of Formula (I), A is NR 3 If R 3 and R 1 A and R 1 together with the carbon atom to which it is attached form an optionally substituted 4- to 7-membered aliphatic In some aspects of these embodiments, the 4- to 7-membered aliphatic heterocyclic ring is The cyclic ring is selected from the group consisting of: [ka] where x indicates the point of attachment to E and y indicates R 1 indicates the point of attachment to the carbon atom to which it is attached .

[0062] In some embodiments of Formula (I), A is NR 3 If R 3 and R 2 A, R 1 The carbon atom to which is bonded, and R 2 Together with the carbon atom to which it is attached, any It forms a 4- to 8-membered aliphatic heterocyclic ring substituted with

[0063] In some embodiments, the compound of formula (I) has any one of the following formulae: Or maybe [ka] JPEG2025023928000020.jpg190166 or a pharma- ceutically acceptable salt thereof.

[0064] In some embodiments, the compound of formula (I) can be a compound of formula (II) as described herein. It is one of the compounds.

[0065] Compound of formula (II) In one general aspect, the application relates to a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein: The aliphatic portion is a polymer, R P , and Polymer-L-(CH2) m - and polymer-L-(CH2-CH2-O) p -(CH 2) m -, R P But, with any substitution C 1-6 Alkyl, optionally substituted C 1-3 Alkyl-O -(CH2-CH2-O) p -(CH2) m - and optionally substituted C 3-7 Cyclo alkyl, L is a linking group; m and p are each independently an integer from 1 to 10; D comprises a residue of a GLP-1 polypeptide or an analog thereof; Z 1 is O, S, and N(R N ), Z 3 is O and N(R N ) or Z 3 does not exist, Z 4 is selected from O and S; A is O and N(R N ), R N is H and optionally substituted C 1-4 alkyl, M A is a diradical selected from a) a self-immolative group having any one of the formulae (a) to (i): [ka] In the formula, x is Z 1 indicates the point of attachment to Z 3 indicates the point of attachment to, and b) A stable diradical selected from any one of formulas (j) to (l): [ka] In the formula, x is Z 1 indicates the point of attachment to Z 3 indicates the point of attachment to R 1 and R 2 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 aryl, and optionally substituted 5- to 14-membered heteroaryl or selected from the group Or, R 1 and R 2 are bonded together with the carbon atom to which they are attached to any Replaced by C 3-7 Cycloalkyl rings, optionally substituted 4- to 7-membered aliphatic heterocyclic rings , optionally substituted C 6-10 Aryl or optionally substituted 5-14 membered heteroaryl Form a reel or Or, R 1 and R 2 are linked together to form a ribose ring system, R 7 and R8 are independently H, C 1-6 Alkyl, amino, (C 1-6 Alkyl) Amino, di-(C 1-6 Selected from alkylamino, acylamino, and protected amino groups And, E is a cleavable moiety.

[0066] In some embodiments of Formula (I) or Formula (II), the aliphatic moiety is a polymer, R P and the formula polymer-L-(CH2) m - is selected from the group P is arbitrarily replaced C 1-6 Alkyl and optionally substituted C 3-7 cycloalkyl; m is selected from An integer between 1 and 10.

[0067] In some embodiments of Formula (I) or Formula (II), D is a G LP-1 polypeptide or an analog thereof (e.g., D comprises a residue of liraglutide. In some embodiments of Formula (I) or Formula (II), and D is any of the GLP-1 polypeptides or analogs thereof described herein. or one residue (e.g., D is the residue of liraglutide).

[0068] In some embodiments of Formula (I) or Formula (II), the aliphatic moiety has the formula: polymer- L-(CH2) m In some aspects of these embodiments, L is a hetero L is a linking group containing cycloalkylene or heteroarylene. For example, L is succinyl. In some embodiments, L is a linking group comprising an amido or triazole. is any one of the linking groups [ka] During the ceremony, [ka] indicates the point of attachment of the linking group to the polymer or CH2 group.

[0069] In some embodiments, the linking group L is a linking group of the formula: [ka] During the ceremony, [ka] indicates the point of attachment of the linking group to the polymer or CH2 group.

[0070] In some embodiments, L is of the formula (L 1 ) group, [ka] wherein ring C is an optionally substituted C 8-16 Cycloalkyl and optionally substituted 8- 16-membered heterocycloalkyl; [ka] indicates the point of attachment of the linking group to the polymer or to the CH2 group. In one embodiment, 8-16 Cycloalkyl is optionally fused to one or two benzene rings. In another aspect of these embodiments, C 8-16 Cycloalkane The halogens, OH, C 1-3 Alkyl, and C 1-3 1 selected from alkoxy Cyclooctenyl is optionally substituted with one, two, or three substituents. Chlooctenyl is a substituted or unsubstituted aryl group having one or two fluoro or one or two methoxy groups. may be substituted with

[0071] In some embodiments, the formula (L 1 ) group is selected from one of the following formulas will be done. [ka]

[0072] In some embodiments, the formula (L 1 ) is a group [ka]

[0073] In some embodiments, the formula (L 1 ) is a group [ka]

[0074] In some embodiments, the formula (L 1 ) is a group [ka] It is.

[0075] In some embodiments, the formula (L 1 ) is a group [ka] It is.

[0076] In some embodiments, the formula (L 1 ) is a group [ka] It is.

[0077] In some embodiments, the formula (L 1 ) is a group [ka] It is.

[0078] In some embodiments, m is an integer from 1 to 6. For example, m is 1, 2, 3, 4, , 5, or 6. In some embodiments, m is an integer from 1 to 4.

[0079] In some embodiments, the aliphatic moiety is any one of the following formulas: [ka]

[0080] In some embodiments, the aliphatic moiety is any one of the following formulas: [ka]

[0081] In some embodiments of Formula (I) or Formula (II), the aliphatic moiety is a polymer (e.g., For example, any one of the polymers described herein. The aliphatic portion of the polymer is , poly(alkylene glycol), poly(oxyethylated polyol), poly(olefin) poly(α-hydroxy acid), poly(vinyl alcohol), polyoxazo In some embodiments, the aliphatic moiety may be selected from the group consisting of aryl, arylphosphoric acid ... The polymer of the aliphatic portion is polyethylene glycol. For example, the aliphatic portion is a linear polyethylene The copolymer includes branched polyethylene glycol or branched polyethylene glycol.

[0082] In some embodiments of Formula (I) or Formula (II), the aliphatic moiety is R P It is. In some embodiments, R P is an arbitrarily substituted C 1-6 Alkyl or optionally substituted C 3-7 Cycloalkyl. For example, R P is C 1-6 Alkyl, C 1-6 Shea Noalkyl, and C 3-7 cycloalkyl. The aliphatic moiety is selected from R P If In this case, the aliphatic portion is C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl) butyl, n-butyl, isobutyl, tert-butyl, amyl, or hexyl) For example, the aliphatic moiety can be cyanoethyl. In some embodiments, the aliphatic moiety is In other embodiments, the aliphatic moiety can be 2-cyanoethyl. 3-7 Cyclo Alkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) In some embodiments, R P is isopropyl. In terms of form, R P is cyanoethyl.

[0083] In some embodiments, R P is selected from any one of the groups of the following formulae: . [ka]

[0084] In some embodiments, R P is selected from any one of the groups of the following formulae: . [ka]

[0085] In some embodiments, R P is the substituted C of the following formula: 1-6 is alkyl, [ka] In the formula, p is an integer from 1 to 6. For example, p is 1, 2, 3, 4, 5, or 6. In some embodiments, p is an integer from 1 to 4.

[0086] In some embodiments, R P is selected from any one of the following formulas: [ka]

[0087] In some embodiments, R P is selected from any one of the following formulas: [ka]

[0088] In some embodiments, R P teeth, [ka] It is.

[0089] In some embodiments, R P teeth, [ka] and In the formula, p is an integer of 1 to 6.

[0090] In some embodiments of Formula (I) or Formula (II), Z 1 is O, S, and N(R N In some embodiments, Z 1is O. In some embodiments, is Z 1 is NH. In some embodiments, Z 1 is N(C 1-6 Alkyl) In some embodiments, Z 1 is S.

[0091] In some embodiments of Formula (I) or Formula (II), Z 3 is O and N(R N )mosquito In some embodiments, Z 3 is not present. In some embodiments, Z 3 is O. In some embodiments, Z 3 In some embodiments, is Z 3 is N(C 1-6 alkyl).

[0092] In some embodiments of Formula (I) or Formula (II), Z 1 is O and Z 3 is N H. In some embodiments, Z 1 is NH and Z 3 is O. Some In the embodiment, Z 1 is O and Z 3 is absent. In some embodiments, Z 1 is O and Z 3 is O. In some embodiments, Z 1 is NH and Z 3 is NH. In some embodiments, Z 1 is NH and Z 3 does not exist. In some embodiments, Z 1 is S and Z 3 is O. In some embodiments , Z 1 is S and Z3 is NH. In some embodiments, Z 1 is S , Z 3 does not exist.

[0093] In some embodiments of Formula (I), Z 4 is O. In another embodiment of Formula (I), , Z 4 is S.

[0094] In some embodiments of Formula (I) or Formula (II), M A is a diradical and is At or Z 1 together with, upon nucleophilic attack on the phosphorus atom in formula (I) or formula (II), M A (Z 3 -D) is more preferred than any one of the aliphatic moieties described herein. It is characterized by creating a good leaving group. For example, as shown in the following Scheme 2, Upon nucleophilic attack on the phosphorus atom by the 2' hydroxyl group of the boson unit, Both the propionate and polyethylene glycol fragments produced equally good leaving groups. , the nucleophilic substitution reaction is non-selective. Scheme 2 [ka]

[0095] In contrast, in some embodiments of Formula (I) or Formula (II) described herein, , -Z 1 -M A Groups containing the -fragment are better leaving groups than aliphatic moieties (e.g., poly ethylene glycol), thereby ribose monosaccharides were synthesized under similar conditions as compared to Scheme 2. Upon nucleophilic attack on the phosphorus atom by the 2' hydroxyl group at the 2' position, polyethylene glycol The fragment is still covalently attached to the phosphorus atom, -Z 1 -M A -Fragment-containing groups are selective will be disconnected.

[0096] In some embodiments of Formula (I) or Formula (II), M A is a diradical and is At or Z 1 together with nucleophilic attack on the phosphorus atom in formula (I) or formula (II) To, M A (Z 3 -D) creates a better leaving group than polyethylene glycol In some embodiments, the formula HZ 1 -M A -Z 3 -D RuZ 1 -M A -Z 3 The conjugate acid of the -D moiety is conjugated to a compound of formula (I) or formula (II). In some embodiments, the carboxyl group has a lower pKa value than the conjugate acid of the condensed aliphatic moiety. is HZ 1 -M A -Z 3 The D group has a lower p than polyethylene glycol or alcohol. In some aspects of these embodiments, Z 1 is oxygen, M A teeth , containing aromatic moieties (e.g., M A In some embodiments, Z includes phenylene. 1 is nitrogen, M A contains an aromatic moiety (e.g., M A includes phenylene), HZ 1 -M A -Z 3 The conjugate base of the -D compound is M A Z to the aromatic ring of 1 The nitrogen atom of Due to the delocalization of the isomeric electron pairs, it is better than any one of the aliphatic moieties described herein. It is a good leaving group.

[0097] In some embodiments, the compound of Formula (I) or Formula (II) comprises a single sacrificial functional group. In some embodiments of Formula (I) or Formula (II), M A is a self-immolative group. In some embodiments, M A For example, Alouane, A. et al., “Se lf-immolative spacers:kinetic aspects,st ructure-property relationships, and appli cations”,Angew.Chem.Int.Ed.,2015,54,7492 - 7509. is M A For example, Kolakowski, R. et al., “The Methy lene Alkoxy Carbamate Self-Immolative Un it:Utilization for the Targeted Delivery of Alcohol-Containing Payloads with Ant ibody-Drug Conjugates”,Angew.Chem.Int.Ed Among the self-immolative groups listed in ., 2016, 55(28), 7948-7951, It is one of them.

[0098] In some embodiments, M A The compound has any one of the formulas (a) to (i). It is a degradable group, [ka] In the formula, x is Z 1 indicates the point of attachment to Z 3 The attachment points to the

[0099] In some embodiments of Formula (I) or Formula (II), the self-immolative group is PZ 1 Bond Breaking the fragments generate a cascade of decomposition reactions (e.g., a hydrolysis cascade as described herein); Finally, i)Z 3 Compound HZ in the presence 3 -D release of the conjugate base, or ii) Z 3 In the absence of The present invention is characterized by the above.

[0100] In some embodiments, the formula HZ 3 The conjugate base of the compound of formula - Z 3 In the -D part In some embodiments, the conjugate base of the compound of formula HO-(C=O)-D is - O -(C=O)-D part.

[0101] In some embodiments of Formula (I) or Formula (II), Z 3 (e.g., Z 3 teeth , O or NH, M A is a self-immolative group. In some embodiments, the self-immolative group , PZ 1 Bond cleavage produces a cascade of decomposition reactions, ultimately resulting in the compound HZ 3 - This results in the release of the conjugate base of D.

[0102] In some aspects of these embodiments, PZ 1 The bond is broken by Z 1 =M A’ , CO 2, and compound HZ 3 -D, where M A’ is expressed as A self-immolative group lacking a moiety (e.g., a self-immolative group of any of the formulae (a) to (g)) It is a fragment. [ka]

[0103] In one example, M A is a self-immolative group of formula (b), M A’ is a fragment of the formula [ka] In the formula, x is Z 1 indicates the point of attachment to Z 3 The attachment points to the

[0104] In one example, M A is a self-immolative group of formula (b), M A’ is a fragment of the formula [ka] In the formula, x is Z 1 indicates the point of attachment to Z 3 The attachment points to the

[0105] In one example, M A is a self-immolative group of formula (d), M A’ is a fragment of the formula [ka] In the formula, x is Z 1 indicates the point of attachment to Z 3 The attachment points to the

[0106] In some embodiments, Z 1 But, M A’ In the compound, Z 1 and M. A’ Between The second bond is Z 1 And, M. A’ Connects any one of the atoms in the group. For example, M A is a self-immolative group of formula (a), Z 1 and M. A’ The second bond between Before the meeting, Z 1 And Z 1 Connect the carbon atom of formula (a) that was in position β to [ka]

[0107] Z 1 But, M A’ Another example of a compound where M A When the self-immolative group of formula (b-1) is , Z 1 and M. A’ The second bond between 1 And Z 1 M is bound to A’ Carbon atom of Connect the M A’ The remaining bonds are delocalized. [ka]

[0108] In another aspect of the above embodiment, PZ 1 The bond breakage occurs in the compound HZ 3 -D and below This results in the formation of a conjugate base of a compound of the formula: [ka]

[0109] In some embodiments of Formula (I) or Formula (II), Z 3 does not exist and M A Is self-destructing In some embodiments, the self-immolative group is PZ 1Bond cleavage is the cause of decomposition reactions. cade, ultimately resulting in the release of the conjugate base of the compound HO-(C=O)-D. In some aspects of these embodiments, PZ 1 The bond is broken by Z 1 =M A’ (as described herein) and the conjugate base of the compound HO-(O=C)-D Brings about formation.

[0110] In some embodiments of Formula (I) or Formula (II), Z 1 is S and M A The following is a self-immolative group of formula (a) below: [ka] In the formula, x is Z 1 indicates the point of attachment to Z 3 The attachment points to the

[0111] In some embodiments of Formula (I) or Formula (II), the self-immolative group of formula (b) is Having the formula (b-1), [ka] In the formula, x is Z 1 indicates the point of attachment to Z 3 The attachment points to the

[0112] In some embodiments of Formula (I) or Formula (II), the self-immolative group of formula (b) is Having the formula (b-2), [ka] In the formula, x is Z 1 indicates the point of attachment to Z 3 The attachment points to the

[0113] In some embodiments of Formula (I) or Formula (II), the self-immolative group of formula (c) is Having the formula (c-1), [ka] In the formula, x is Z 1 indicates the point of attachment to Z 3 The attachment points to the

[0114] In some embodiments of Formula (I) or Formula (II), the self-immolative group of formula (d) is Having the formula (d-1), [ka] In the formula, x is Z 1 indicates the point of attachment to Z 3 The attachment points to the

[0115] In some embodiments of Formula (I) or Formula (II), Z 1 is O or NH, M A is a self-immolative group of any one of formulas (b)-(i). So, Z. 1 is O or NH, Z 3 does not exist and M A Among formulas (b) to (i), is one of the self-immolative groups.

[0116] In some embodiments of Formula (I) or Formula (II), Z 1 is O or NH, Z 3 does not exist and M A is a self-immolative group of formula (b), where R 7 and R 8 Each C 1-6 It is alkyl or has the formula (b-2).

[0117] In some embodiments of Formula (I) or Formula (II), Z 1is O and Z 3 NH or not present and M A is a self-immolative group of formula (b), where R 7 and R 8 Yes, that Each of them is H or has the formula (b-1).

[0118] In some embodiments of Formula (I) or Formula (II), Z 1 is O and Z 3 O And M A is a self-immolative group of the following formula (h-1): [ka] In the formula, x is Z 1 indicates the point of attachment to Z 3 The attachment points to the

[0119] In some embodiments of Formula (I) or Formula (II), Z 1 is O and Z 3 O And M A is a self-immolative group of the following formula (i-1): [ka] In the formula, x is Z 1 indicates the point of attachment to Z 3 The attachment points to the

[0120] In some embodiments of Formula (I) or Formula (II), Z 1 is NH and Z 3 teeth, O and M A is a self-immolative group of formula (h-1). In some embodiments, Z 1 teeth, NH and Z 3 is O and M A is a self-immolative group of formula (i-1).

[0121] In some embodiments of Formula (I), M A is a stable diradical. For example, A stable diradical is not a self-immolative group (e.g., a nucleophilic group for the phosphorus atom in formula (I) Upon attack, the stable diradical is Z 1 -M A Bond or M A -Z 3 Causes the breaking of bonds In some embodiments, the stable diradical is PZ 1 The bond breakage occurs according to the formula HZ 1 -M A -Z 3 -D compound, which is stable and does not undergo decomposition reactions. It is characterized by not receiving

[0122] In some embodiments, M A is a compound having any one of the formulas (j) to (l): is a diradical defined as [ka] In the formula, x is Z 1 indicates the point of attachment to Z 3 The points of attachment to the In some embodiments, Z 1 and Z 3 are independently O or NH (e.g., Z 1 is O and Z 3 In some embodiments, M A But the equation (j) If it is a diradical, Z 1 is O. In some embodiments, M A But, the formula (j) is a stable diradical, Z 1 is NH.

[0123] In some embodiments of Formula (I), M Ais a stable diradiometer with the following formula (m): Cal, [ka] In the formula, x is Z 1 indicates the point of attachment to Z 3 The points of attachment to the In some embodiments, Z 1 and Z 3 are independently O or NH (e.g., Z 1 is O and Z 3 In some embodiments, M A However, the equation (m) If it is a diradical, Z 1 is O and R 7 and R 8 are hydrogen, be.

[0124] In some embodiments of Formula (I) or Formula (II), R 7 and R 8 is, independently, H, C 1-6 Alkyl, amino, (C 1-6 Alkyl)amino, di-(C 1-6 Alkyl ) amino, acylamino, and protected amino groups (e.g., protected amino groups Groups are described, for example, in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed.,John Wiley & Sons, New York, NY, 1999. In some embodiments, R 7 and R 8 is In particular, the aryl group is selected from H, methyl, amino, and acylamino. In some embodiments of II), R7 and R 8 are independently H and C 1-6 Al In some embodiments, R 7 and R 8 are independently H and In some embodiments, R 7 and R 8 are hydrogen, be.

[0125] In some embodiments of Formula (I) or Formula (II), R 7 is C 1-6 Alkyl, C 3-7 R8 is selected from cycloalkyl, amino, acylamino, and protected amino groups; is H. In some embodiments, R 8 is C 1-6 Alkyl, C 3-7 Cycloa R is selected from alkyl, amino, acylamino, and protected amino groups; 7 is H.

[0126] In some embodiments of Formula (I) or Formula (II), R 8 is H and R 7 is C 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, or tert- butyl). In some embodiments, R 7 is H and R 8 is C 1-6 Alki (e.g., methyl, ethyl, propyl, isopropyl, or tert-butyl) In some embodiments, R 7 and R 8 are both H. In this state, R 7 and R 8 Both are C 1-6In another example, R 7 and R 8 are both methyl. 7 is methyl, R 8 is ethyl In some embodiments, R 7 and R 8 Both are C 3-7 Cycloalkyl( For example, cyclopropyl or cyclobutyl.

[0127] In some embodiments of Formula (I) or Formula (II), R 7 and R 8 are each and H or acylamino (e.g., acetylamino, propionylamino, or butylamino). In some embodiments, R 7 is amino or acetylamino In some embodiments, R 8 is amino or acetylamino. In some embodiments, R 7 is acetylamino, and R 8 is H. Some implementations In terms of form, R 7 is H. In some embodiments, R 8 is H.

[0128] In some embodiments of Formula (I) or Formula (II), M A Formulas (b), (c), and or (d), and R 7 and R 8 Both are C1 -6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, or tert-butyl) In some embodiments, M A is a stable dipole of formula (k) or formula (l). Radical, R7 and R 8 are independently H or acylamino (e.g., acetyl amino, propionylamino, or butylamino). It is selected.

[0129] In some embodiments of formula (I), the stable diradical of formula (k) is represented by the following formula: -1), [ka] In the formula, x is Z 1 indicates the point of attachment to Z 3 The attachment points to the

[0130] In some embodiments of Formula (I) or Formula (II), R 1 and R 2 is, independently, Hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl and and optionally substituted 5-14 membered heteroaryl. In embodiments, R 1 and R 2 Each is hydrogen. In some embodiments, R 1 and R 2 together form a chemical bond (i.e., a carbon-carbon double bond, R 1 and the carbon to which R is bonded 2 is formed between the carbon atom to which it is bonded).

[0131] In some embodiments of Formula (I) or Formula (II), R 1 and R 2 The conclusion is that Optionally substituted C 3-7 Cycloalkyl ring, any Optionally substituted 4- to 7-membered aliphatic heterocyclic rings, optionally substituted C 6-10 Aryl, or an optionally substituted 5-14 membered heteroaryl. , R 1 and R 2 Together, C 3-7 Cycloalkyl rings (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl). So, R 1 and R 2 together form a 4- to 7-membered aliphatic heterocyclic ring (e.g., pyrrolidine, piperidine, tetrahydrofuran, and tetrahydropyran).

[0132] In some embodiments of Formula (I) or Formula (II), R 1 and R 2 Joined together and the ribose ring system (e.g., adenosine, guanosine, 5-methyluridine, uridine , 5-methylcytidine, cytidine, inosine, xanthosine, and xanthosine, which Each of which is substituted as described herein. In some embodiments, the ribonucleoside is uridine. 1 and R 2 together form a ribose ring system of the formula [ka] In the formula, a represents the point of attachment to O and b represents the point of attachment to A, or a represents the point of attachment to A and b represents the point of attachment to O; W represents H, an acyl group, a protecting group (e.g., For example, a protecting group other than acyl is selected from the group consisting of. without the need for lyxofuranosides, as compared to the ribofuranose analogs described herein. Base-based nucleotides are believed to have similar reactivities.

[0133] Similarly, in one example, intramolecular cleavage to a phosphotriester occurs even though the 5'-OH is three carbons away. It is possible to assume that the typical Although more demanding than the two-carbon distance interaction, this lyxo isomer reverses the orientation of the 3'OH. Therefore, the reaction can be promoted by adding 2'-deoxy, 3'-xylonucleotides. Osides are the complementary ribonucleotides to the ribose scaffold described above for use as cleavable units. It is a suitable alternative.

[0134] In some embodiments of Formula (I) or Formula (II), the nucleobase is adenine, cytosine, The group consisting of guanine, thymine, uracil, and other natural and unnatural nucleobases is selected from.

[0135] In some embodiments of Formula (I) or Formula (II), the nucleobase is The aryl group may be provided in a modified form (e.g., benzoyl or fatty acyl).

[0136] In some embodiments of Formula (I) or Formula (II), the nucleobase is uracil. In some embodiments, the nucleobases are adenine, cytosine, guanine, thymine, and In some embodiments, the nucleobase is selected from the group consisting of 5-methyl, ... Cytosine, pseudouridine, dihydrouridine, inosine, 7-methylguanosine, hyaluronan poxanthine, and xanthine.

[0137] In some embodiments of Formula (I) or Formula (II), the nucleobase is a fluorescent group (e.g., In some embodiments, the nucleobase comprises adenine, cysteine, It is a fluorescent analogue of tosine, guanine, thymine, or uracil.

[0138] In some embodiments of Formula (I) or Formula (II), R 1 and R 2 Together, forming a ribose ring system according to any one of the formulas below: [ka] In the formula, a represents the point of attachment to O and b represents the point of attachment to A, or a represents the point of attachment to A and b represents the point of attachment to O; W represents H, an acyl group, a protecting group (e.g., For example, a protecting group other than acyl.

[0139] In some embodiments of Formula (I) or Formula (II), R 1 and R 2 Together, forming a ribose ring system according to any one of the formulas below: [ka] In the formula, a represents the point of attachment to O and b represents the point of attachment to A, or a represents the point of attachment to A and b represents the point of attachment to O; W represents H, an acyl group, a protecting group (e.g., For example, a protecting group other than acyl.

[0140] In some embodiments of Formula (I) or Formula (II), R 1 and R 2 Together, Forming a ribose ring system of the formula below, [ka] In the formula, a represents the point of attachment to O and b represents the point of attachment to A, or a represents the point of attachment to A and b represents the point of attachment to O; W represents H, an acyl group, a protecting group (e.g., For example, a protecting group other than acyl. So, the aliphatic part is R P For example, R P is C 1-6 Alkyl (e.g., ethyl or isopropyl). In another example, R P is cyanoethyl. In other embodiments, the aliphatic moiety is a polymer (e.g., polyethylene glycol). In another aspect of the above embodiment, the aliphatic moiety has the formula: polymer-L-(CH2) m -of It is based on

[0141] In some embodiments of Formula (I) or Formula (II), W is a protecting group. For example, W is a hydroxyl protecting group, e.g., methoxymethyl ether (MOM), benzyl oxy Dimethyl ether (BOM), benzyl ether, p-methoxybenzyl ether (PM B), trityl ethers, silyl ethers (e.g., TMS, TIPS), or e.g. , PGMWuts and TW Greene, Protective Gr. oups in Organic Synthesis, 4 th Ed.,Wiley & Sons, Inc., New York (2006), the entire contents of which are incorporated herein by reference. The hydroxyl protecting groups may be any of those described in US Pat. No. 6,393,363, which is incorporated herein by reference. In some embodiments, W is t-butyldimethylsilyl, diethylisopropylsilyl. , triphenylsilyl, formate, methoxymethyl carbonate, t-butyl carbonate , 9-fluorenylmethyl carbonate, N-phenylcarbamate, 4,4'-dimeth methoxytrityl, trityl, and pixyl. It is an alcohol protecting group that can be used.

[0142] In some embodiments, W is hydrogen.

[0143] In some embodiments, W is an acyl group.

[0144] In some embodiments of Formula (I) or Formula (II), W is an acyl group as described herein. groups (e.g., W is formyl, acetyl, propionyl, aryl, acyl groups selected from acyl, pivaloyl, and benzoyl. In embodiments, W is pivaloyl or benzoyl. and E are the same (e.g., W and E are each an acyl group). In some embodiments, W is an acyl group and E is a cleavable group other than an acyl group. In some embodiments, the acyl group is selected from the group consisting of the numerous hydrolases present in vivo. It can be hydrolyzed in the presence of either one.

[0145] In some embodiments of Formula (I) or Formula (II), A is selected from the group consisting of O and N(R N )from In some embodiments, A is selected from the group consisting of 1, 2, 3, 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, 30, 31, , N(R N In some embodiments, A is NH. So, A is N(C 1-6 In some embodiments, A is N(CH 3). In some embodiments, A is N(CH2CH3).

[0146] In some embodiments, A is N(R N ), then R N and R 1 A and R 1 together with the carbon atom to which it is attached form an optionally substituted 4- to 7-membered aliphatic heterocyclic ring In some aspects of these embodiments, the 4- to 7-membered aliphatic heterocyclic ring is , selected from the group consisting of: [ka] where x indicates the point of attachment to E and y indicates R 1 indicates the point of attachment to the carbon atom to which it is attached .

[0147] In some embodiments, R N and R 2 A, R 1 The carbon atom to which BiR 2 together with the carbon atom to which it is attached, form an optionally substituted 4- to 8-membered aliphatic heterocycle. Forms a cyclic ring.

[0148] In some embodiments, when A contains N, the moiety: [ka] 2-amino alcohols other than serine or its derivatives, threonine or its derivatives or cis-aminoindanol or a derivative thereof. , 2-aminoalcohol is not aminoethanol.

[0149] In some embodiments, the compound of formula (II) has the formula (II-1a): [ka] or a pharma- ceutically acceptable salt thereof.

[0150] In some embodiments, the compound of formula (II) has the formula (II-1b): [ka] or a pharma- ceutically acceptable salt thereof.

[0151] In some embodiments, the compound of formula (II) has the formula (II-1c): [ka] or a pharma- ceutically acceptable salt thereof.

[0152] In some embodiments, the compound of formula (II) has the formula (II-2a): [ka] or a pharma- ceutically acceptable salt thereof.

[0153] In some embodiments, the compound of formula (II) has the formula (II-2b): [ka] or a pharma- ceutically acceptable salt thereof.

[0154] In some embodiments, the compound of formula (II) has the formula (II-3a): [ka] or a pharma- ceutically acceptable salt thereof.

[0155] In some embodiments, the compound of formula (II) has the formula (II-3b): [ka] or a pharma- ceutically acceptable salt thereof.

[0156] In some embodiments, the compound of formula (II) has the formula (II-4a): [ka] or a pharma- ceutically acceptable salt thereof.

[0157] In some embodiments, the compound of formula (II) has the formula (II-4b): [ka] or a pharma- ceutically acceptable salt thereof.

[0158] In some embodiments, the compound of formula (II) is represented by the following formulae (II-5) to (II-7) ) or [ka] In the formula (II-7), A is O. or a pharma- ceutically acceptable salt thereof.

[0159] In some embodiments, the compound of formula (II) has the formula (II-8): [ka] or a pharma- ceutically acceptable salt thereof.

[0160] In some embodiments, the compound of formula (II) has the formula (II-9): [ka] or a pharma- ceutically acceptable salt thereof.

[0161] In some embodiments, the compound of formula (II) has the formula (II-10): [ka] or a pharma- ceutically acceptable salt thereof.

[0162] In some embodiments, the compound of formula (II) has the formula (II-10a): [ka] or a pharma- ceutically acceptable salt thereof.

[0163] In some embodiments, the compound of formula (II) has the formula (II-11a): [ka] or a pharma- ceutically acceptable salt thereof.

[0164] In some embodiments, the compound of formula (II) has the formula (II-11): [ka] or a pharma- ceutically acceptable salt thereof.

[0165] In some embodiments, the compound of formula (II) has the formula (II-12a): [ka] or a pharma- ceutically acceptable salt thereof.

[0166] In some embodiments, the compound of Formula (II) has the formula (II-12b): [ka] or a pharma- ceutically acceptable salt thereof.

[0167] In some embodiments, the compound of formula (II) has the formula (II-13): [ka] or a pharma- ceutically acceptable salt thereof.

[0168] In some embodiments, the compound of formula (II) has the formula (II-14): [ka] or a pharma- ceutically acceptable salt thereof.

[0169] In some embodiments, the compound of formula (II) has the formula (II-15): [ka] or a pharma- ceutically acceptable salt thereof.

[0170] In some embodiments, the compound of formula (II) has the formula (II-16): [ka] or a pharma- ceutically acceptable salt thereof. In some aspects of these embodiments, R P is an arbitrarily substituted C 1-6 Alkyl (e.g., isopropyl or cyanoethyl) be.

[0171] In some embodiments, the compound of formula (II) has the formula (II-17): [ka] or a pharma- ceutically acceptable salt thereof.

[0172] In some embodiments, the compound of formula (II) has the formula (II-18): [ka] or a pharma- ceutically acceptable salt thereof.

[0173] In some embodiments, R N is H. In some embodiments, R N is C1 -6 Alkyl (eg, methyl, ethyl, propyl, isopropyl).

[0174] In some embodiments, the compound of formula (II) has the formula (II-19a): [ka] or a pharma- ceutically acceptable salt thereof.

[0175] In some embodiments, the compound of formula (I) or formula (II) is a compound that is not , [ka] or a pharma- ceutically acceptable salt thereof, wherein U is uracil.

[0176] Cleavable E group In some embodiments of Formula (I) or Formula (II), E upon cleavage provides a free AH group ( where H is hydrogen. The cleavable moiety E can be, for example, , 1) an E moiety cleavable by any one of the following enzymes:

[0177] a) Esterase All esters, carbonates, and methyloxyesters are hydrolyzed by the enzyme esterase. The reactivity of these functional groups in enzymatic reactions depends on the different electron donating groups. By selecting a carboxylic acid moiety of the ester functionality that contains This can be regulated by making harmful esters. Both the aryl and alcohol moieties can be sterically hindered.

[0178] b) reductase Methyl dithioether, methyl azide group, and 2-oxymethyleneanthraquinone The carbonate (MAQC) can be cleaved off both by the reductase enzyme Examples of cleavable moieties E include methyl reductase cleavable moieties E, The moiety E may be an azide group or may be of the formula: [ka]

[0179] c) glycosidase AE is a sugar residue that forms a glycosidic bond with the remainder of the compound of formula (I) or formula (II). When the heteroatom is substituted with a group, the action of a glycosidase in vivo cleaves E. and can liberate free AH.

[0180] 2) via a β-elimination mechanism (e.g., a β-elimination trigger), by base, but not by physiological pH-cleavable moiety E.

[0181] a) For example, moiety E is a fluorenylmethylcarbamide type trigger having the formula: Possibly, [ka] In the formula, R is H, C 1-10 Alkyl, OH, NO2, CN, halogens, and acetyl The introduction of an electron-withdrawing substituent R increases the rate of β-elimination and release of free AH. In another example, the moiety E below has an electron-withdrawing -SO2- group. [ka]

[0182] b) Substituted β-phenylsulfonylethyl carbamates and carbonates: [ka] In the formula, R is H, C 1-10 Alkyl, OH, NO2, CN, halogens, and acetyl These functional groups are cleaved via a β-elimination mechanism at about pH 7.4, The rate of the process can be controlled by the substituent R on the phenyl ring.

[0183] In some embodiments, E is an esterase, a specific or non-specific peptidase, Reductases, oxidases, glycosidases, hydrolases, glycosyltransferases and transaminases. In some embodiments, E is an esterase, a reductase, an oxidase, a glycos ... selected from the group consisting of glycosides, hydrolases, and glycosyltransferases It is cleavable by an enzyme.

[0184] 3) Acid-cleavable moieties. Any acid-cleavable alcohol protecting group can be used as the cleavable moiety E. For example, acetals, ortho-esters, and phenyl-substituted ethers can be used. Examples of such cleavable moieties include THF, MTHP, or MDMP. and protecting groups such as methoxyisopropyl acetal or methoxycyclohexenyl This type of acetal is cleaved in an acidic environment. Other examples of the cleavable moiety E include dimethoxytrityl, trimethoxytrityl, and It contains a pixyl group.

[0185] In some embodiments, E contains a dithio group that is cleavable by a biological thiol. In some embodiments of Formula (I) or Formula (II), the moiety E is selected from the group consisting of glutathione and carboxyl groups. Therefore, cutting is possible.

[0186] In some embodiments, E is a group of any one of the following formulae: [ka] In the formula, R E But, C 1-6 Some are selected from the group consisting of alkyl and benzyl. In embodiments, R E is C 1-6 In some embodiments, R E Is, It's Njil.

[0187] In some embodiments, A is O and E is a group of the formula: [ka]

[0188] In some aspects of these embodiments, A is NH and E is a group of the formula: do. [ka]

[0189] In some embodiments of Formula (I) or Formula (II), E is an esterase, a reductase, The enzymes consist of glycosidases, oxidases, and glycosidases or glycosyltransferases. In another embodiment, E is cleavable by an enzyme selected from the group consisting of: In some embodiments, E is acyl. acyl group, O-methyl-acyl group, methyl azide group, sugar residue, protected acetal, or carbonate residue. In some of these embodiments, A is O. In other embodiments, A is NH.

[0190] In some embodiments of formula (I) or formula (II), the acyl group is formyl, acetyl, or acetyl. acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, cyanoacetyl, mono- Methyl malonate, mono-ethyl malonate, methoxyacetyl, ethoxyacetyl, t -Butoxyacetyl, phenoxyacetyl, t-butylphenoxyacetyl, glycolate Acetyl glycolate, propionate, 2-chloropropionate, 3-chloropropionate propionate, 2-cyanopropionate, 3-cyanopropionate, N-acetyl- Glycinate, N-trifluoroacetylglycinate, N-acetylalanilate, N -Trifluoroacetyl alanilate, N-acetylphenyl alanilate, N-trifluoro Fluoroacetyl phenylalanilate, N-acetylvalinate, N-trifluoroacetate Cetylvalinylate, N-acetylvalinyl-citrunylate te), N-trifluoroacetylvalinyl-citronylate, butyrate, isobutyrate oxalate, pivaloate, levulinate, monomethyl oxalate, mono-ethyl oxalate ester, mono-methylsuccinate, mono-ethylsuccinate, hydroxybutyrate , Acetoxybutyrate, Acetylbutyrate, Hexanoate, Palmitate, Stearate benzoate, chloro-benzoate, dichloro-benzoate, pentachloro Benzoate, cyano-benzoate, aminobenzoate, acetamino-benzoate phthalate, mono-methyl-phthalate, mono-ethyl-phthalate, methoxy-benzoate, Trimethoxybenzoate, trifluoromethylbenzoate, dimethylaminobenzoate methylsulfonyl benzoate, and methylsulfonyl benzoate. In the form, E is formyl, acetyl, propionyl, acrylyl, pivaloyl, and benzoyl.

[0191] In some embodiments of Formula (I) or Formula (II), E is catalyzed by an esterase enzyme. For example, E can be an acyl group (e.g., any of the acyl groups described herein). ), carbonate ester, or O-methyl-acyl ester.

[0192] In some embodiments of Formula (I) or Formula (II), E is cleavable by a reductase. It is possible to determine this.

[0193] In some aspects of these embodiments, A is O and E is a group of the formula: . [ka]

[0194] In some aspects of these embodiments, A is NH and E is a group of the formula: do. [ka]

[0195] In some embodiments of Formula (I) or Formula (II), E is cleavable by glutathione. In some aspects of these embodiments, A is NH. In another embodiment, E is a moiety of the formula: [ka]

[0196] In some embodiments of Formula (I) or Formula (II), E is hydrolyzed by a glycosidase. In some aspects of these embodiments, E is a sugar (e.g., glucose). The residues are either saccharide, galactose, or mannose.

[0197] In some embodiments of Formula (I) or Formula (II), E is generated via a β-elimination mechanism. For example, E is selected from any one of the groups of the following formulae: Selected, [ka] In the formula, R is H, C 1-10 Alkyl, OH, NO2, CN, halogens, and acetyl In another example of a moiety cleavable at physiological pH, E is an acyl group (e.g., , pivaloyl, or benzoyl, any one of the acyl groups described herein. It is.

[0198] Another example of a moiety cleavable at physiological pH via a β-elimination mechanism is A, NR N or NR 3 and E is a cleavable moiety of the formula: [ka] During the ceremony, R 9H, optionally substituted C 6-10 Aryl and optionally substituted C 1-6 a Selected from Rukyr, R 10 and R 11 are independently H, CN, NO2, and COR 12 , SOR 1 2 or SO2R 12 , optionally substituted C 1-6 Alkyl, optionally substituted C 6-1 aryl, and optionally substituted 5- to 14-membered heteroaryl; Ruiha R 10 and R 11 may be optionally substituted with one or more carbon atoms to which they are attached. Replaced C 6-10 Optionally substituted C fused to an aryl ring 3-7 Cycloalkyl ring Formation, R 12 But, with any substitution C 1-6 Alkyl and optionally substituted C 6-10 Ants In some aspects of these embodiments, A is NH and R 9 teeth , H and optionally substituted C 6-10 aryl.

[0199] In some embodiments of formula (I) or formula (II), E is any one of the following formulae (E-1) to (E-2): E-12), (E-37) and (E-39) to (E-41) It is a determinable part, [ka] In the formulae (E-1) to (E-12), (E-37) and (E-39) to (E-41), One of the phenyl rings is C1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 1 selected from alkoxy, OH, NO2, CN, halogen, and acyl; Optionally substituted with 2, 3, 4, or 5 substituents. In this embodiment, E is a cleavable moiety of any one of formulas (E-1) to (E-12). In some embodiments, the formulas (E-1) to (E-12), (E-37), and The substituents on the phenyl ring of (E-39) to (E-41) are selected based on the stability and unstability of the cleavable group. In one embodiment, the cleavable moiety E is a fluorenyl group having the formula: It may be of the methylcarbamido type. [ka]

[0200] In one embodiment, the cleavable moiety E is a fluorenylmethylcarbamide having the formula: It can be a type. [ka]

[0201] For example, electron-withdrawing substitutions such as cyano, halogen, nitro, sulfonyl, or acyl The introduction of the group R can increase the rate of β-elimination and release of free AH. In contrast, , e.g., C 1-6 The introduction of an electron-donating substituent R, such as alkyl or silyl, reduces the likelihood of β-elimination. The moiety E can be stabilized by

[0202] Substituted β-phenylsulfonylethyl carbamates and carbonates, such as (4-X The -phenyl)sulfonylethoxycarbonyl (PSEC or XPSEC) group is Here is an example of a useful part of [ka] In the formula, the substituent X is H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Al The alkyl group is selected from the group consisting of oxy, OH, NO2, CN, halogen, and acyl. In some embodiments, X is selected from H, Cl, and methoxy.

[0203] In some embodiments, the PSEC group is a group of the formula: [ka]

[0204] In some embodiments of formula (I) or formula (II), the formulae (E-1) to (E-12) are Any one of the phenyl rings in (E-37) or (E-39) to (E-41) is , 1, 2, 3 selected from F, Cl, CN, acetyl, NO2, and CF3, or For example, (E-1) may be optionally substituted with one or more substituents to give the formula (E-42): can be replaced by F. [ka]

[0205] In some embodiments of Formula (I) and Formula (II), E is not (E-38).

[0206] In some embodiments of Formula (I) or Formula (II), E is cleavable at acidic pH. For example, E may be an acetal, an ortho-ester, or a substituted triphenylmethyl ether. Further examples of moieties E that are cleavable at acidic pH include moieties selected from: Tetrahydrofuranyl, 4-methoxytetrahydropyran-4-yl, 1,5-dicarboxyl -Methoxypentanyl, methoxyisopropyl acetal, methoxycyclohexenyl acetal acetal, dimethoxytrityl, trimethoxytrityl, and pixyl. do.

[0207] In some embodiments of Formula (I) or Formula (II), the moiety E is reacted with , which is cleavable by base at physiological pH or the most basic amino group of the E group In one example, such an E moiety can be cleaved in an autocatalytic manner starting with deprotonation. In some of these embodiments, the amide is a triamide (e.g., a diamide or a triamide). In this embodiment, A is nitrogen (e.g., A is NH). For example, E is any of the groups described in U.S. Pat. Publication No. US2015 / 0057221, Publication No. US2014 / 0249093 , U.S. Patent No. 8,377,917, U.S. Patent No. 8,906,847, U.S. Patent No. 9, 173,953, or the oligoamines described in U.S. Pat. No. 9,062,094. No. 6,399,413, all of which are incorporated herein by reference. In one embodiment, E is selected from any one of the following formulae (E-13) to (E-36): is a selected cleavable moiety, [ka] JPEG2025023928000116.jpg143166 where R is as described herein.

[0208] In some embodiments of Formula (I) or Formula (II), e.g., via a β-elimination mechanism: The moiety E that is cleavable at physiological pH can be any of the moieties described, for example, in U.S. Pat. No. 9,387,245 or U.S. Pat. any one of the β-elimination moieties described in US Pat. No. 8,754,190, both of which are incorporated herein by reference.

[0209] In some embodiments of formula (I) or formula (II), the moiety E has the following formula: E )of is attached to A using a group, [ka] wherein a represents the point of attachment to A and b represents the point of attachment to E. In some of these embodiments, In aspects of these embodiments, A is O. In other aspects of these embodiments, upon cleavage of moiety E, a compound of formula L E The group undergoes a decomposition reaction to give CO2 and a compound of the formula: [ka] Therefore, free A - to the phosphorus atom of the compound of formula (I) or (II). A can undergo nucleophilic attack. - The group can also be protonated to give the AH group prior to nucleophilic attack. It is possible.

[0210] In one example, in the compound of formula (II-8a), the chloro-PSEC cleavable moiety E is formula L E The chloro-PSEC moiety in compound (II-8a) is bonded to A using the group When the moiety is nonenzymatically cleaved via a β-elimination mechanism, the resulting moiety L E minutes The solution may occur, for example, as shown in Scheme 3. Scheme 3 [ka]

[0211] In some embodiments, any of the cleavable moieties (E-1) to (E-36) One is the formula (L E ) moiety can be used to attach to A.

[0212] In some embodiments, the E moiety undergoes beta-elimination at physiological pH via enzyme catalysis. It may be cleaved through a mechanism or may be hydrolyzed at acidic pH. For example, When a compound of formula (I) or formula (II) is subjected to enzymatic conditions at physiological pH, the E Groups are cleaved by enzymes depending on which reaction is kinetically favored under given conditions. In another example, the cleavage may be by β-elimination or by both. When a compound of formula (I) or (II) is subjected to enzymatic conditions at an acidic pH, The E group of the enzyme is hydrolyzed by the enzyme depending on the difference in activation energy between the enzymatic and acidic hydrolysis reactions. can be cleaved by enzymes or by hydrolysis, or both It could be.

[0213] GLP-1 Polypeptides or Analogues Thereof In some embodiments of Formula (I) or Formula (II), D is a glucan as described herein. any one of the GLP-1 polypeptides or analogs thereof The GLP-1 polypeptide of formula (I) or (II) or its analogues Residues of the drug may be designated as "D" or "drug", and these symbols are used interchangeably herein. Used interchangeably.

[0214] In some embodiments of Formula (I) or Formula (II), HZ 3 - is a polypeptide backbone It may also represent the amino or hydroxyl group of the side chain of an amino acid (e.g., lysine) in , D represents the remainder of the polypeptide backbone. For example, HZ 3 - is the ε-amino group of lysine Possible. Another example is HZ 3 - may be the OH- group of serine.

[0215] In some embodiments of Formula (I) or Formula (II), HZ 3 - is a polypeptide backbone can also represent the terminal amino or hydroxyl group of Often, D represents the remainder of the polypeptide backbone. For example, HZ 3 - is the N-terminal amino acid (e.g. For example, it may be the N-terminal amine group of histidine. 3 - Polypeptide The OH-group of the C-terminal carboxylic acid of the terminal amino acid of the amino acid sequence may be the OH-group of the C-terminal carboxylic acid of the amino acid sequence ...

[0216] In some embodiments of the compounds of Formula (I) or Formula (II), Z 3 If does not exist Prior to being conjugated to form a compound of formula (I) or formula (II), The peptide or analog thereof may be described as a compound of the formula H2N-D. In this example, any one of the self-immolative groups M A The following part of the formula in [ka] The portion of the drug after it has been conjugated to form a compound of formula (I) or formula (II) In this portion, x represents the self-immolative group M A’ (as described herein) represents the point of attachment, or the point of attachment of the drug H2N-D to H prior to conjugation, and y represents the point of attachment to D Represents a bond point.

[0217] In some embodiments of the compounds of Formula (I) or Formula (II), Z 3 If does not exist Prior to being conjugated to form a compound of formula (I) or formula (II), The polypeptide or analog thereof may be described as a compound of the formula H2N-D, where: When the GLP-1 polypeptide or analog thereof has the formula H2N-D, the moiety H2N- is represents the terminal amine group of a GLP-1 polypeptide or analog thereof; D represents the terminal amine group of a GLP-1 polypeptide or analog thereof; The peptide may comprise a residue of a polypeptide or an analog thereof.

[0218] In one example, to form a compound of formula (I) or formula (II) described herein, Prior to being conjugated for use in the treatment of cancer, the GLP-1 polypeptide or analog thereof may be represented by the formula HZ 3 D compound, HZ 3 - GLP-1 polypeptide or analogue thereof Represents a reactive amino group or a hydroxyl group (Z 3 are nitrogen or oxygen, In this case, D comprises a residue of a GLP-1 polypeptide or an analog thereof. Conjugates to form compounds of formula (I) or formula (II) as described herein. Prior to being administered, the GLP-1 polypeptide or analogue thereof may be represented by the formula HZ 3 D compound. It can be listed, HZ 3 - is a reactive amino group or represents a hydroxyl group (Z 3 is nitrogen or oxygen, respectively), D is the GLP -1 polypeptide or an analog thereof.

[0219] Non-limiting examples of GLP-1 polypeptides or analogs thereof include: GLP-1(1-37): HDEFERHAEGTFTSDV SSYLEGQAAK EFIAWLVKGR G (SEQ ID NO:1) GLP-1(7-37): HAEGTFTSDV SSYLEGQAAK EFIAWLVKGR G (SEQ ID NO: 2 ) wherein this sequence corresponds to amino acids 7-37 of the GLP-1(1-37) polypeptide sequence. Respond.

[0220] Liraglutide (VICTOZA®, K26 liraglutide) is a lysine-binding agonist. GLP-1 with a C16 fatty acid chain (palmitic acid) via a glutamyl spacer It is a polypeptide analogue and is represented as follows: HAEGTFTSDV SSYLEGQAAK(γ-Glu-palmitoyl)EFIAW LVRGR G (SEQ ID NO: 3) wherein the sequence corresponds to amino acids 7-37 of the GLP-1(1-37) polypeptide sequence. It is similar.

[0221] Liraglutide Fragment 1: HAEGTFTSDV SSYLEGQAAK EFIAWLVRGR G (SEQ ID NO: 4 ) Liraglutide Fragment 2: EGTFTSDV SSYLEGQAAK EFIAWLVRGR G (SEQ ID NO: 5) Liraglutide Fragment 3: TSDV SSYLEGQAAK EFIAWLVRGR G (SEQ ID NO: 6) Liraglutide Fragment 4: AK EFIAWLVRGRG (SEQ ID NO: 7)

[0222] Dulaglutide (LY2189265, TRULICIT Y®) is a molecule consisting of two identical disulfide-linked chains, each of which has a low Human immunoglobulin G4 (IgG4) heavy chain fragment (Fc ) covalently linked to an analog sequence of human GLP-1.

[0223] The GLP-1 analog sequence is represented as follows: HGEGTFTSDV SSYLEEQAAK EFIAWLVKGG G (SEQ ID NO: 8 )

[0224] The immunoglobulin sequences are represented as follows: ESK YGPPCPPCPA PEAAGGPSVF LFPPKPKDTL MIS RTPEVTC VVVDVSQEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTYR VVSVLTVLHQ DWLNGKEYKC KVSNKG LPSS IEKTISKAKG QPREPQVYTL PPSQEEMTKN QV SLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDS D GSFFLYSRLT VDKSRWQEGN VFSCSVMHEA LHNHY TQKSL SLSLG (SEQ ID NO: 9)

[0225] The small peptide linker is represented as follows: GGGGSGGGG SGGGGSA (SEQ ID NO: 10)

[0226] One monomer of dulaglutide (LY2189265, TRULICITY (registered trademark) The full-length sequence of the target gene is represented as follows: HGEGTFTSDV SSYLEEQAAK EFIAWLVKGG GGGGGSG GGGSGGGSAESK YGPPCPPCPA PEAAGGPSVF LFPPKPKDTL MISRTPE VTC VVVDVSQEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTYR VVSVLTV LHQ DWLNGKEYKC KVSNKGLPSS IEKTISKAKG QPR EPQVYTL PPSQEEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD GSFFLYSRLT VDKSRW QEGN VFSCSVMHEA LHNHYTQKSL SLSLG (SEQ ID NO: 11) * *Disulfide bridge position: 55-55′ 58-58′ 90-150 90′-150′ 196-254 19 6′-254′

[0227] Exenatide (BYETTA®, BYDUREON , Exendin-4) and Exenatide LAR (GLP-1 portion is the same). HGEGTFTSDL SKQMEEEAVR LFIEWLKNGG PSSGAPP PS (SEQ ID NO: 12)

[0228] Taspoglutide HXEGTFTSDV SSYLEGQAAK EFIAWLVKXR (SEQ ID NO: 13) where X is 2-methylalanine.

[0229] Lixisenatide (LYXUMIA®) HGEGTFTSDL SKQMEEEAVR LFIEWLKNGG PSSGAPP SKK KKKK (SEQ ID NO: 14) where T is threonine and I is isoleucine.

[0230] Albiglutide (TANZEUM®) is a 17 A polypeptide consisting of 645 proteinogenic amino acids with 1 disulfide bridge Amino acids 1-30 and 31-60 constitute two copies of modified human GLP-1. Complete.

[0231] The GLP1 fragment is represented by: HGEGTFTSDV SSYLEGQAAK EFIAWLVKGR (SEQ ID NO: 15)

[0232] The full length sequence of albiglutide is represented as follows: HGEGTFTSDV SSYLEGQAAK EFIAWLVKGR HGEGTFT SDV SSYLEGQAAK EFIAWLVKGR DAHKSEVAHR FKD LGEENFK ALVLIAFAQY LQQCPFEDHV KLVNEVTEFA KTCVADESAE NCDKSLHTLF GDKLCTVATL RETYGE MADC CAKQEPERNE CFLQHKDDNP NLPRLVRPEV DV MCTAFHDN EETFLKKYLY EIARRHPYFY APELLFFAK R YKAAFTECCQ AADKAACLLP KLDELRDEGK ASSAK QRLKC ASLQKFGERA FKAWAVARLS QRFPKAEFAE V SKLVTDLTK VHTECCHGDL LECADDRADL AKYICENQDS ISSKLKE CCE KPLLEKSHCI AEVENDEMPA DLPSLAADFV ESK DVCKNYA EAKDVFLGMF LYEYARRHPD YSVVLLLRLA KTYETTLEKC CAAADPHECY AKVFDEFKPL VEEPQN LIKQ NCELFEQLGE YKFQNALLVR YTKKVPQVST PT LVEVSRNL GKVGSKCCKH PEAKRMPCAE DYLSVVLNQ L CVLHEKTPVS DRVTKCCTES LVNRRPCFSA LEVDETYVPK EFNAETFTFH ADICTLS EKE RQIKKQTALV ELVKHKPKAT KEQLKAVMDD FAA FVEKCCK ADDKETCFAE EGKKLVAASQ AALGL (sequence number 16)

[0233] Semaglutide (OZEMPIC®) H-Aib-EGTFTSDV SSYLEGQAAK(AEEAc-AEAc-γ-G lu-17-carboxyheptadecanoyl)EFIAWLVRGR G (SEQ ID NO: 17) Here, Aib is α-aminoisobutyric acid.

[0234] A diagram of the selection of GLP-1 analogs is provided in FIG. 8. See also Dods, R. L. and Donnelly, D.Bioscience Reports 36(1)e2085 (Jan.15,2016), and Li,Y et al.Reviews in N See also eurosciences 27(7):689-711(2016).

[0235] In some embodiments, glucagon-like peptide 2 (GLP-2) or an analog thereof is may be used in place of the GLP-1 polypeptides and analogs thereof described herein. Non-limiting examples of GLP-2 polypeptides and analogs thereof include: can be done. GLP-2 HADGSFSDEM NTILDNLAAR DFINWLIQTK ITD (sequence number No. 18)

[0236] Teduglutide (GATTEX®) HGDGSFSDEM NTILDNLAAR DFINWLIQTK ITD (sequence number No. 19)

[0237] FE203799 HGDGSFSDENle[d-Phe]TILDLLAARDFINWLIQTKIT D (SEQ ID NO: 20) Grepaglutide (ZP1848) HGEGTFSSEL ATILDALAAR DFIAWLIATK ITD-KKK KKK (SEQ ID NO:21)

[0238] Elsiglutide (ZP1846) HGEGSFSSELSTILDALAARDFIAWLIATKITDKKKKK(distribution Column number 22)

[0239] Any of the above sequences have at least 80% sequence identity to any of the above sequences For example, the compounds provided herein may be present in a polypeptide having the following properties: At least 80%, at least 85%, at least 88%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, For example, D may comprise a polypeptide having at least 99% sequence identity with GLP and comprising residues of a GLP-1 polypeptide or analog thereof. Analogs may have at least one analogue thereof to the GLP-1 polypeptides or analogs thereof provided herein. at least 80% sequence identity (e.g., at least 85%, at least 88%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%).

[0240] In some embodiments, the polypeptide is between 30 and 100 amino acids in length. 31-100 amino acids long, 35-100 amino acids long, 40-100 amino acids long, 50-1 00 amino acid length, 60-100 amino acid length, 70-100 amino acid length, 80-100 amino acid length amino acid length, 90-100 amino acid length, 30-90 amino acid length, 30-80 amino acid length, 30 ~70 amino acids long, 30~60 amino acids long, 30~50 amino acids long, 30~40 amino acids long 40-60 amino acids long, 50-70 amino acids long, 31-41 amino acids long, or 31 In some embodiments, the polypeptide is less than 50 amino acids in length. For example, less than 45 amino acids in length, less than 40 amino acids in length, or less than 35 amino acids in length. In some embodiments, the polypeptide is between 30 and 300 amino acids in length. For example, 31-300 amino acids long, 50-300 amino acids long, 80-300 amino acids long, 90-300 amino acids in length, 100-300 amino acids in length, 150-300 amino acids in length, or 200-300 amino acids in length.

[0241] Between a particular nucleic acid or amino acid sequence and a sequence referenced by a particular sequence identification number Percent sequence identity is determined as follows: First, BLASTN version 2. BLASTZ stand containing version 0.14 and BLASTP version 2.0.14 Nucleotide sequences were analyzed using the BLAST2 sequence (B12seq) program from Alonversion. Or compare the amino acid sequence to the sequence set forth in a particular sequence identification number. The Alon version of BLASTZ is available at fr.com / blast or ncbi.nlm The B12seq program is available online at nih.gov. Instructions for use can be found in the readme file that accompanies BLASTZ. B12seq uses either the BLASTN or BLASTP algorithm to Performs a comparison between two sequences. BLASTN is used to compare nucleic acid sequences, while BLASTP is used to compare amino acid sequences. To do this, set the following options: -i includes the first nucleic acid sequence to be compared. The -j option is set to the file containing the seql.txt file (e.g., C:\seql.txt), and -j is the 2, a file containing the nucleic acid sequence (e.g., C:\seq2.txt), is set to blastn and -o is any desired filename (e.g. C:\out put.txt), -q is set to -1, -r is set to 2, and everything else is The options are left at their default settings. For example, use the following command to An output file can be generated containing the comparison between the two sequences: C:\B12seq -ic:\seql.txt-j c:\seq2.txt-p blastn-o c:\output.txt-q-1-r 2. To compare two amino acid sequences, Set the B12 sequence options as follows: -i is the first amino acid sequence to be compared. -j is set to the file containing the sequences (e.g., C:\seql.txt) and -j is set to Set to a file (e.g., C:\seq2.txt) that contains the second amino acid sequence to be where -p is set to blastp and -o is any desired filename (e.g. :\output.txt) and all other options are set to their default settings. For example, use the following command to find a comparison between two amino acid sequences: You can generate output files such as: C:\B12seq-i c:\seql.t xt-j c:\seq2.txt-p blastp-o c:\output.tx t. If the two compared sequences share homology, the specified output file will The homologous regions of the two sequences are presented as an aligned sequence. If the two compared sequences do not share homology, The specified output file will not present the aligned sequences.

[0242] When aligned, the number of matches is determined by the number of identical nucleotides or amino acid residues present in both sequences. Percent sequence identity is determined by counting the number of positions where the match occurs. , the length of the sequence shown in the identified sequence (e.g., SEQ ID NO: 1), or the combined length ( For example, 100 consecutive nucleotides or nucleotides from the sequence shown in the identified sequence. amino acid residues) and then multiplying the resulting value by 100. For example, when aligned with the sequence shown in SEQ ID NO:1, there are 25 matches. The amino acid sequence is 95.6% identical (i.e., 25 / 31 × 100 = 80.6). Percent sequence identity values ​​are rounded to the nearest tenth. For example, 75.11, 75.12, 75.13, and 75 .14 ​​is rounded down to 75.1, 75.15, 75.16, 7.17, 75.18, and 7.19 will be rounded up to 7.2. Also note that length values ​​are always integers. I want to be.

[0243] Analogs provided herein include, for example, one or more amino acid substitutions, deletions, or insertions. In some embodiments, the variants include polypeptide variants having at least one In some embodiments, the nucleotide sequence has at least one amino acid substitution, deletion, or insertion. A variant has at least two amino acid substitutions, deletions, or insertions. In one embodiment, the variant comprises at least three amino acid substitutions, deletions, or insertions. As used herein, analogs include fragments. A "fragment" as applied to a peptide is generally at least 10 residues in length, more typically less than 10 residues in length. At least 20 residues, preferably at least 30 residues (e.g., 50 residues), Analogs (e.g., variants and fragments) are known to those skilled in the art. The protein may be defined by known methods, for example, by enzymatic digestion of native or recombinant proteins. by recombinant DNA technology using expression vectors encoding the selected fragments, or by chemical synthesis. It can be generated by:

[0244] In some embodiments, the GLP-1 polypeptides include those of SEQ ID NO: 1 to SEQ ID NO: 22. The tide or analog thereof has the formula (I) (I) (II) (III) (III) (IV ... When conjugated to an aliphatic moiety (e.g., PEG) such as formula (I) or (II), In such cases, the polypeptide is biologically inactive or only weakly biologically active. is released from an aliphatic portion (e.g., a PEG portion) of a compound of formula (I) or formula (II). After the addition of the compound of formula (I) or formula (I The compounds of formula I) have the ability to function as prodrugs in mammals (e.g., humans). In one embodiment, the GLP-1 polypeptide or analog thereof has an aliphatic moiety of formula (I) or formula (II): The unconjugated GLP-1 polypeptide is not released from the PEG moiety (e.g., PEG moiety). In some cases, the β-lactamase inhibitors shown in FIG. As shown, compound 7 (a polypeptide, liraglutide, conjugated to a PEG moiety) The liraglutide is released from the aliphatic portion of compound 7 (e.g., the PEG moiety). It remains inactive compared to unconjugated liraglutide until See Results and Discussion).

[0245] polymer In some embodiments, the aliphatic moiety can be a polymer. Thus, the polymer may be branched or linear. For example, the polymer may be 2 to 100 Ends (e.g., 2-80, 2-75, 2-60, 2-50, 2-40, 2-35, 2- 25, 2~10, 2~5, 4~20, 5~25, 10~50, 25~75, 3~6, ​​5~ In some embodiments, the polymer may have 2 to 5, 4 to 6, 5 to 15 ends. In some embodiments, the polymer is linear. In some embodiments, one end of the polymer is , is covalently bonded to any one of the structures of the formulas provided herein.

[0246] The polymer may be, for example, poly(alkylene glycol), poly(oxyethylated polyol), Poly(olefin alcohol), poly(β-hydroxy acid), poly(vinyl alcohol) The polyalkylene glycol may be a polyoxyethylene glycol, a polyoxazoline, or a copolymer thereof. The polyols include linear or branched polymeric polyether polyols. Alkylene glycols include polyethylene glycol (PEG), polypropylene glycol, Polybutylene glycols, polybutylene glycols, and their derivatives. Other exemplary embodiments are described, for example, in the US Pat. Catalog of "Polyethylene glycols and derivatives for biomedical applications" (200 1) and other commercial supplier catalogs.

[0247] In some embodiments, such polymeric polyether polyols have a molecular weight of about 0.1 kD For example, such a polymeric polyether polyether has an average molecular weight of about 100 kDa. Oars include, but are not limited to, about 500 Da to about 100,000 Da or more. The molecular weight of the polymer may be from about 500 Da to about 100,000 Da. For example, As used herein, the polymers are of about 100,000 Da, 95,000 Da, 90, 000Da, 85,000Da, 80,000Da, 75,000Da, 70,000D a, 65,000Da, 60,000Da, 55,000Da, 50,000Da, 45 ,000Da, 40,000Da, 35,000Da, 30,000Da, 25,000 Da, 20,000Da, 15,000Da, 10,000Da, 9,000Da, 8, 000Da, 7,000Da, 6,000Da, 5,000Da, 4,000Da, 3, 000Da, 2,000Da, 1,000Da, 900Da, 800Da, 700Da, In some embodiments, the polymer may have a molecular weight of 600 Da, 500 Da, or 600 Da. The molecular weight of the polysaccharide is about 500 Da to about 50,000 Da. The molecular weight of the mer is from about 500 Da to about 40,000 Da. The molecular weight of the polymer is from about 1,000 Da to about 40,000 Da. In some embodiments, the molecular weight of the polymer is about 5,000 Da to about 40,000 Da. In one embodiment, the molecular weight of the polymer is from about 10,000 Da to about 40,000 Da. .

[0248] In some embodiments, the polymer is a linear or branched poly(ethylene glycol ).

[0249] In some embodiments, the poly(ethylene glycol) molecule is a linear polymer. Linear PEG can be alkylated (e.g., methylated or ethylated) at one end. However, they can be used in the present specification using the free terminus in its underivatized hydroxyl form. The linear P may be incorporated into any one of the conjugates of the formula disclosed in The molecular weight of the EG may be about 1,000 Da to about 100,000 Da. The linear PEGs used in the specification are approximately 100,000 Da, 95,000 Da, and 90,000 Da. 0Da, 85,000Da, 80,000Da, 75,000Da, 70,000Da, 65,000Da, 60,000Da, 55,000Da, 50,000Da, 45,0 00Da, 40,000Da, 35,000Da, 30,000Da, 25,000Da , 20,000Da, 15,000Da, 10,000Da, 9,000Da, 8,00 0Da, 7,000Da, 6,000Da, 5,000Da, 4,000Da, 3,00 The molecular weights may be 0 Da, 2,000 Da, and 1,000 Da. In this embodiment, the molecular weight of the linear PEG is about 1,000 Da to about 50,000 Da. In some embodiments, the molecular weight of the linear PEG is from about 1,000 Da to about 40,000 Da. In some embodiments, the molecular weight of the linear PEG is about 5,000 Da to about 40,000 Da. In some embodiments, the molecular weight of the linear PEG is from about 5,000 Da to about It is 20,000Da.

[0250] In some embodiments, the poly(ethylene glycol) molecule is a branched polymer. For example, branched PEGs can be V-shaped or T-shaped, depending on how the PEG was synthesized. The molecular weight of the branched PEG may be about 1,000 Da to about 100,000 Da. For example, branched PEGs as used herein are those having a molecular weight of about 100,000 Da, 95,000 Da, or 100,000 Da. 0Da, 90,000Da, 85,000Da, 80,000Da, 75,000Da, 70,000Da, 65,000Da, 60,000Da, 55,000Da, 50,0 00Da, 45,000Da, 40,000Da, 35,000Da, 30,000Da , 25,000Da, 20,000Da, 15,000Da, 10,000Da, 9,0 00Da, 8,000Da, 7,000Da, 6,000Da, 5,000Da, 4,0 The molecular weights may be 0, 3,000 Da, 2,000 Da, and 1,000 Da. In some embodiments, the molecular weight of the branched PEG is from about 1,000 Da to about 50,000 Da. In some embodiments, the molecular weight of the branched PEG is about 1,000 Da to about 1,000 Da. In some embodiments, the molecular weight of the branched PEG is about 5, In some embodiments, the branched PEG molecule is from about 1,000 Da to about 40,000 Da. The amount is about 5,000 Da to about 20,000 Da.

[0251] In some embodiments, the polyethylene glycol (linear or branched) is about 50 0Da~approx. 40,000Da, approx. 1,000Da~approx. 30,000Da, approx. 1,000Da and an average molecular weight of about 5,000 Da to about 20,000 Da. .

[0252] In some embodiments, the polymers provided herein (e.g., polyethylene glycol) are Cole) has the following structural formula: [ka]

[0253] In some embodiments, n is 1 to 1,000, 1 to 800, 1 to 300, or 1 In some embodiments, n is an integer between 10, 20, 50, 100, 2 00, 250, 300, 500, 600, and 1000.

[0254] Further examples of suitable polymers can be found, for example, in Chen. S. et al. Polymer 51 (2010) 5283-5293, which is hereby incorporated by reference in its entirety. The body is incorporated herein.

[0255] Exemplary Compounds Non-limiting examples of compounds provided herein include: [ka] JPEG2025023928000123.jpg207166JPEG2025023928000124.jpg81166, or a pharma- ceutically acceptable salt thereof, wherein liragluzide is a residue of liragluzide. and Ura is uracil.

[0256] Pharmaceutically acceptable salts In some embodiments, the compound of formula (I) or formula (II) disclosed herein A salt is formed between an acidic and a basic group of a compound, such as an amino functional group, or a carboxyl functional group. According to another embodiment, the compound The compound is a pharma- ceutically acceptable acid addition salt.

[0257] In some embodiments, the compound of formula (I) or formula (II) disclosed herein Acids commonly used to form pharma- ceutically acceptable salts include inorganic acids, e.g. , hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, as well as organic acids. , e.g., para-toluenesulfonic acid, salicylic acid, tartaric acid, ditartaric acid, ascorbic acid , Maleic acid, Fumaric acid, Gluconic acid, Glucuronic acid, Formic acid, Glutamic acid, Methanesulfonate sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromopheny sulfonic, carbonic, succinic, citric, benzoic, and acetic acids, and related inorganic acids. Such pharma- ceutically acceptable salts include those derived from organic acids and organic acids. , sulfate, pyrosulfate, bisulfate, sulfite, hydrogen sulfite, phosphate, monohydrogen phosphate , dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, Propionate, decanoate, caprylate, formate, isobutyrate, caprate, heptahydrate Tannate, propiolate, oxalate, malonate, succinate, suberate, sebacate Synthetic acid salts, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6 -Dioates, benzoates, chlorobenzoates, methylbenzoates, hydroxybenzoates Salt, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate Phosphate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate Salt, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfone acid salt, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate In one embodiment, pharma- ceutically acceptable salts include phosphates, mandelates, and other salts. Suitable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, particularly malic acid. Examples include those formed with organic acids such as leic acid.

[0258] In some embodiments, the compound of formula (I) or formula (II) disclosed herein Bases commonly used to form pharma- ceutically acceptable salts include sodium, Alkali metal hydroxides, including potassium and lithium; calcium and magnesium hydroxides of alkaline earth metals such as aluminum; hydroxides of other metals such as aluminum and zinc Ammonia, unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkyl Amines, organic amines such as dicyclohexylamine; tributylamine; pyridine; N- Methyl, N-ethylamine; Diethylamine; Triethylamine; N,N-Dimethyl-N -(2-hydroxyethyl)amine, such as mono-, bis-, or tris-(2-OH- (C1-C6)-alkylamine; morpholine; thiomorpholine; or tri-(2- Hydroxyethylamine;N-Methyl-D-glucamine;Morpholine;Thiomorpholine piperidine; pyrrolidine; and amino acids such as arginine and lysine. can be.

[0259] In some embodiments, a compound of formula (I) or formula (II) disclosed herein: or a pharma- ceutically acceptable salt thereof is substantially isolated.

[0260] In some embodiments, the present application relates to any one of the processes described herein. or a compound of formula (I) or formula (II) disclosed herein, prepared by Pharmaceutically acceptable salts thereof are provided.

[0261] Hydrolytic cascade The conjugates provided herein comprise a conjugate of a GLP-1 polypeptide or an analog thereof. In some embodiments, release of the drug occurs under physiological conditions. In some embodiments, the compound undergoes selective cleavage of one or more chemical bonds. Without being bound by any particular theory, the conjugate may be represented by the following scheme: According to any one of the mechanisms described, GLP-1 polypeptides or analogs thereof It is believed that it may provide bodily release. Scheme 4 [ka]

[0262] Compounds of formula (I) or (II) can be prepared by reacting the hydrolysis product with the amine as depicted in Scheme 4. Cade and biologically active drug HZ 3 -D or HO-(C=O)-D Referring to Scheme 4, a compound of formula (I) or formula (II) can be prepared by the synthesis described herein. When subjected to physiological pH, acidic pH, or enzymatic conditions, moiety E is selectively cleaved and reacted. Compound 2a-1 is left containing a reactive nucleophilic group -AH (e.g., -OH), which is then reacted with the phosphorus atom. Accordingly, the cyclic compound 2a-2 and the self-immolative group M A leading to the formation of compound 2a-5, The decomposition of the self-immolative group in compound 2a-5 is carried out by the reaction of the group M A’ and the biologically active drug HZ 3 - This leads to the formation of compounds 2a-4 containing cyclic phosphotrimethylsilyl groups, D or HO-(C=O)-D. Ester 2a-2 can be further hydrolyzed at physiological pH to open the five-membered ring and to give both heterocyclic groups. This can result in the formation of a dimer phosphodiester. [ka]

[0263] In some embodiments, the compound of Formula (I) or Formula (II) can be prepared according to the method described in Scheme 5. As shown, the hydroxyl group can undergo a hydrolytic cascade to release the biologically active drug. Scheme 5 [ka]

[0264] In some embodiments, the compound of Formula (I) or Formula (II) can be prepared according to the method described in Scheme 6. As shown in FIG. 1, the GLP-1 polypeptide undergoes a hydrolytic cascade to release the GLP-1 polypeptide or its analog. It can be released. Scheme 6 [ka]

[0265] In some embodiments, M A is of formula (I) or formula (II) is of formula (i) group, the release cascade can occur according to the mechanism shown in Scheme 7. Scheme 7 [ka]

[0266] In some embodiments, M A is of formula (I) and is a stable diradical of formula (l) In some cases, the release cascade can occur according to the mechanism shown in Scheme 8. Scheme 8 [ka]

[0267] Exemplary Methods for Studying Cleavage Reaction Ratios The degree of release of biologically active drugs from conjugates containing cleavable acyl groups An exemplary method for studying the degree of cleavage is shown in the following scheme. In some embodiments of any of, U is an optionally substituted uracil. Scheme 9 [ka]

[0268] Referring to Scheme 9, cleavage of the phosphotriester followed by reverse phase (RP) HPLC Separation and quantification of the liberated DMTr-hydroxybenzyl alcohol is performed. Scheme 10 [ka]

[0269] Referring to Scheme 10, the progress of the release reaction is observed by observing the umbelliferone fluorescence that occurs. This can be monitored by Scheme 11 [ka]

[0270] Referring to Scheme 11, the disappearance of fluorescence from the high MW starting material and the formation of the low MW product. The formation can be monitored using gel permeation chromatography with fluorescence detection.

[0271] Method of preparation Compounds of formula (I) or (II) The compounds provided herein are disclosed in PCT / IB2018 / 051579 (WO2018 It can be prepared using methods similar to those described in (163131). No. 6,399,433, which is incorporated herein by reference in its entirety.

[0272] Exemplary synthetic methods for preparing compounds of Formula (I) or Formula (II) of the present disclosure are described below. Please see below. Scheme 12 [ka]

[0273] In some embodiments, the present application provides a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, Compounds of formula (II-IV) [ka] formula HZ 3 -D with a biologically active drug, In the formula, R 1 , R 2 , Z 1 , Z 3 ,D, A , A, E, E 1 , LG, and the aliphatic portion are As described herein.

[0274] In some embodiments, the reaction is carried out in an aqueous solvent.

[0275] In some embodiments, the reaction is carried out in 0.1-0.5 M phosphate buffer, HEPES (4 -(2-hydroxyethyl)-1-piperazineethanesulfonic acid) or in carbonate buffer. In some embodiments, the reaction is carried out at a pH of about 7.2 to about 8.5 and at a temperature of about 0° C. to about In some embodiments, the reaction is carried out at about room temperature for about 30 minutes to about 12 hours. It is held.

[0276] In some embodiments, the compound of formula (II-IV) is i) deprotecting the compound of formula (II-Va), [ka] Obtaining a compound of formula (II-Vb), [ka] ii) reacting the compound of formula (II-Vb) with a compound containing a leaving group to give a compound of formula (II-I V).

[0277] In some embodiments, the deprotection comprises treating a compound of Formula (II-Va) with an acid. include.

[0278] In some embodiments, the compound containing a leaving group is an activated carbonate. For example, The activated carbonate has formula (Vc) or formula (Vd) as described herein. [ka]

[0279] In some embodiments, the compound of formula (II-Va) is a compound of formula (II-VIa) of, [ka] with an aliphatic moiety (e.g., a polymer) that contains a reactive hydroxyl group. It is prepared by the method.

[0280] In some embodiments, the reaction is carried out with an activating reagent (e.g., stoichiometrically with phosphate). This reacts to form a mixed acid anhydride, which is then converted to, for example, methyl imidazolide, and finally In some embodiments, the reaction is carried out in the presence of an active agent, which reacts with the OH groups of the polymer. The activating agent is mesitylenesulfonyl chloride or mesitylenesulfonyl nitrotriazole. (MSNT) or tosyl chloride.

[0281] In some embodiments, the compound of formula (II-VIa) is a compound of formula (II-VIb) It is prepared by deprotecting the compound. [ka]

[0282] In some embodiments, the deprotection is performed by removing the phosphate protecting group, PG 1 is selectively removed , so as to obtain compounds of formula (II-VIa).

[0283] In some embodiments, the deprotection is carried out in the presence of a base. The base is diisopropylethylamine or 1,8-diazabicyclo[5.4.0 ]undec-7-ene (DBU) or triethylamine.

[0284] In some embodiments, the compound of formula (II-VIb) is a compound of formula (II-VIIa) The mixture, [ka] with a compound of formula (II-VIIb), [ka] wherein each R is independently a C1-C6 alkyl, or two R groups are Together with the N to which it is attached, it forms a 5- or 6-membered ring. In some embodiments, each R is isopropyl. In some embodiments, the two R groups together form a morpholine ring. Form.

[0285] In some embodiments, the reaction is carried out in the presence of an activating reagent. The drugs are tetrazole, 2-ethylthiotetrazole, 2-benzylthiotetrazole, 4, 5-Dicyanoimidazole, activator 42, pyridinium hydrochloride and pyridinium trifluoroacetate.

[0286] In some embodiments, step 2 of the reaction is carried out in the presence of an oxidizing reagent. For example, an oxidizing agent can convert a phosphorus atom to the oxidation state P +3 to oxidation state P +5 Oxidizing agent Examples of such agents include iodine, hydrogen peroxide, t-butyl hydrogen peroxide, or acetone peroxide. Can be obtained.

[0287] In some embodiments, the compound of formula (II-VIIa) has the formula (II-VIIIa) The compound [ka] with a compound of formula (VIIIb), [ka] wherein Hal is a halogen atom (e.g., Cl, Br, or I) and R is as defined herein. In some embodiments, Hal is Cl.

[0288] In some embodiments, the reaction is carried out in the presence of a base.

[0289] In some embodiments, Z 3 When is not present, the compound of formula (II) can be, for example, It can be prepared from compounds of formula (II-Vb) according to scheme 13. Scheme 13 [ka]

[0290] In some embodiments, a compound of formula (II) can be prepared as depicted in Scheme 14. It can be manufactured. Scheme 14 [ka]

[0291] In some embodiments, compounds of formula (II) can be prepared as depicted in Scheme 15. It can be manufactured. Scheme 15 [ka]

[0292] In some embodiments, compounds of formula (II) can be prepared as depicted in Scheme 16. It can be manufactured. Scheme 16 [ka]

[0293] In some embodiments, M A is a stable diradical of formula (k-1), Compounds of formula (II) may be prepared as described in Scheme 17. Scheme 17 [ka]

[0294] In some embodiments, the present document provides a compound of formula [ka] The present invention provides a compound of formula (I) or (II), or a pharma- ceutically acceptable salt thereof, wherein the aliphatic moiety, R 1 , R 2 , A, E, and D are as described herein The method is as described above, A compound of the formula [ka] wherein LG is a leaving group as described herein, 3 -D GLP-1 This involves reacting with a polypeptide or an analog thereof.

[0295] In some embodiments, the compound of the formula: [ka] (i) by deprotecting a compound of the formula: 1 is a protecting group as described herein. be), [ka] Obtaining a compound of formula [ka] (II) reacting the compound obtained in step (i) with a compound containing a leaving group as described herein; and reacting with

[0296] In some embodiments, the compound of the formula: [ka] (i) reducing a compound of the formula: [ka] Obtaining a compound of formula [ka] (II) reacting the compound obtained in step (i) with a compound containing a leaving group as described herein; and reacting the compound with a compound having the formula (i) to effect the reduction of the compound. Suitable examples of such reagents include, but are not limited to, NaBH4 and LiAlH4. do.

[0297] Suitable methods for the synthesis of starting materials, intermediates, and products are readily available by reference to the literature. The reference source is Advances in Heterocycli c Chemistry,Vols.1-107(Elsevier,1963-201 2), Journal of Heterocyclic Chemistry Vol. s.1-49(Journal of Heterocyclic Chemistry ,1964-2012), Carreira,et al.(Ed.)Science of Synthesis, Vols.1-48(2001-2010), Katrit zky et al.(Ed.);Comprehensive Organic Fu nctional Group Transformations II (Elsev ier,2 nd Edition, 2004), Smith et al., March 's Advanced Organic Chemistry:Reactions, Mechanisms, and Structures, 6 th Ed. (Wiley, 2 007), Trost et al. (Ed.), Comprehensive Org. Anic Synthesis (Pergamon Press, 1991) is an example. do.

[0298] Preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups. The chemistry of protecting groups is described, for example, in PGM Wuts and TW Greene, Pr otective Groups in Organic Synthesis,4 th Ed., Wiley & Sons, Inc., New York (2006) Chemistry and protecting group strategies related to nucleosides and nucleotides are described in detail in the Pi Methods in Molecula, edited by E. et Hardewijn r Biology-Oligonucleotide Synthesis(Huma na Press Inc. 2005) and edited by Sudhir Agrawal Compiled Protocols for Oligonucleotide Conjugation The method can also be found in the book "The Humana Press Inc. 1994." The materials and intermediates are readily available from a variety of commercial sources.

[0299] Methods of Use of the Disclosed Compounds Methods of Treating a Disease or Condition In some embodiments, the present disclosure provides a method for treating a mammal (e.g., a mammal in need of such treatment). The present invention provides a method for treating a disease, disorder, or condition in a mammal (human), comprising administering to the mammal a compound according to the present invention. A compound of formula (I) or formula (II) disclosed in, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition containing same.

[0300] For example, the compounds of the present disclosure may be administered to a subject a GLP-1 polypeptide or is useful in treating a disease or condition that is beneficially treated by administering an analog thereof. do.

[0301] In some embodiments, the compounds of the disclosure are useful for, e.g., regulating or suppressing appetite in a subject. This is useful in reducing food intake by a subject.

[0302] In some embodiments, the disease or condition is obesity.

[0303] In some embodiments, the disease or condition is diabetes, including type 1 diabetes, type 2 diabetes , gestational diabetes, surgery-induced diabetes, and chemically-induced diabetes, as well as adults (LADA or This includes latent autoimmune diabetes in type 1.5 or type 2 diabetes.

[0304] Combination therapy For the treatment of a disease, disorder or condition described herein, one or more additional agents or or a method of treatment in combination with any one of the conjugates described herein. The drugs can be combined with the compounds in a single dosage form. Alternatively, the agents may be administered simultaneously or sequentially as separate dosage forms.

[0305] Suitable additional agents contemplated for use in combination with the compounds of the present disclosure are described herein. The present invention relates to a method for treating a patient having a disease comprising administering to said patient a therapeutically effective amount of GLP-1 or an analog thereof, ... can.

[0306] Non-limiting examples of additional agents include insulin (e.g., fast-acting insulin (within minutes) (effective within 2-4 hours); normal-acting or short-acting insulin (acts within 30 minutes and lasts for 3-6 hours); intermediate-acting insulin (acts within 1-2 hours) long-acting insulin (effective within 1-2 hours, lasts up to 18 hours); long-acting insulin (acts within 1-2 hours and lasts for 42 hours) )); AFREZZA® (inhaled insulin); TRESIBA® (insulin degludec and insulin aspart injection); RYZODEG (registered trademark Target) 70 / 30 (insulin degludec and insulin aspart injection); LEVEM IR (registered trademark) (insulin detemir); LANTUS (insulin glargine); B YETTA® (exenatide; exenden-4); VICTOZA (registered trademark SAXENDA® (liraglutide); ALBIGLU TIDE® (Tanzum, Eperzan); TRULICITY® (De tulaglutide; OZEMPIC (registered trademark) (semaglutide); chlorpropamide (D iabinese (registered trademark), glimepiride (Amaryl (registered trademark), zide (Glucotrol®), glyburide (Diabeta®, Glynase®), nateglinide (Starlix®), and Increasing insulin production by the pancreas, including repaglinide (Prandin®) Medications that cause side effects include acarbose (Precose®), miglitol (Glyset®), drugs that decrease glucose absorption by the intestine, such as pioglitazone (Actos®); body insulins such as rosiglitazone (Avandia®) and rosiglitazone (Avandia®). Drugs that improve the way you use your medicine; such as metformin (Glucophage®) Alogliptin (Ne) is a drug that reduces glucose production by the liver and improves insulin resistance. sina®), dulaglutide (Trulicity®), Liptin (Tradjenta®), Exenatide (Byetta®) ), Bydureon®), liraglutide (Victoza®), Lixisenatide (Adlyxin®), saxagliptin (Onglyza®), ), sitagliptin (Januvia®), and semaglutide ( Ozempic®) to increase insulin production by the pancreas and its blood levels drugs that reduce glucose production from the cerebrospinal fluid and / or liver; canaglifozin (Invok ana®), dapagliflozin (Farxiga®), and enantiostat Pagliflozin (Jardiance®) inhibits glucose reabsorption by the kidneys A drug that blocks sodium-glucose cotransport and increases urinary glucose excretion. SGLT2 inhibitors; pramlinitide (Symlin®); Empagliflozin Flozin / linagliptin (Glyxambi®); orlistat (XEN ICAL®; lorcaserin (BELVIQ®); phentermine - Topiramate (QSYMIA®); Naltrexone-Bupropion (CON TRAVE®) Phentermine; Benzphetamine; Diethylpropion; and phendimetrazine.

[0307] In some embodiments, the methods provided herein comprise two or more of the methods provided herein. The above compounds may be included in combination. For example, two compounds may have different release profiles. (e.g., a longer T1 / 2 and a shorter T1 / 2).

[0308] Methods for the safe and effective administration of most of these drugs are known to those of skill in the art. The administration of many drugs is described in the standard literature. The Physicians' Desk Reference (PDR, e.g., 1 996 edition,Medical Economics Company,Mo (St. Vale, NJ), the disclosure of which is incorporated herein in its entirety. No. 6,399,413, which is incorporated herein by reference as if fully set forth herein.

[0309] Pharmaceutical Compositions and Formulations The present application also relates to a compound comprising an effective amount of any of formula (I) or formula (II) disclosed herein. or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier. Also provided are pharmaceutical compositions. The carrier(s) are compatible with the other ingredients of the formulation and are pharma- ceutically acceptable. Possible carriers include those that, in the amounts employed in the formulation, are not harmful to the recipient thereof. "Acceptable" in taste.

[0310] Pharmaceutically acceptable carriers, adjuvants, etc. that may be used in the pharmaceutical compositions of the present application. The vehicle may be an ion exchanger, alumina, aluminum stearate, lecithin, etc. Serum proteins (e.g. human serum albumin), buffers (e.g. phosphate), glycine, Sorbate, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salt, Electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, chloride Sodium, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone , Cellulosic materials, Polyethylene glycol, Sodium carboxymethylcellulose , polyacrylate, wax, polyethylene-polyoxypropylene-block polymer Examples of suitable polyether ether esters include, but are not limited to, polyethylene glycol, and wool fat.

[0311] The composition or dosage form may comprise a compound of formula (I) or formula (II) described herein in an amount of 0. The remainder may be in the range of 0.05% to 100% of a suitable pharma- ceutically acceptable excipient. The contemplated compositions are comprised of a compound represented by formula (I) or (II) as provided herein. The compound may contain 0.001% to 100%, and in one embodiment, 0.1 to 95%. In another embodiment, the content may be 75 to 85%, and in a further embodiment, the content may be 20 to 80%. The remainder is any pharma- ceutically acceptable excipient described herein, or any of these excipients. It may be comprised of any combination of excipients.

[0312] Route of administration and dosage form Pharmaceutical compositions of the present application include those suitable for any acceptable route of administration. Possible routes of administration include, but are not limited to, intraoral, intradermal, intracervical, intrasinus, intraperitoneal ... Intraluminal, enteral, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intravesical, intracerebral, intracisternal, coronary Intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, lymphatic Intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intranasal sinus, spinal cord intravenous, intrasynovial, intratesticular, intramedullary, intrathecal cavity, intracanal, intratumor, intrauterine, intravascular, intravenous, intranasal, Nasogastric, oral, parenteral, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical These include transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and intravaginal.

[0313] The compositions and formulations described herein may be conveniently presented in unit dosage form, e.g., tablets, sustained release formulations, or the like. The compositions may be provided in capsules, and liposomes, and may be prepared by any method well known in the art of pharmacy. For example, see Remington: The Science and Practice ice of Pharmacy, Lippincott Williams & Wi See Links, Baltimore, MD (20th ed. 2000). Such preparations may include the step of bringing into association with the administered molecule one or more accessory ingredients. Generally, the composition includes a step of providing the active ingredient in a liquid carrier, Uniformly and intimately associated with liposomes, or finely divided solid supports, or both. and then, if necessary, forming the product.

[0314] In some embodiments, the compounds of formula (I) or (II) disclosed herein The compositions of the present application suitable for oral administration are each administered in a predetermined amount (e.g., an effective A separate unit, such as a capsule, sachet, granule or tablet, powder or tablet containing a quantity (amount) of active ingredient or granules, solutions or suspensions in aqueous or non-aqueous liquids, oil-in-water liquid emulsions, It has been presented as a water-in-oil liquid emulsion, loaded into liposomes, or as a bolus. Soft gelatin capsules may be useful for containing such suspensions, In the case of tablets for oral use, the commonly used Carriers include lactose, sucrose, glucose, mannitol, as well as silicic acid and Other acceptable excipients include: a) starch, lactose. , fillers or bulking agents such as sucrose, glucose, mannitol, and silicic acid, b ) For example, carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidino b) binders such as glycerol, sucrose, and acacia; c) humectants such as glycerol; d) cold storage agents such as glycerol. Celery, calcium carbonate, potato or tapioca starch, alginic acid, certain silicic acids disintegrants such as salts and sodium carbonate; e) dissolution retardants such as paraffin; f) quaternary g) absorption enhancers such as ammonium compounds, e.g., cetyl alcohol and monostearate h) wetting agents such as glycerol phosphate, and absorbents such as kaolin and bentonite clays; and i) talc, calcium stearate, magnesium stearate, stearin salts, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For oral administration in capsule form, useful diluents include laminar When administered orally, the aqueous suspension contains The ingredients are combined with emulsifying and suspending agents. Optionally, certain sweetening agents and / or Compositions suitable for oral administration may contain flavoring and / or coloring agents. Lozenges containing the sucrose component, usually sucrose and acacia or tragacanth, and in an inert base such as gelatin and glycerin, or sucrose and acacia. Pastilles containing the active ingredient are included.

[0315] Compositions suitable for parenteral administration include those containing antioxidants, buffers, bacteriostats, and formulations that are suitable for parenteral administration. Aqueous and non-aqueous sterile injection or infusion solutions that may contain solutes to make them isotonic with the patient's blood. These include solutions, as well as aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents. The formulations may be presented in single-dose or multi-dose containers, e.g., sealed ampoules and vials. A sterile liquid carrier, such as water for injection, saline or 5% dextrose, may be provided. The freeze-dried (lyophilized) form requires only the addition of the lyophilized solution immediately before use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets. Injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and Sterile injectable preparations can also be formulated using non-toxic parenteral agents and suspensions. as a solution in a commercially acceptable diluent or solvent, for example in 1,3-butanediol The acceptable vehicles and compositions that may be employed may also be used in the preparation of pharmaceutical compositions, such as pharmaceutical compositions, ... Among the solvents are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids and their glyceride derivatives, such as glyceryl esters, are naturally occurring, pharma- ceutical and / or soluble fatty acids, and their glyceride derivatives are useful in the preparation of injectables. In particular, the polyoxygenases thereof are suitable for use in the preparation of polyoxyethylene terephthalate-based products, for example olive oil or castor oil. These oil solutions or suspensions also contain long chain alcohols. The composition may also contain a diluent or dispersant.

[0316] The pharmaceutical compositions of the present application may be administered in the form of suppositories for rectal administration. The composition comprises a compound of the present application that is solid at room temperature but liquid at rectal temperature, and thus It is prepared by mixing with a suitable non-irritating excipient which melts in the rectum and releases the active ingredient. Such materials include cocoa butter, beeswax, and polyethylene glycol. Includes but is not limited to recalls.

[0317] The pharmaceutical compositions of the present application may be administered by nasal aerosol or inhalation. The compounds are prepared according to techniques well known in the art of pharmaceutical formulation, and may be prepared by adding benzyl alcohol or or other suitable preservatives, absorption enhancers to enhance bioavailability, fluoro Using carbon, and / or other solubilizing or dispersing agents known in the art. The drug may be prepared as a solution in saline. See, for example, U.S. Pat. No. 6,803,031. Additional formulations and methods for intranasal administration are described in Ilium, L., JP harm Pharmacol,56:3-17,2004 and Ilium,L. , Eur J Pharm Sci 11:1-18,2000.

[0318] The topical compositions of the present disclosure may be in the form of an aerosol spray, a cream, an emulsion, a solid, a liquid, Dispersions, foams, oils, gels, hydrogels, lotions, mousses, ointments, powders, patches, In the form of pomades, solutions, pump sprays, sticks, towelettes, soaps, or topically and / or other forms commonly used in the field of cosmetic and skin care formulations. The topical composition may be in the form of an emulsion. Topical administration of the pharmaceutical compositions of the present application allows the desired treatment to be easily accessible by topical application. These compositions are particularly useful when they involve an area or organ. A compound of formula (I) or formula (II) disclosed herein and one or more additional components, carriers, Combinations of carriers, excipients, or diluents, including but not limited to, absorbents, anti-irritants, anti-inflammatory agents, Acne agents, preservatives, antioxidants, colorants / pigments, emollients (moisturizers), emulsifiers, film-forming agents Retention agents, Fragrances, Leave-on scrubs, Prescription drugs, Preservatives, Scrubbing agents, Silicones , skin identity agents / repair agents, slip agents, sunscreen actives, surfactants / detergents, cleaning agents, Penetration enhancers, and viscosity enhancers.

[0319] The compounds of the present application may be used in prostheses, artificial valves, vascular grafts, stents, or catheters. The composition may be incorporated into compositions for coating implantable medical devices such as catheters. Suitable coatings and the general preparation of coated implantable devices are described in detail in US Pat. As known in the art, U.S. Pat. Nos. 6,099,562 and 5,886,026 and 5,304,121. The coating is typically Hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol Biocompatible polymers such as poly(lactic acid), ethylene vinyl acetate, and mixtures thereof The coating is optionally made of fluorosilicone, polysaccharide, polyethylene glycol, etc. The polymer may be further covered by a suitable topcoat of oleyl, phospholipid, or combination thereof. The coating for the invasive device may be a medicament for providing controlled release properties to the composition. As these terms are used herein, pharma- ceutically acceptable carriers, adjuvants, Or should be included within the definition of vehicle.

[0320] According to another embodiment, the present application provides a composition comprising a compound of the present application or a compound of the present application. and providing an implantable drug delivery device impregnated with or containing the compound, whereby the compound is delivered to the subject It is released from the device and is therapeutically active.

[0321] Dosage and Regimen In the pharmaceutical compositions of the present application, the compound of formula (I) or formula (II) disclosed herein is The combination is present in an effective amount (eg, a therapeutically effective amount).

[0322] The effective dose will depend on the disease being treated, the severity of the disease, the route of administration, the sex, age, and activity of the subject. and overall health, excipient use, possible co-use with other therapeutic treatments, e.g. other effects It may vary depending on the use of the substance and the judgment of the treating physician.

[0323] In some embodiments, the compound of formula (I) or formula (II) disclosed herein The effective amount is, for example, about 0.001 mg / Kg to about 500 mg / Kg (for example, about 0.00 1mg / Kg ~ approx. 200mg / Kg; approx. 0.01mg / Kg ~ approx. 200mg / Kg; approx. 0 .01mg / Kg~about 150mg / Kg;about 0.01mg / Kg~about 100mg / Kg; Approx. 0.01mg / Kg~Approx. 50mg / Kg; Approx. 0.01mg / Kg~Approx. 10mg / Kg; Approx. 0.01mg / Kg ~ Approx. 5mg / Kg; Approx. 0.01mg / Kg ~ Approx. 1mg / Kg; Approx. 0 .01mg / Kg~about 0.5mg / Kg;about 0.01mg / Kg~about 0.1mg / Kg; Approx. 0.1mg / Kg~Approx. 200mg / Kg; Approx. 0.1mg / Kg~Approx. 150mg / Kg; Approx. 0.1mg / Kg~Approx. 100mg / Kg;Approx. 0.1mg / Kg~Approx. 50mg / Kg;Approx. 0.1mg / Kg~Approx. 10mg / Kg; Approx. 0.1mg / Kg~Approx. 5mg / Kg; Approx. 0.1 mg / Kg to about 1 mg / Kg; about 0.1 mg / Kg to about 0.5 mg / Kg) It is possible.

[0324] The aforementioned dosages may be administered daily (e.g., as a single dose or as two or more divided doses, once a day, twice a day, three times a day) or not every day (e.g., every other day, every other day) can be administered once a week, once every three days, once a week, twice a week, once every two weeks, or once a month .

[0325] kit The present invention also relates to methods for treating, for example, the disorders, diseases and conditions mentioned herein. Useful pharmaceutical kits include pharmaceutical compositions containing therapeutically effective amounts of the compounds of the present disclosure. Such a kit may optionally contain one or more containers for containing the items. Various conventional pharmaceutical kit components, such as, for example, one or more pharma- ceutically acceptable carriers, The container may further include a container having a body, an additional container, etc. such as the amount of the ingredient to be administered, guidelines for administration, and / or Instructions providing mixing guidelines may also be included in the kit. EXAMPLES

[0326] Unless otherwise stated, all reagents were obtained from known commercial suppliers. Standard laboratory and analytical procedures were employed unless otherwise noted.

[0327] Example 1 - Synthesis of FMOC-based liraglutide conjugates [ka] Step 1. Reacting FMOC-Cl with aminouridine to give carbamate 1 2'-aminouridine (1 mol equivalent) was dissolved in water (10 ml / mmol) to obtain a 1M solution. A mixture of aqueous NaHCO3 (3 mol equivalents) and approximately 20% dioxane was added and mixed. The mixture was cooled to 0° C. Fluorenylmethyl chloroformate (2 mol equiv.) was dissolved in dry The solubility of the reaction mixture was reduced by the addition of dioxane. After stirring for 1 h, chloroformic acid (1 mol equiv.) was added and the mixture was stirred for another 1 The cooling was removed and the aqueous reaction mixture was extracted three times with 10% MeOH / DCM. The organic phase was evaporated to dryness. The residue was purified by elution with a MeOH-DCM gradient (2–4–6% ) and chromatographed through silica gel 60A to obtain 2'-N-(F 2'-N-(FMOC)uridine (2'-N-(FMOC)uridine) is a white solid. The compounds were isolated as isomers (yields: 65-75%).

[0328] Step 2. Uridine 2'-N-carbamate 1 is 5'-O-pivaloylated to give 5'- Methods for obtaining O-pivaloyluridine-2'-N-carbamate 2 Compound 1 (1 mol equivalent) was dried by coevaporation with dry pyridine, and the residue was was dissolved in dry pyridine (2.5 mL / mmol) and cooled to 0°C. 1.2 mol equivalent) was dissolved in dichloromethane (2.5 mL / mmol) and pyridine dissolved. After complete addition, the mixture was stirred at room temperature for 15 hours (overnight). The reaction was quenched with MeOH and after a few minutes the mixture was diluted with 0.2 M phosphoric acid (pH 7.0) and dichloromethane. The oily residue was partitioned between dichloromethane and DCM / MeOH (0-2-3-4% M Chromatography of the organic phase was performed using a gradient of MeOH / DCM (product comes in 3-4% MeOH). Chromatographic evaporation and coevaporation with toluene through silica gel 60A produced a white The product 2 was obtained in the form of a foam (yield 70-80%).

[0329] Step 3. Preparation of phosphodiester compound 3 Preparation of 4-(4,4'-dimethoxytrityloxymethyl)phenol Iyer,RPet al.Tetrahedron Letters,2001 Compound 3 was synthesized using a method similar to that published in Briefly, 4-hydroxybenzyl alcohol (1 mol equiv.) was dissolved in dry pyridine. The mixture was dissolved in 10 mL of 4,4'-dimethoxytrityl chloride (1.1 mol equivalents) in dry DCM (approximately 5 mL / mmol) and the solution was stirred for 1 hour. Then, add the mixture dropwise from the dropping funnel to the pyridine solution. After complete addition, the reaction solution was cooled to room temperature for a short The mixture was stirred for at least 16 hours.

[0330] Work-up and purification: The reaction was quenched by adding MeOH and allowed to stand for a while. After stirring for a while, the solvent was evaporated. The residue was dissolved in DCM and the organic phase was washed with saturated aqueous NaHCO3. The aqueous phase was extracted twice more with DCM. The combined DCM phases were evaporated. The residue was co-evaporated with toluene. The residue was extracted with ethyl acetate (EtAc) / petroleum ether ( PetEt) (20-30-50% EtAc / PetEt+0.1% pyridine, 30 Chromatographed through silica gel 60A using a gradient of 1000 ppm (eluted with 100% EtAc). The product phenol was obtained in high yield upon purification. 1 H-NMR, 500MHz ( CDCl3):7.51-6.80(m,17H),4.61(br,s,1H)OH, 4.07(br s,2H)CH2,3.78(s,6H)2 x OMe.

[0331] Triethylammonium salt of phosphodiester compound 3. (4-(4,4'-dimethoxytrimethylol) in dry MeCN solution (7 mL / mmol) (1.0 mol equivalent) + dry pyridine (3.5 mL / mmol) was dissolved in vigorously stirred, dry MeCN under nitrogen at 20°C for 10 min at 37°C. The resulting solution was stirred at room temperature under nitrogen for 1 hour at room temperature. The mixture was stirred for about 1 to 1.5 hours.

[0332] A solution of compound 2 (0.95 mol equiv.) in dry MeCN (9 mL / mmol) was mixed. The reaction was stirred at room temperature for about 2 hours. The mixture is quenched with triethylammonium hydrogen (approximately 8 mL / mmol scale) and The residue was concentrated using a rotary evaporator. The mixture was poured into ethyl acetate and extracted three times with DCM. The solution was evaporated. The residue was diluted with DCM / EtOH. (0-4-8-10-15-20% EtOH / DCM + 0.1% pyridine, product Chromatographed through silica gel 60A using a gradient of 8% to 15% EtOH (elution). By subjecting the O-aryl-O-alkyl phosphodiester 3 to The compounds were obtained as nium salts (yields: 50-65%).

[0333] Step 4. Method for the preparation of MeOPEG phosphotriester compound 4 Phosphodiester 3 (1 mol equivalent), mPEG-OH (3 mol equivalent), and N- Methylimidazole (24 mol equivalents) was dissolved in dry MeCN and evaporated to dryness. The residue was coevaporated once more with dry MeCN to obtain less than 5 mL / mmol MeCN( The viscous solution was concentrated to a semi-viscous state. 1-mesitylenesulfonyl chloride was added while swirling the viscous solution. (12 mol equiv.) in concentrated MeCN (1.25 mL / mmol) was added dropwise. After addition The solution was rotated in a round bottle at room temperature for 66-72 hours (all inside the flask wall). To ensure that the material is involved in the reaction. A shaking device can be used.

[0334] The reaction mixture was quenched with MeOH and the mixture was evaporated to dryness on a rotary evaporator. The residue was recrystallized from isopropanol (using approximately 13 mL / g of PEG). The mixture was kept at 55 °C to allow the solid material to dissolve, and the PEGylated material was cooled to room temperature. The solid mass was recrystallized on a P3 or P4 glass sintered filter and cooled. It was washed with propanol and finally with diethyl ether and dried under vacuum.

[0335] The crude solid was treated with C 18 Analysis by RP-HPLC verified the presence of triester product 4. The main UV-Vis by-product was a triester with a shorter R t Meals with mPEG was ethylenesulfonylated. All free hydroxyls of mPEG were phosphorylated. There is reason to believe that the aldehydes were consumed either by oxidation or by sulfonylation. Available C 18 Depending on the size of the RP HPLC column, the following solvent mixtures and gradients were used: The triester 4 can be separated in batches from the by-products using: Sample diluent: 20% MeCN in water Buffer A: 0.1 M triethylammonium acetate / 5% MeCN in water. Buffer B: 100% MeCN Gradient: 30-60% B over 60 min. Monitoring: 270nm

[0336] The collected fractions were pooled, evaporated to dryness and the residue was kept under high vacuum for several hours. The residue (45–55% yield) was used in step 5.

[0337] Step 5. Method for the Preparation of MeOPEG Phosphotriester Hydroxyl Blocked Compound 5 4-(4,4'-Dimethoxytrityloxymethyl)phenylphosphotriester compound The compound 4 (1 mol equivalent) was dissolved in 80% acetic acid (approximately 350 mL / mmol), and the solution was The mixture was kept at room temperature for 2 hours. The volatiles were evaporated and the residue was co-evaporated with toluene. The residue was recrystallized from isopropanol as described in step 4 to give O-alkylated benzene. -O-(mpegyl)-O-[(4-hydroxymethyl)phenyl]phosphoriene Stell 5 was obtained and used directly in the next step 6.

[0338] Step 6. Method for the preparation of MeOPEG phosphotriester NHS carbonate compound 6 The above hydroxyl block (1 mol equivalent) was dissolved in dry DCM (140 μL / μmol ), then 15% by weight of phosgene (190 mol equivalents) was added, and the solution was heated to room temperature. The mixture was stirred at room temperature for 2-3 hours. The volatiles were evaporated and the residue was coevaporated with toluene several times. Ta.

[0339] Crude chloroformic acid (1 mol equiv.) was dissolved in dry THF (6 mL / mmol) and dry DCM. (1.2 mL / mmol). Then, N-hydroxysuccinimide (75 mM ol equiv.) was added followed by dry pyridine (100 mol equiv.) and the mixture was allowed to stand at room temperature. The mixture was stirred at rt for 2 h. The mixture was evaporated to dryness and the residue was co-evaporated with toluene (at least The residue was then triturated with diethyl ether, the supernatant was decanted, and the solid was The mixture was dried under vacuum to give O-alkyl-O-mPEGyl-O-[4-( NHS-(carbonyloxy-methyl)phenyl]phosphotriester 6 was obtained. C18 RP-HPLC analysis showed one broad homogeneous peak corresponding to product 6. Another single peak at the beginning of the matogram was the excess NHS. Sample diluent: 20% MeCN in water Buffer A: 0.1% TFA / 5% MeCN in water. Buffer B: 0.1% TFA in MeCN Gradient: 30-60% B over 60 min (for column size 250x10mm) Monitoring: 270 nm (also 254 nm for parallel channels)

[0340] Step 7. Releasable MeOPEG-liraglutide conjugate 7 (mPEG-liraglutide Preparation method of tide Liraglutide (1 mg, 0.27 μmol, SEQ ID NO: 3) was placed in a 2 mL plastic 0.3 M HEPES buffer (pH 7.4, 400 μL) in a crucible cap vial and MeCN (20 μL). Solid compound 6 (24 mg, 0.81 μL) was then dissolved in 100 μL of MeCN (20 μL). mol) was added and the solid was dissolved by occasional sonication (1-2 sec each time, approximately 3 ~4 times), and the solution was stirred at room temperature for 2 to 2.5 hours.

[0341] Workup: Dilute the reaction mixture to 1 mL with deionized (or distilled) water and dilute to 80% The reaction was quenched by acidifying with 100 mL of AcOH (pH 3-4). If necessary, the solution was filtered through a 0.45 μm disk filter before injection into the HPLC column. Use a column (RP 250 x 10 mm) and gradient system as in step 6. The conjugate was identified as a broad peak in the 50-55 min region. The tide eluted around 60 min. All other components eluted earlier than 45 min.

[0342] The product fractions were collected, pooled and evaporated. The glassy residue was then washed with a small amount of 2 It was dissolved in 0% MeCN / water and lyophilized (94 nmol, 35%).

[0343] In the following experiments, the T1 / 2 at pH 8 is calculated to be approximately 11 hours, compared with pH 7. Approximately 1 mg of conjugate is dissolved in 20% water. A volume of MeCN was dissolved in water. An appropriate amount of azidothymidine (AZT) was used as an internal standard. Add and hydrolyze by adding a volume of 0.3 M TRIS buffer at pH 8.0 The reaction mixture was then maintained at 37° C. Aliquots of 30 μL were added at each time point. The samples were collected at 100°C and acidified by the addition of 20 μL of 1 M AcOH before injection into the HPLC. Ta.

[0344] Example 2 - CPSEC-based Liraglutide Conjugate 8 Using a method similar to that described in Example 1, CPSEC-based liraglutide Conjugate 8 was prepared. [ka]

[0345] In Tris buffer at pH 8 and 37°C, compound 8 exhibited a pH-induced catalysis of approximately 2.5 hours. The patient has a pronounced T1 / 2 (measured as described in Example 1).

[0346] Example 3 - Liraglutinin based on FMOC derivative (1-fluorenylethoxycarbonyl) Conjugates of Do 9 Using a method similar to that described in Example 1, the FMOC derivative (1-fluorenyl ether) was A toxycarbonyl-based conjugate of liraglutide, 9, was prepared. [ka]

[0347] In Tris buffer at pH 7.4 and 37°C, compound 9 induces pH-induced oxidative stress for approximately 36 days. This assumption is supported by the hydrolysis of compound 1 (FEC group) ( The process is based on the process outlined in Tester 1. This allows the T 1 / 2 Get This turned out to be close to one month (27 days). Multiplying it by a factor of 4 (factor 4X) gave a pH of 7. For 4, it is 4 months (2560 hours). In previous experiments, aminouridine derivatives like 1 Mixed T 1 / 2 and T of the final conjugate 1 / 2 There is an approximate factor of 3X between This is probably due to the effect of the phosphotriester group. ), 2560 hours / 3 = 854 hours (36 days).

[0348] Example 4 - DPEC-based Liraglutide Conjugate 10 Using a method similar to that described in Example 1, the composition of DPEC-based liraglutide was Jugate 10 was prepared. [ka]

[0349] Hydrolysis of compound 1 resulted in a T1 / 2 of 12 days at pH 8 and is detailed in Example 3. Based on calculations, an estimated T1 / 2 of 16 days was obtained for compound 10 at pH 7.4. It was made.

[0350] Example 5 - FPEC (Fluorenylphenylethoxycarbonyl) Based Liraglutide Conjugates of 11 Using a method similar to that described in Example 1, FPEC (fluorenyl phenyl ethoxycarbonyl cyanide) was A (xycarbonyl)-based conjugate of liraglutide 11 was prepared. [ka]

[0351] Example 6 - DFDPEC-based Liraglutide Conjugate 12 Using a method similar to that described in Example 1, DFDPEC-based liraglutide Conjugate 12 was prepared. [ka]

[0352] Example 7 - DTBFMOC-based Liraglutide conjugate 13 Using a method similar to that described in Example 1, DTBFMOC-based rerugation was performed. The conjugate 13 of tide was prepared. [ka]

[0353] Example 8 - Liraglution using phosphodichloridate methodology for the synthesis of PEG reagents Preparation of tide conjugates [ka] Steps 1-2. Steps 1 and 2 are carried out according to the same method and procedure as in Example 1. can be.

[0354] Step 3. N3-benzoylated 5'-O-pivaloyluridine-2'-N-carbamate Preparation method of To8-2. Compound 2 (1 equivalent) was dissolved in dry pyridine (7 mL / mmol). Trisilane (TMS-Cl, 3 equivalents) was added to the pyridine solution at room temperature and the mixture was cooled to room temperature. Benzoyl chloride (2 eq.) was then added and the mixture was stirred for 2 days. The reaction mixture was quenched with methanol and after 15 min it was rotary evaporated. The organic phase was concentrated in 100 ml of water and partitioned between saturated aqueous sodium bicarbonate and dichloromethane. After evaporation, the residual oil was co-evaporated with toluene to remove traces of pyridine. The residue was 80% in AcOH (10 mL / mmol) for 10 min to cleave the silyl ether. Stir, then rotovaporolyze to dryness and coevaporate with toluene. The residue was purified by column chromatography on silica gel 60A using a gradient of MeOH in DCM (0–2–4%). Chromatography gave the product 8-2 as a white solid. The usual rate was about 80%.

[0355] Step 4. Preparation of the triethylammonium salt of phosphodiester compound 3. A solution of 4-formylphenyl phosphorodichloridate (2 equiv.) was added to the Engberts ,JBFNet al.Langmuir 1996,12,5773-578 Prepare according to 0.0 and use crude without distillation, dissolve in dry MeCN (1 mL / mmol). The solution was dissolved in water and added dropwise to compound 8-2 (1 equivalent) dissolved in dry pyridine (4 mL / mmol). The resulting mixture was stirred at room temperature for about 2 hours. The reaction was diluted with 1M triethylammonium bicarbonate and The mixture was quenched with ammonium hydroxide and extracted three times with DCM. The organic phase was evaporated and co-evaporated with toluene. The residue was evaporated to dryness and reconstituted with DCM / MeOH (0-2-4-6-8% MeOH / D Chromatography over silica gel 60A using a gradient of 1000 mM CM + 0.1% pyridine The product was eluted with 4–6% MeOH as the triethylammonium salt. O-Aryl-O-alkyl phosphodiesters 3 were obtained (isolated yields: 50–65%).

[0356] Step 5. Preparation of MeOPEG phosphotriester aldehyde 4 Phosphodiester 3 (1 eq.), pre-dried mPEG-OH (3 eq.), and N-Methylimidazole (24 eq.) was dissolved in dry MeCN and evaporated to dryness. The mixture was once again coevaporated with dry MeCN and concentrated to a semi-viscous MeCN solution. , a solution of 1-mesitylenesulfonyl chloride (12 eq.) in a minimum amount of dry MeCN, After the addition, the reaction mixture in the round bottom flask was shaken at room temperature for 16 hours.

[0357] The reaction mixture was quenched with MeOH and concentrated to dryness on a rotary evaporator. The residue was recrystallized from isopropanol (40 mL / 3 gm PEG). The solid material was dissolved by heating at 0.8 °C. The PEGylated material crystallized upon cooling to room temperature. The crystallized material was filtered on a glass sintered filter, washed with cold isopropanol, and then The mixture was washed with diethyl ether and dried under vacuum (yields were typically calculated based on the yield of the product used in the reaction). (approximate amount of mPEG-OH).

[0358] The crude solid was treated with C 18 Analysis by RP-HPLC confirmed the presence of the phosphotriester product 4. The product usually appears as the largest peak in the chromatogram and contains all the PEG. The crude material was used directly in the next step. It was not purified at this step due to the risk of conversion to the hydrate on contact.

[0359] Step 6. Method for the Preparation of MeOPEG Phosphotriester Hydroxyl Blocked Compound 5 . The crude aldehyde phosphotriester 4 (3.5 g, 0.059 mmol) was dissolved in MeCN (15 mL) and pour the solution into water (70 mL) in a glass beaker while stirring. The glass rod from the pH meter was left immersed in the resulting solution. To the mixture, NaBH4 (5 equiv.) was added in small portions with a spatula and the increase in pH was monitored. After complete addition, the pH reached about 8.9 within a few minutes. 1M citric acid was added dropwise to lower the pH to about 6.5-6.6.

[0360] The resulting clear solution was evaporated with the addition of some n-butanol as an antifoaming agent. The residue was dissolved in MeCN, stirred for 5 min, and the fine suspension was filtered through Celite. The clear filtrate was evaporated and dissolved in 30% acetonitrile / water solution.

[0361] Preparative RP HPLC (Lichrospher 100 RP-18) was run with the following solvents: Using mixtures and gradients, the triester 5 was separated from the by-products. Buffer A: 0.1 M triethylammonium acetate in 5% MeCN / water. Buffer B: 100% MeCN Gradient: 30-60% B over 60 min. Monitoring: 270nm

[0362] The collected fractions were pooled together, evaporated to dryness, and the residue was kept under high vacuum for several hours. The sticky residue of pure compound 5 and the remaining triethylammonium acetate buffer were dissolved in warm isopropanol. The compound was dissolved in methanol (55° C.) and crystallized upon cooling as a white solid. was 60%.

[0363] Steps 7-9. Conversion of compound 5 to the NHS carbonate derivative 6 and its conjugation with liraglutide Conjugation to produce the final conjugate 14 can be carried out according to the appropriate steps presented in Example 1. The final conjugation step was carried out in 0.3 M HEPES buffer. The mixture was diluted with water (10x) and equilibrated in 20 mM phosphate buffer (pH 7.0). Anion exchange column (OptioBio 40Q 10x100-Bio-Works, The separation was started under isocratic conditions and Buffer A - 20 mM phosphate buffer pH 7.0 was used. Following a linear gradient to buffer B (20 mM phosphate buffer pH 7.0 + 1.0 M NaCl), The procedure was continued for 15 min until the excess uncharged PEGylation reagent was eluted. Collect fraction B, which represents the jugate, and concentrate 10x by evaporation in a rotary evaporator. The material was concentrated and acidified to pH 5 by the addition of 1M acetic acid. The Superdex 200 Increase 10 / 300SEC column, flow rate 0.5mL / min at room temperature Up to 2.5 mL of sample was purified further by running at 100°C for 10 min at 37°C. The collected fractions containing the pure conjugate were diluted in 2 volumes and injected without any reaction. The pure relaxant was preserved by adding 0.3 M citrate buffer (pH 4). PEG conjugate 14 obtained during lute-SEC separation. Glutide showed a retention time of 29 min.

[0364] Example 9 - Preparation of liraglutide conjugates with lipophilic protection of uracil. [ka] Conjugate 1 was prepared according to methods and procedures similar to those described in Example 8. I got a 5.

[0365] Example 10 - Preparation of conjugates of liraglutide with a hydrophobic 5'-DMTr group. [ka] The conjugates were prepared according to methods and procedures similar to those described in Example 8. He got 16th place.

[0366] Example 11 - Proteolytic stability and biological activity of compound 7 Lyra in the presence of the protease dipeptidyl peptidase IV (DPP-IV) Analysis of the proteolytic stability of glutide and compound 7 by LC-ESI-MS Analyzed.

[0367] Liraglutide (SEQ ID NO: 3) was dissolved in 10 mM Na2HPO4 (pH 7.4), Compound 7 was dissolved in 50 mM ammonium acetate buffer (pH 4.0) at a concentration of 10 mg / mL. .5) to a concentration of 10 mg / mL.

[0368] Both samples were diluted with 10 mM Na2HPO4 (pH 7.4) to give a concentration of 2.67 μM. In the presence of 50mU / mL DPP-IV (porcine kidney, Merck), The digestion was performed at 37° C. Samples were digested at 2, 10, 24, 34, 48, 72, and 96 hours after 9- To stop the reaction, 57 μL of the sample was acidified with 3 μL of 10% TFA. The mixture was then stored at -20°C until the measurement.

[0369] The sample was loaded onto a reversed-phase column (MAbPac RP 4 μm 2.1 × 100 mm, Thermo o Scientific) on the LaChrom Ultra HPLC system. The separation was performed on a column of a column (VWR). The eluent was 0.1% FA in water and 0.1% acetonitrile. Mass spectrometry was performed using a microTOF-QII (Bruker Dalto The experiment was carried out using the nik.

[0370] The recorded LC-ESI-MS spectra were analyzed based on the theoretical mass of liraglutide. Extracted ion chromatograms (EICs) were obtained for the compounds shown in Figure 1. The compounds observed in the EIC were integrated and the intensity was calculated as 382.86 m / z. Compound (unknown, not observed in blank measurements but specific to digest) The relative intensities of each compound are shown in arbitrary units.

[0371] Digestion of liraglutide and compound 7 by DPP-IV resulted in different liraglutide fragments. Piece (Figure 1): Liraglutide AA9-37 (EGTFTSDV SSYLEGQAAK E FIAWLVRGR G (SEQ ID NO: 5)), liraglutide AA13-37 (TSDV S SYLEGQAAK EFIAWLVRGR G (SEQ ID NO: 6)), and liraglutide AA25-37 (AK EFIAWLVRGR G (SEQ ID NO: 7)) was generated. The results were analyzed using 50mU / mL DPP-IV at pH 7.6 for 15 hours at 37°C. We present the results of the first trial run of the compound, in which liraglutide AA9-37 and Two liraglutide fragments of raglutide AA13-37 were observed. The fragment (liraglutide AA25-37) has not yet been observed. The pH was reduced to 7.4, decreasing the release of PEGylation from compound 7.

[0372] Proteolytic stability of liraglutide and compound 7 measured by LC-ESI-MS Figure 3 shows the amount of DPP-IV in the samples after 96 hours of digestion at pH 7.4 and 37°C. Extracted ion chromatograms (EICs) of full-size liraglutide and liraglutide fragments ) trace. Peaks observed in the EICs were integrated and normalized. and reported in arbitrary units.

[0373] Figure 4 shows the kinetics of non-PEGylated liraglutide after digestion with DPP-IV for two samples. The concentrations are shown. The following was observed: Liraglutide has a half-life of approximately 25 to 35 hours. Compound 7 showed an increase in non-PEGylated liraglutide over the first 34 hours, with only slight increases in arginine. It is produced by release of PEGylation at a potassium pH. After 34 hours, the released liraglutide in the compound 7 samples was 100% of the liraglutide released in the first 34 hours. The decrease in concentration was slower than that of glutathione. This was due to the incubation at 37°C. This may be partially explained by a decrease in enzyme activity after conversion, whereas the Control studies indicate that significant enzyme activity should still have been present. These results indicate that proteolytic cleavage of PEG-liraglutide was reduced. It appears to be. These results indicate that compound 7 has a greater proteolytic stability compared to liraglutide. Indicates that the value is significantly higher than the actual value.

[0374] FIG. 5 shows the concentrations of liraglutide fragments following digestion of liraglutide with DPP-IV. Apparently, liraglutide was first developed as liraglutide AA9-37 and liraglutide AA1. 3-37. Then, during digestion, from the digestion of the first two liraglutide fragments, The third liraglutide fragment (liraglutide AA25-37) was generated and showed a decrease.

[0375] FIG. 6 shows the concentration of liraglutide fragments after digestion of compound 7 with DPP-IV. In this study, digestion with DPP-IV mainly produced liraglutide AA9-37. This observation suggests that compound 7 was digested differently from liraglutide. In this study, the production of liraglutide AA13-37 and liraglutide AA25-37 was significantly reduced. A little.

[0376] Figure 7 shows all detected liraglutide and compound 7 after digestion with DPP-IV. The total concentration of liraglutide fragments obtained after 34 hours is shown (see also Tables 1 and 2). The obvious decrease in digestion products in the sample liraglutide indicates that liraglutide fragments are digested by this method. This is most likely due to further digestion into smaller fragments that were not detected during The higher proteolytic stability of compound 7 is highly significant during the first 24 h. After 24 hours, liraglutide showed approximately 5-fold more digestion products than an equimolar sample of compound 7. After 96 hours, compound 7 shows a higher concentration of observed digestion products. The liraglutide in the sample was further digested into smaller fragments that were not analyzed by this method. The actual concentration of digestive products was most likely due to the liraglutide in the samples. This is because, as shown in Figure 4, liraglutide was , supported by the fact that it showed less full-length liraglutide. Table 1. DPP-I at 50 mU / mL in 10 mM Na2HPO4 (pH 7.4) at 37°C Liraglutide (SEQ ID NO: 3, PQ001-2018-001) and Compound 7 (PEG-liraglutide, PQ001-2018-003) Concentrations of liraglutide in the blood and the sum of all liraglutide fragments observed. [Table 1] [Table 2]

[0377] The proteolytic stability of compound 7 was significantly higher than that of liraglutide. After 4 hours, liraglutide showed approximately 5-fold more digestion products than an equimolar sample of compound 7. Over time, compound 7 showed a loss of PEGylation, resulting in a decrease in the digestion products. However, after 96 hours, compound 7 was still produced under the conditions described. It showed about 7-8 times more liraglutide.

[0378] In another experiment, liraglutide (SEQ ID NO: 3) and compound 7 were incubated with pepsin in vitro. The digest was successfully completed and analyzed by mass spectrometry using MALDI-TOF-MS. The spectra of intact compound 7 and pepsin digested compound 7 are shown in Fig. 1. The N-terminus of liraglutide (SEQ ID NO: 3) was compared with that of liraglutide (SEQ ID NO: 3). It was determined that this was the PEGylation site of compound 7. In addition, the N-terminal peptide of compound 7 The significantly lower intensity of the N-terminus confirmed that the N-terminus was protected by PEGylation. It was acknowledged.

[0379] In summary, compound 7 was synthesized by the synthesis of 1,2-diamino-1,2-diphenyl-2,3-dimethylphenyl-1,2-triphenylphosphine oxide using standard fatty acyl modifications (e.g., γ-Glu-palmitoyl). compared to a conjugate of liraglutide with the liraglutide modification, SEQ ID NO: 3) Provides increased proteolytic stability and longer half-life of liraglutide. In contrast to the lu-fatty acyl modification, the PEGylation site in compound 7 is Compound 7 is located close to the plasma proteolytic site, which may be due to a mechanistically distinct plasma proteolytic pathway ( protein degradation) and otherwise in any other form of liraglutide. In fact, compound 7 increases the transcriptional activity of the polypeptide. The γ-Glu acyl tail modification is not required to provide proteolytic stability (although However, acyl-modified GLP polypeptides may still be used in the conjugates of the present disclosure. GLP polypeptides that do not contain an acyl tail (e.g., liraglutide) can be After being released from the conjugate, it is in its native form, which advantageously exhibits increased hydrophilicity. This leads to better solubility and reduced side effects associated with fatty acyl modifications. Thus, the conjugates provided herein are natural ("bio-better") derivatives of GLP. It can emit a "better" form.

[0380] In addition, compound 7 was analyzed by RP-HPLC and determined to be approximately 97% pure. It was done.

[0381] In a separate experiment, a cell-based bioactivity assay (cAMP Hunter™ Li Using the raglutide Bioassay Kit (DiscoverX), The biological activity of various amounts of liraglutide (SEQ ID NO: 3) and compound 7 was evaluated. When the amount of lutide was increased (SEQ ID NO: 3), an increase in biological activity was detected, whereas compound 7 In a separate experiment, the biological activity of compound 7 remained low even when the amount was increased (Figure 9). Compound 7 was incubated in rat plasma for 0, 6, 24, 48, and 6 h at 37°C (pH 7.4). After each time point, the materials were subjected to a cell-based bioactivity assay ( AMP Hunter™ Liraglutide Bioassay Kit, D Using iscoverX, the bioactivity of any liraglutide released from compound 7 was examined. The biologically active liraglutide released from compound 7 was detected. (Figure 10). These results indicate that compound 7 acts as a prodrug until liraglutide is released from the PEGylated portion of compound 7. , demonstrating that it remains inactive compared to liraglutide (SEQ ID NO: 3).

[0382] Example 12 - In vivo performance of compound 7 A stock solution of liraglutide (SEQ ID NO: 3) was prepared by dissolving liraglutide in 10 mM NaHCO The compound was prepared by dissolving in PO4 (pH 7.4) to a concentration of 10 mg / mL. A stock solution of compound 7 was prepared by dissolving compound 7 in 50 mM ammonium acetate (NHAc) buffer. The concentration of the drug was adjusted to 10 mg / mL by dissolving in 100% ethanol (pH 4.5). Before administration, the stock solution was dissolved in PBS (pH 7.4) to a final concentration (5.8 nmol l / kg).

[0383] Two groups of six Sprague Dawley rats were used. The first group (group 1) received liraglutide (SEQ ID NO: 3) at a dose of 5.8 nmol / kg, 1 mL / The second group (Group 2) received Compound 7, 5.8 nmol The injections were given intravenously in a volume of 1 mL / kg at a dose of 100 mg / kg. All injections were delivered over a 15 second period. The injection was a tail vein bolus injection.

[0384] Blood samples were collected from the sublingual vein into EDTA precoated vials. 200 μL of blood was Eight blood samples containing , 30, and 48 hours) were collected from each rat. Samples were centrifuged at 4500 g for 5 min. A fixed volume of 0.5 M acetic acid was added to the vial and 100 μL of plasma was transferred to a new 1.5 mL vial. Ammonium was added to bring the plasma pH to 5.5. After acidification, the samples were kept at 4°C until analysis. The plasma levels of liraglutide from both groups were measured using a high-sensitivity GLP- 1 Determined using an ELISA kit (Merck EZGLPHS-35K), while The amount of active liraglutide in the samples was measured using a cell-based bioactivity assay. .

[0385] Liraglutide measured by ELISA in pooled samples for each time point in Group 1 The amount of total liraglutide measured by ELISA in pooled samples from Group 2 at each time point was The amounts of liraglutide and free liraglutide were plotted in comparison with each other (Figure 11). Active liraglutide (nmol / L) was measured in individual samples by activity assay in The concentrations were compared to those measured for group 2 (Figure 12). These results indicate that compound 7 is more stable than liraglutide (SEQ ID NO: 3) and It has a long half-life (7.3 hours for compound 7 vs. 2.9 hours for non-PEGylated liraglutide) These results also demonstrate that compounds The biological activity of liraglutide released from 7 was confirmed, and compound 7 was shown to be effective in treating type 2 diabetes patients. This study demonstrates that the drug can be used as a once-weekly treatment in patients with

[0386] In summary, the results provided herein demonstrate that the drug conjugated to PEG as described herein The drug (e.g., liraglutide) is released from the PEG with little or no This demonstrates that the compound can be formulated into a prodrug that has no biological activity during administration. Low fluctuations in plasma concentrations during the interstitial phase allow for fewer adverse side effects in drug treatments The results provided herein also demonstrate that drugs (e.g., liraglutide) can Dipeptidyl peptidase IV (DPP IV) is linked to PEG as described herein. It has been demonstrated that the stability of drugs against degradation by enzymes such as cyclohexyl ester (IV) can be increased. In addition, the results provided herein demonstrate that drugs (e.g., liraglutide) In order to provide a controlled release of a drug having a desired biological activity, The present invention demonstrates that the linkers provided herein can be linked to PEG in a manner similar to that described herein. This may allow for the selection of a desired release time or a desired half-life of the selected drug.

[0387] Example 13. Evaluation of various cleavable groups The multistep cleavage of the phosphotriester bond and release of the free drug are initiated by hydrolysis of functional group E. This is usually the rate-limiting step, causing all subsequent steps to run much faster. In this example, as presented in Example 15, different β-elimination protecting groups are used for the 2' Carbamates obtained from -aminouridine and chloroformates were dissolved in acetonitrile. The solution was dissolved and 200 μL was added to 0.3 M TRIS buffer (PBS) pH 8.0 (1 This was followed by addition of the 3' HPLC internal standard reference material. -Azidothymidine was added immediately and the samples were incubated at 37°C. A sample of this mixture was collected and analyzed to determine the disappearance of the starting carbamate and the 2'-aminourethane residue. The formation of gin was monitored by simply multiplying the results obtained at pH 8.0 by 4. It can be recalculated for pH 7.4 (physiological conditions) (i.e., the decrease in OH concentration small).

[0388] The results of these studies are presented in the table below. [ka]

[0389] Specific Embodiments In some embodiments, this document provides a compound according to formula (I) and and compounds of formula (II), as well as pharmaceutical compositions and methods of using these compounds. provide.

[0390] A compound of the first formula (I), [ka] or a pharma- ceutically acceptable salt thereof, The aliphatic portion is a polymer, RP , and Polymer-L-(CH2) m - and polymer-L-(CH2-CH2-O) p -( CH2) m -, R P But, with any substitution C 1-6 Alkyl, optionally substituted C 1-3 Alkyl-O- (CH2-CH2-O) p -(CH2) m - and optionally substituted C 3-7 Cycloa Selected from Rukyr, L is a linking group; m and p are each independently an integer from 1 to 10; D is a residue of a GLP-1 polypeptide or an analog thereof; Z 1 is O, S, and N(R N ), Z 3 is O and N(R N ) or Z 3 does not exist, A is O or N, and when A is O, R 3 does not exist, R N is H and optionally substituted C 1-6 alkyl, R 3 But H and C 1-6 alkyl; or R 3 and R 1 But A and R 1 together with the carbon atom to which it is attached, Forming a 4- to 7-membered aliphatic heterocyclic ring, or R 3 and R 2 But, A, R 1 The carbon atom to which is bonded, and R 2 Carbon atom to which together with the alkyl group to form an optionally substituted 4- to 8-membered aliphatic heterocyclic ring, M A is a self-immolative group having any one of the formulae (a) to (i), [ka] In the formula, x is Z 1 indicates the point of attachment to Z 3 indicates the point of attachment to R 1 and R 2 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 The group consisting of aryl and optionally substituted 5- to 14-membered heteroaryl Selected from or Or, R 1 and R 2 are bonded together with the carbon atom to which they are attached, and optionally Replaced C 3-7 cycloalkyl ring, optionally substituted 4- to 7-membered aliphatic heterocyclic ring, Optionally substituted C 6-10 Aryl or optionally substituted 5-14 membered heteroaryl Form a pool or Or, R 1 and R 2 are linked together to form a ribose ring system, R 7 and R 8 but independently, H and C 1-6 alkyl, The compound or a pharma- ceutically acceptable salt thereof, wherein E is a cleavable moiety.

[0391] A compound of the second formula (II), [ka] or a pharma- ceutically acceptable salt thereof, The aliphatic portion is a polymer, R P, and Polymer-L-(CH2) m - and polymer-L-(CH2-CH2-O) p -( CH2) m -, R P But, with any substitution C 1-6 Alkyl, optionally substituted C 1-3 Alkyl-O- (CH2-CH2-O) p -(CH2) m - and optionally substituted C 3-7 Cycloa Selected from Rukyr, L is a linking group; m and p are each independently an integer from 1 to 10; D is the residue of a biologically active drug; Z 1 is O, S, and N(R N ), Z 3 is O and N(R N ) or Z 3 does not exist, Z 4 is selected from O and S; A is O and N(R N ), R N is H and optionally substituted C 1-4 alkyl, M A is a diradical selected from i. A self-immolative group having any one of the formulae (a) to (i): [ka] And ii. A stable diradical selected from any one of formulas (j) to (l): [ka] In the formula, x is Z1 indicates the point of attachment to Z 3 indicates the point of attachment to R 1 and R 2 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 The group consisting of aryl and optionally substituted 5- to 14-membered heteroaryl Selected from or Or, R 1 and R 2 are bonded together with the carbon atom to which they are attached, and optionally Replaced C 3-7 cycloalkyl ring, optionally substituted 4- to 7-membered aliphatic heterocyclic ring, Optionally substituted C 6-10 Aryl or optionally substituted 5-14 membered heteroaryl Form a pool or Or, R 1 and R 2 are linked together to form a ribose ring system, R 7 and R 8 are independently H, C 1-6 Alkyl, amino, (C 1-6 Alkyl)a Minho, Ji-(C 1-6 (alkyl)amino, acylamino, and protected amino groups. R, The compound or a pharma- ceutically acceptable salt thereof, wherein E is a cleavable moiety.

[0392] Item 3: The aliphatic portion is a polymer, R P and selected from the group of the following formulas: Polymer-L-(CH2) m - R P But, with any substitution C 1-6 Alkyl and optionally substituted C 3-7 Cycloal wherein m is an integer of 1 to 10. Compound.

[0393] Item 4 The aliphatic moiety has the formula: polymer-L-(CH2) m - Based on the above, any one of items 1 to 3 A compound according to any one of claims 1 to 4.

[0394] The fifth item, L, is a linking group containing heterocycloalkylene or heteroarylene. The compound according to any one of claims 1 to 4.

[0395] Item 6: Any of items 1 to 5, wherein L is a linking group containing succinimide or triazole. A compound according to any one of claims 1 to 4.

[0396] The seventh item, L, is a linking group having any one of the following formulae: [ka] During the ceremony, [ka] indicates the point of attachment of the linking group to the polymer or to the CH2 group. The compounds listed above.

[0397] Item 8 The linking group L is a linking group of the following formula: [ka] During the ceremony, [ka] indicates the point of attachment of the linking group to the polymer or to the CH2 group. The compounds listed above.

[0398] Item 9 The linking group L is represented by the formula (L 1 ) group, [ka] wherein ring C is an optionally substituted C 8-16 Cycloalkyl and optionally substituted 8- 16-membered heterocycloalkyl; [ka] indicates the point of attachment of the linking group to the polymer or to the CH2 group. The compounds listed above.

[0399] The 10th term (L 1 ) groups selected from any one of the following formulas: The compound according to any one of claims 1 to 5. [ka]

[0400] Item 11: The compound according to any one of items 1 to 10, wherein m is an integer of 1 to 6.

[0401] Item 12: The compound according to any one of items 1 to 11, wherein m is an integer of 1 to 4.

[0402] Item 13. The compound according to any one of items 1 to 12, wherein the aliphatic moiety is a polymer. .

[0403] Item 14: The polymer is poly(alkylene glycol), poly(oxyethylated polyol). Poly(olefin alcohol), poly(α-hydroxy acid), poly(vinyl alcohol) a first polymer selected from the group consisting of polyoxazolines, polyoxazolines, and copolymers thereof; The compound according to any one of claims 1 to 13.

[0404] Item 15. The method according to any one of items 1 to 14, wherein the polymer is polyethylene glycol. The compound described.

[0405] Item 16. The polyethylene glycol according to any one of items 1 to 15, wherein the polyethylene glycol is linear. The compounds listed above.

[0406] Item 17. The method according to any one of items 1 to 16, wherein the polyethylene glycol is branched. The compounds listed above.

[0407] Item 18: Polyethylene glycol has an average molecular weight of about 500 Da to about 40,000 Da. 18. The compound according to any one of items 1 to 17, having the formula:

[0408] Item 19: Polyethylene glycol has an average molecular weight of about 1,000 Da to about 30,000 Da. 19. The compound according to any one of items 1 to 18, having a molecular weight.

[0409] Item 20: Polyethylene glycol has an average molecular weight of about 1,000 Da to about 20,000 Da. 20. The compound according to any one of items 1 to 19, having a molecular weight.

[0410] Item 21 Polyethylene glycol has an average molecular weight of about 5,000 Da to about 20,000 Da. 21. The compound according to any one of items 1 to 20, having a molecular weight.

[0411] Item 22. Any of items 1 to 21, wherein the polyethylene glycol has the following structural formula: The compound according to claim 1. [ka]

[0412] Item 23: The compound according to any one of items 1 to 22, wherein n is an integer from 1 to 1,000. Compound.

[0413] Item 24: The compound according to any one of items 1 to 23, wherein n is an integer of 1 to 800. .

[0414] Item 25: The compound according to any one of items 1 to 24, wherein n is an integer of 1 to 300. .

[0415] Item 26: The compound according to any one of items 1 to 25, wherein n is an integer of 1 to 100. .

[0416] 27th term n is 10, 20, 50, 100, 200, 250, 300, 500, 600 27. The compound according to any one of claims 1 to 26, selected from:

[0417] Item 28: Aliphatic moiety, R P 28. The compound according to any one of items 1 to 27,

[0418] Section 29R P But, with any substitution C 1-6 Any of items 1 to 28, which is alkyl. The compound according to claim 1.

[0419] Section 30R P 30. The compound according to any one of items 1 to 29, wherein is isopropyl.

[0420] Section 31R P The compound according to any one of items 1 to 30, wherein is cyanoethyl.

[0421] Section 32R P is selected from any one of the groups of the following formulae 1 to 31. A compound according to any one of claims 1 to 4. [ka]

[0422] Section 33R P is selected from any one of the groups of the following formulae 1 to 32. A compound according to any one of claims 1 to 4.

[0423] [ka]

[0424] Section 35R P Any of items 1 to 34, in which the formula is selected from one of the following formulas: The compound according to any one of claims 1 to 5. [ka]

[0425] Section 36Z 1 But S and M A is a self-immolative group of formula (a), [ka] In the formula, x is Z 1 indicates the point of attachment to Z 3 Any of paragraphs 1 to 35 indicating the point of attachment to The compound according to any one of claims 1 to 5.

[0426] Section 37R 7 and R 8 are independently selected from H and methyl. The compound according to any one of claims 1 to 5.

[0427] Section 38R 1 and R 2 and each of the formulas 1 to 37 is hydrogen. The compounds listed above.

[0428] Section 39R 1 and R 2 But together, C 3-7 1 to 3, which form a cycloalkyl ring 9. The compound according to any one of claims 8.

[0429] Section 40C 3-7The cycloalkyl ring is cyclopropyl, cyclobutyl, cyclopentyl, 39. The compound according to any one of claims 1 to 39, wherein the compound is selected from the group consisting of aryl, cyclohexyl, and cyclohexyl. The compounds listed above.

[0430] Section 41R 1 and R 2 together form a 4- to 7-membered aliphatic heterocyclic ring, 40. A compound according to any one of claims 1 to 40.

[0431] Item 42: The 4- to 7-membered aliphatic heterocyclic ring is pyrrolidine, piperidine, tetrahydrofuran, 42. Any one of items 1 to 41, wherein the aryl group is selected from the group consisting of tetrahydropyran and tetrahydropyran. The compound according to claim 1,

[0432] Section 43R 1 and R 2 Together, they form the ribose ring system of ribonucleosides. 43. The compound according to any one of items 1 to 42.

[0433] Section 44R 1 and R 2 together form a ribose ring system of the formula: [ka] wherein a represents the point of attachment to O and b represents the point of attachment to A, or a represents the point of attachment to A. where b represents the point of attachment to O, and W represents H, an acyl group, and a protecting group. 44. The compound according to any one of items 1 to 43, selected from the group consisting of the following groups:

[0434] Item 45 Nucleotide bases are adenine, cytosine, guanine, thymine, uracil, and other 45. Any one of claims 1 to 44, wherein the base is selected from the group consisting of natural and unnatural nucleobases The compound according to claim 1,

[0435] Item 46: Nucleotides consisting of adenine, cytosine, guanine, thymine, and uracil The compound according to any one of items 1 to 45, selected from the group consisting of:

[0436] Item 47: Nucleotide bases are 5-methylcytosine, pseudouridine, dihydrouridine, isopropyl uridine, Selected from the group consisting of guanosine, 7-methylguanosine, hypoxanthine, and xanthine The compound according to any one of items 1 to 46,

[0437] Item 48. The compound according to any one of items 1 to 47, wherein the nucleobase comprises a fluorescent group.

[0438] Item 49. The compound according to any one of items 1 to 48, wherein the nucleobase comprises a polymer.

[0439] Section 50R 1 and R 2 together form a ribose ring system of the formula The compound according to any one of claims 1 to 5. [ka]

[0440] Section 51R 1 and R 2 together form a ribose ring system of the formula: The compound according to any one of claims 1 to 5. [ka]

[0441] Item 52: The compound according to any one of items 1 to 51, wherein A is O.

[0442] Section 53A of the NR 3 Item 53. The compound according to any one of items 1 to 52, wherein

[0443] Section 54R 3 and R 1 But A and R 1 together with the carbon atom to which it is attached, 54. The method according to any one of claims 1 to 53, wherein the aryl group is a 4- to 7-membered heterocyclic ring. compound.

[0444] Item 55: The 4- to 7-membered aliphatic heterocyclic ring is selected from the group consisting of: [ka] where x indicates the point of attachment to E and y indicates R 1 indicates the point of attachment to the carbon atom to which it is attached 54. The compound according to any one of items 1 to 54.

[0445] Section 56R 3 and R 2 But, A, R 1 The carbon atom to which is bonded, and R 2 is combined The first carbon atom forms, together with the carbon atom adjacent thereto, an optionally substituted 4- to 8-membered aliphatic heterocyclic ring. 55. The compound according to any one of claims 1 to 55.

[0446] Item 57. The compound according to any one of items 1 to 56, wherein A is NH.

[0447] 58A is N(C 1-6 58. The method according to any one of claims 1 to 57, wherein compound.

[0448] Item 59E is an enzyme that is an esterase, specific or non-specific peptidase, reductase, oxidase, or Oxidases, glycosidases, hydrolases, glycosyltransferases, and 1 to 58, which is cleavable by an enzyme selected from the group consisting of transaminase The compound according to any one of claims 1 to 5.

[0449] Item 60E is an esterase, reductase, oxidase, glycoside, hydrolase, and glycosyltransferases, 60. The compound according to any one of items 1 to 59, which is capable of inhibiting the inflammatory bowel disease.

[0450] 61. The compound according to claim 1, wherein E is non-enzymatically cleavable at acidic or physiological pH. The compound according to any one of claims 1 to 5.

[0451] Item 62 E is an acyl group, an O-methyl-acyl group, a methyl azide group, a sugar residue, a protected acetonitrile, Item 62. The compound according to any one of items 1 to 61, which is a tar or a carbonate ester.

[0452] 63. Any one of claims 1 to 62, wherein E is cleavable by a reductase enzyme. Item 1. The compound according to item 1.

[0453] Item 64: The invention relates to any one of items 1 to 63, in which A is O and E is a group of the formula The compound described. [ka]

[0454] Item 65. E contains a dithio group that is cleavable by a biological thiol. The compound according to any one of claims 1 to 5.

[0455] 66. The compound according to any one of claims 1 to 65, wherein E is cleavable by glutathione. The compound described.

[0456] Item 67 E is a group of any one of the following formulae: [ka] In the formula, R E But, C 1-6 1 to 66 are selected from the group consisting of alkyl and benzyl. The compound according to any one of claims 1 to 5.

[0457] Item 68: The invention relates to any one of items 1 to 67, in which A is O and E is a group of the formula The compound described. [ka]

[0458] 69. The method according to any one of claims 1 to 68, wherein E is cleavable by a glycoside hydrolase enzyme. A compound according to any one of claims 1 to 4.

[0459] Item 70 E is selected from glucose, galactose, mannose, and glucuronic acid 70. The compound according to any one of items 1 to 69, wherein the saccharide residue is a sugar residue that is linked to the saccharide.

[0460] 71. Any one of claims 1 to 70, wherein E is cleavable by an esterase enzyme. Item 1. The compound according to item 1.

[0461] Item 72 E is selected from the group consisting of acyl groups, carbonate esters, and O-methyl-acyl esters. The compound according to any one of items 1 to 71,

[0462] 73. Any of items 1 to 72, wherein E is hydrolytically cleavable at physiological pH. The compound according to any one of claims 1 to 5.

[0463] Item 74: The compound according to any one of items 1 to 73, wherein E is an acyl group.

[0464] Section 75A of the NR N or NR 3 and E is a cleavable moiety of the formula: [ka] During the ceremony, R 9 H, optionally substituted C 6-10 Aryl and optionally substituted C 1-6 Al Selected from the kill, R 10 and R 11 are independently H, CN, NO2, and COR 12 , SOR 12 or SO2R 12 , optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 aryl, and optionally substituted 5-14 membered heteroaryl; Iwa R 10 and R 11 together with the carbon atom to which they are attached, may be optionally substituted with one or more C 6-10 Optionally substituted C fused to an aryl ring 3-7 Cycloalkyl ring Completed, R 12 But, with any substitution C 1-6 Alkyl and optionally substituted C 6-10 Ally The compound according to any one of items 1 to 74, wherein the compound is selected from the group consisting of

[0465] 76. A is NH and R 9 is H and optionally substituted C 6-10 Aryl? The compound according to any one of items 1 to 75, selected from the following:

[0466] Item 77 E is the following formulas (E-1) to (E-12) and (E-37) to (E-42) and [ka] JPEG2025023928000198.jpg44166, where formula (E-1) to (E-12), (E-37), or (E-39) to (E-41) One of the phenyl rings is C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 1 selected from alkoxy, OH, NO2, CN, halogen, and acyl 1, 2, 3, 4, or 5 substituents, The compound described.

[0467] Item 78 E is any of the formulas (E-1) to (E-12), (E-37), or (E-39) to ( E-41), any one of the cleavable moieties of any one of items 1 to 77. The compound according to claim 1,

[0468] 79th Term (E-1) to (E-12), (E-37), or (E-39) to (E-4 1) Any one of the phenyl rings is F, Cl, CN, acetyl, NO2, and CF3; The compound according to any one of claims 1 to 5.

[0469] Item 80 E is any one of the groups represented by the following formulae (E-13) to (E-36). , [ka] JPEG2025023928000200.jpg75166In the formula, R is C 1-6 80. The compound according to any one of the preceding claims, wherein R is alkyl.

[0470] 81. The compound according to any one of claims 1 to 80, wherein E is cleavable at acidic pH. thing.

[0471] Item 82E covers acetals, ortho-esters, and substituted triphenylmethyl ethers. The compound according to any one of items 1 to 81, wherein the R 1 -R 2 are a group selected from the group consisting of aryl, ... and aryl.

[0472] Item 83E is tetrahydrofuranyl, 4-methoxytetrahydropyran-4-yl, 1,5-Dicarb-methoxypentanyl, methoxyisopropyl acetal, methoxysilane Cyclohexenyl acetal, dimethoxytrityl, trimethoxytrityl, and pixyl The compound according to any one of items 1 to 82, wherein the compound is selected from the group consisting of

[0473] Item 84: The cleavable moiety E is of the formula (L E ) group to A, [ka] Any of items 1 to 83, wherein a represents the point of attachment to A and b represents the point of attachment to E. The compound according to claim 1.

[0474] 85. The compound according to any one of claims 1 to 84, wherein D is a residue of a GLP-1 polypeptide. The compound described.

[0475] 86. Any of paragraphs 1 to 85, wherein D is a residue of a GLP-1 polypeptide analogue. The compound according to claim 1.

[0476] Item 87. Any of items 1 to 86, wherein the GLP-1 polypeptide analog is liraglutide. The compound according to any one of claims 1 to 5.

[0477] Item 88: The compound of formula (I) has any one of the following formulae: [ka] 88. The compound according to any one of items 1 to 87, which is JPEG2025023928000203.jpg176166 or a pharma- ceutically acceptable salt thereof.

[0478] Item 89: The compound of formula (II) has the formula (II-1), The compound according to claim 1, [ka] or a pharma- ceutically acceptable salt thereof.

[0479] Item 90: The compound of formula (II) has the formula (II-2), The compound according to claim 1, [ka] or a pharma- ceutically acceptable salt thereof.

[0480] Item 91: The compound of formula (II) has the formula (II-3), The compound according to claim 1, [ka] or a pharma- ceutically acceptable salt thereof.

[0481] Item 92: The compound of formula (II) has the formula (II-4), The compound according to claim 1, [ka] or a pharma- ceutically acceptable salt thereof.

[0482] The compound of formula (II) in paragraph 93 is represented by any one of the following formulae (II-5) to (II-7). or one of the compounds according to any one of items 1 to 92, [ka] or a pharma- ceutically acceptable salt thereof, A compound or a salt thereof, wherein when the compound has formula II-7, A is O.

[0483] Item 94: The compound of formula (II) has the formula (II-8), The compound according to claim 1, [ka] or a pharma- ceutically acceptable salt thereof.

[0484] The compound of formula (II) of item 95 has any one of the following formulas: The compound according to any one of claims 1 to 5, [ka] JPEG2025023928000211.jpg62166, or a pharma- ceutically acceptable salt thereof.

[0485] Item 96: The compound of formula (II) has the formula (II-10a), The compound according to any one of claims 1 to 5, [ka] or a pharma- ceutically acceptable salt thereof.

[0486] Item 97: Any of items 1 to 96, wherein the compound of formula (II) has the formula (II-10): The compound according to claim 1, [ka] or a pharma- ceutically acceptable salt thereof.

[0487] Item 98: The compound of formula (II) has the formula (II-11a), The compound according to any one of claims 1 to 5, [ka] or a pharma- ceutically acceptable salt thereof.

[0488] Item 99: Any of items 1 to 98, wherein the compound of formula (II) has the formula (II-11): The compound according to claim 1, [ka] or a pharma- ceutically acceptable salt thereof.

[0489] Item 100: The compound of formula (II) has the formula (II-12), The compound according to any one of claims 1 to 5, [ka] or a pharma- ceutically acceptable salt thereof.

[0490] The compound of the formula (II) of any one of the items 1 to 100 has the formula (II-14). The compound according to any one of claims 1 to 5, [ka] or a pharma- ceutically acceptable salt thereof.

[0491] The compound of the formula (II) of the item 102 is any one of the items 1 to 101 having the formula (II-15) The compound according to any one of claims 1 to 5, [ka] or a pharma- ceutically acceptable salt thereof.

[0492] Item 103: The compound of formula (II) has the formula (II-16), The compound according to any one of claims 1 to 5, [ka] or a pharma- ceutically acceptable salt thereof.

[0493] Section 104R P But, C 1-6 Item 104. The method according to any one of items 1 to 103, wherein the aryl group is alkyl. compound.

[0494] Section 105R P is isopropyl. thing.

[0495] Section 106R P is cyanoethyl. thing.

[0496] Item 107: The compound of formula (I) [ka] The compound according to any one of items 1 to 106, or a pharma- ceutically acceptable salt thereof, A compound or a salt thereof, wherein the liraglutide is a residue of liraglutide.

[0497] Item 108: The compound of formula (I) [ka] The compound according to any one of items 1 to 107, or a pharma- ceutically acceptable salt thereof, A compound or a salt thereof, wherein the liraglutide is a residue of liraglutide.

[0498] Item 109: The compound of formula (I) [ka] The compound according to any one of items 1 to 108, or a pharma- ceutically acceptable salt thereof, A compound or a salt thereof, wherein the liraglutide is a residue of liraglutide.

[0499] The compound of formula (I) according to paragraph 110, [ka] The compound according to any one of items 1 to 109, or a pharma- ceutically acceptable salt thereof, A compound or a salt thereof, wherein the liraglutide is a residue of liraglutide.

[0500] Item 111: The compound of formula (I) [ka] The compound according to any one of items 1 to 110, or a pharma- ceutically acceptable salt thereof, A compound or a salt thereof, wherein the liraglutide is a residue of liraglutide.

[0501] The compound of formula (I) according to item 112, [ka] The compound according to any one of items 1 to 111, or a pharma- ceutically acceptable salt thereof, A compound or a salt thereof, wherein the liraglutide is a residue of liraglutide.

[0502] Item 113: The compound of formula (I) [ka] The compound according to any one of items 1 to 112, or a pharma- ceutically acceptable salt thereof, A compound or a salt thereof, wherein the liraglutide is a residue of liraglutide.

[0503] The compound of item 114 is [ka] A compound according to any one of items 1 to 113, or a pharma- ceutically acceptable derivative thereof, which is not A compound or a salt thereof, wherein U is uracil.

[0504] Item 115: The compound according to any one of items 1 to 114, wherein E is not (E-38). thing.

[0505] The compound of item 116 is [ka] The compound according to any one of items 1 to 115, or a pharma- ceutically acceptable salt thereof, salt.

[0506] The compound of item 117 is [ka] The compound according to any one of items 1 to 116, or a pharma- ceutically acceptable salt thereof, salt.

[0507] The compound of item 118 is [ka] The compound according to any one of claims 1 to 117, or a pharma- ceutically acceptable salt thereof, salt.

[0508] Section 119 Drugs (e.g., liraglutide, GLP-1 polypeptides, or analogs thereof) ) is conjugated to a compound of formula (I) or formula (II), The drug is inactive or has a weaker biological activity compared to the drug in its acetone form, and the drug is ) or the compound of formula (II) which regains its biological activity after being released from the compound of formula (II), 19. A compound according to any one of clauses 18.

[0509] Item 120: A compound according to any one of items 1 to 119 or a pharma- ceutically acceptable salt thereof. and a pharma- ceutical composition comprising a salt thereof and a pharma- ceutical acceptable carrier.

[0510] Item 121. A method for treating a disease or condition in a subject in need of treatment, comprising administering to said subject an A therapeutically effective amount of a compound according to any one of items 1 to 120 or a pharmacopoeial equivalent thereof is administered to the subject. 117. A method comprising administering an acceptable salt or a pharmaceutical composition of claim 116.

[0511] Item 122: The method according to item 117, wherein the disease or condition is selected from diabetes and obesity. method.

[0512] Item 123: A compound according to any one of items 1 to 122, having the following formula: [ka] or a pharma- ceutically acceptable salt thereof, the method comprising: (i) reacting a compound of the formula: [ka] formula HZ 3 -D or an analog thereof, method.

[0513] Item 124 Compounds of the following formula: [ka] (i) a compound of the formula: 1 is a protecting group) and [ka] Obtaining a compound of formula [ka] (II) reacting the compound obtained in step (i) with a compound containing a leaving group; 124. The method according to claim 123, wherein the method is obtained by a method comprising:

[0514] Compounds of the following formula: [ka] (i) reducing a compound of the formula: [ka] Obtaining a compound of formula [ka] (II) reacting the compound obtained in step (i) with a compound containing a leaving group; 125. The method according to claim 124, wherein the method is obtained by a process comprising the steps of:

[0515] Item 126: The compound according to any one of items 1 to 125, wherein D is a residue of liraglutide. method.

[0516] Other embodiments Although the present application has been described in detail with respect to the present invention, the foregoing description is illustrative and not restrictive. It is not intended to limit the scope of the application, the scope of which is defined by the appended claims. It should be understood that other aspects, advantages, and modifications are set forth in the following claims. is within the range.

Claims

1. A compound of formula (I), 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, The aliphatic moiety is a polymer, R Ｐ , and Polymer-L-(CH ２ ) ｍ - and polymer-L-(CH ２ -CH ２ -O) ｐ - (CH ２ ) ｍ - is selected from the group selected from R Ｐ is optionally substituted C １－６ Alkyl, optionally substituted C １－３ Alkyl-O - (CH ２ -CH ２ -O) ｐ - (CH ２ ) ｍ - and optionally substituted C ３－７ Cyclo alkyl, L is a linking group; m and p are each independently an integer from 1 to 10; D is a residue of a GLP-1 polypeptide or an analog thereof; Z １ is O, S, and N (R Ｎ ) are selected from Z ３ is O and N(R Ｎ ) or Z ３ does not exist, A is O or N, and when A is O, R ３ does not exist, R Ｎ is H and optionally substituted C １－６ alkyl, R ３ H and C １－６ alkyl; or R ３ and R １ A and R １ together with the carbon atom to which it is attached, can be optionally substituted forming a 4- to 7-membered aliphatic heterocyclic ring; or R ３ and R ２ But, A, R １ and the carbon atom to which R ２ Carbon to which together with the atoms form an optionally substituted 4- to 8-membered aliphatic heterocyclic ring, M Ａ is a self-immolative group having any one of the formulae (a) to (i): 【Chemistry 2】 In the formula, x is Z １ indicates the point of attachment to Z ３ indicates the point of attachment to R １ and R ２ are independently hydrogen, optionally substituted C １－６ Alkyl, optionally substituted C ６－１０ aryl, and optionally substituted 5- to 14-membered heteroaryl or selected from the group Or, R １ and R ２ are bonded together with the carbon atom to which they are attached to any C replaced by ３－７ Cycloalkyl rings, optionally substituted 4- to 7-membered aliphatic heterocyclic rings , optionally substituted C ６－１０ aryl, or optionally substituted 5-14 membered heteroaryl Form a reel or Or, R １ and R ２ are linked together to form a ribose ring system, R ７ and R ８ independently, H and C １－６ alkyl, The compound or a pharma- ceutically acceptable salt thereof, wherein E is a cleavable moiety.

2. A compound of formula (II), 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof, The aliphatic moiety is a polymer, R Ｐ , and Polymer-L-(CH ２ ) ｍ - and polymer-L-(CH ２ -CH ２ -O) ｐ - ( CH ２ ) ｍ - is selected from the group selected from R Ｐ is optionally substituted C １－６ Alkyl, optionally substituted C １－３ Alkyl-O - (CH ２ -CH ２ -O) ｐ - (CH ２ ) ｍ - and optionally substituted C ３－７ Cyclo alkyl, L is a linking group; m and p are each independently an integer from 1 to 10; D is the residue of a biologically active drug; Z １ is O, S, and N (R Ｎ ) are selected from Z ３ is O and N(R Ｎ ) or Z ３ does not exist, Z ４ is selected from O and S; A is O and N(R Ｎ ) are selected from R Ｎ is H and optionally substituted C １－４ alkyl, M Ａ is a diradical selected from a) a self-immolative group having any one of the formulas (a) to (i): 【Chemistry 4】 And b) a stable diradical selected from any one of formulas (j) to (l): 【Chemistry 5】 In the formula, x is Z １ indicates the point of attachment to Z ３ indicates the point of attachment to R １ and R ２ are independently hydrogen, optionally substituted C １－６ Alkyl, optionally substituted C ６－１０ aryl, and optionally substituted 5- to 14-membered heteroaryl or selected from the group Or, R １ and R ２ are bonded together with the carbon atom to which they are attached to any C replaced by ３－７ Cycloalkyl rings, optionally substituted 4- to 7-membered aliphatic heterocyclic rings , optionally substituted C ６－１０ aryl, or optionally substituted 5-14 membered heteroaryl Form a reel or Or, R １ and R ２ are linked together to form a ribose ring system, R ７ and R ８ are independently H, C １－６ Alkyl, amino, (C １－６ Alkyl) Amino, di-(C １－６ alkyl)amino, acylamino, and protected amino groups And, The compound or a pharma- ceutically acceptable salt thereof, wherein E is a cleavable moiety.

3. The compound of claim 1 or claim 2, wherein the aliphatic moiety is a polymer.

4. The polymer is a poly(alkylene glycol), a poly(oxyethylated polyol), , poly(olefin alcohol), poly(α-hydroxy acid), poly(vinyl alcohol ), polyoxazolines, and copolymers thereof. The compound according to any one of claims 1 to 3.

5. The polymer according to any one of claims 1 to 4, wherein the polymer is polyethylene glycol. Compound.

6. The compound of claim 5 , wherein the polyethylene glycol is linear.

7. The compound of claim 5 , wherein the polyethylene glycol is branched.

8. The polyethylene glycol has an average molecular weight of about 500 Da to about 40,000 Da. The compound according to any one of claims 5 to 7.

9. The polyethylene glycol has an average molecular weight of about 1,000 Da to about 30,000 Da. The compound according to any one of claims 5 to 7, having the formula:

10. The polyethylene glycol has an average molecular weight of about 1,000 Da to about 20,000 Da. The compound according to any one of claims 5 to 7, having the formula:

11. The polyethylene glycol has an average molecular weight of about 5,000 Da to about 20,000 Da. The compound according to any one of claims 5 to 7, having the formula:

12. Any one of claims 5 to 11, wherein the polyethylene glycol has the following structural formula: Item 1. The compound according to item 1. 【Chemistry 6】

13. The compound of claim 12, wherein n is an integer from 1 to 1,000.

14. The compound according to claim 12, wherein n is an integer from 1 to 800.

15. The compound according to claim 12, wherein n is an integer from 1 to 300.

16. The compound according to claim 12, wherein n is an integer from 1 to 100.

17. n is 10, 20, 50, 100, 200, 250, 300, 500, 600, and 13. The compound of claim 12 selected from:

18. R ７ and R ８ is independently selected from H and methyl. The compound according to any one of claims 1 to 5.

19. R １ and R ２ together form a ribose ring system of a ribonucleoside.

18. The compound according to any one of claims 18.

20. R １ and R ２ together form a ribose ring system of the formula: 【Chemistry 7】 In the formula, a represents the point of attachment to O and b represents the point of attachment to A, or a represents the point of attachment to A , b represents a point of attachment to O, and W is selected from H, an acyl group, and a protecting group.

20. The compound of claim 19 selected from the group consisting of:

21. The nucleic acid bases are adenine, cytosine, guanine, thymine, uracil, and other nucleotides.

21. The compound of claim 20, wherein the base is selected from the group consisting of natural and unnatural nucleobases.

22. The nucleic acid base is selected from the group consisting of adenine, cytosine, guanine, thymine, and uracil.

21. The compound of claim 20 selected from:

23. The compound according to any one of claims 1 to 22, wherein A is O.

24. A is NR ３ The compound according to any one of claims 1 to 22,

25. The compound according to any one of claims 1 to 22, wherein A is NH.

26. A is N(C １－６ The compound according to any one of claims 1 to 22, wherein 。

27. E is an esterase, a specific or non-specific peptidase, a reductase, an oxidase, Enzymes, glycosidases, hydrolases, glycosyltransferases, and transactivators Any of claims 1 to 26, which is cleavable by an enzyme selected from the group consisting of amino acids. The compound according to any one of claims 1 to 5.

28. E is an esterase, a reductase, an oxidase, a glycoside, a hydrolase, and and glycosyltransferases. A compound according to any one of claims 1 to 26.

29. 27. Any of claims 1 to 26, wherein E is non-enzymatically cleavable at acidic pH or physiological pH. A compound according to any one of claims 1 to 4.

30. E is an acyl group, an O-methyl-acyl group, a methyl azide group, a sugar residue, a protected acetal, or a carbonate ester.

31. 27. The method according to claim 1, wherein E is cleavable by a reductase enzyme. The compounds listed above.

32. 32. The compound of claim 31 , wherein A is O and E is a group of the following formula: 【Chemistry 8】

33. Any of claims 1 to 26, wherein E is cleavable by a glycoside hydrolase enzyme.

3. The compound according to claim 1 .

34. E is a saccharide selected from glucose, galactose, mannose, and glucuronic acid.

34. The compound of claim 33, which is a residue of:

35. 27. The method according to claim 1, wherein E is cleavable by an esterase enzyme. The compounds listed above.

36. E is selected from an acyl group, a carbonate ester, and an O-methyl-acyl ester; 36. The compound of claim 35.

37. 27. Any one of claims 1 to 26, wherein E is hydrolytically cleavable at physiological pH. Item 1. The compound according to item 1.

38. 38. The compound of claim 37, wherein E is an acyl group.

39. A is NR Ｎ Or N.R. ３ and E is a cleavable moiety of the formula: 【Chemistry 9】 During the ceremony, R ９ is H, optionally substituted C ６－１０ Aryl and optionally substituted C １－６ a Selected from Rukyr, R １０ and R １１ are each independently H, CN, NO ２ , C.O.R. １２ , S.O.R. １ ２ or S.O. ２ R １２ , optionally substituted C １－６ Alkyl, optionally substituted C ６－１ ０ aryl, and optionally substituted 5- to 14-membered heteroaryl; Ruiha R １０ and R １１ may be optionally substituted with one or more of the carbon atoms to which they are attached. Replaced C ６－１０ Optionally substituted C fused to an aryl ring ３－７ Cycloalkyl ring Formation, R １２ is optionally substituted C １－６ Alkyl and optionally substituted C ６－１０ Ants 39. The compound of claim 38, wherein the compound is selected from the group consisting of aryl, arylsulfates ...

40. A is NH and R ９ is H and optionally substituted C ６－１０ Aryl 40. The compound of claim 39.

41. E is any one of the following formulae (E-1) to (E-12) and (E-37) to (E-42): Any one of the cleavable portions, 【Chemistry 10】 【change】 In the formula, the formula (E-1) to (E-12), (E-37) or (E-39) to (E-41) Any one of the phenyl rings is C １－１０ Alkyl, C １－１０ Haloalkyl, C １－１０ Alkoxy, OH, NO ２ , CN, halogen, and acyl; 27. Any one of claims 1 to 26, optionally substituted with 2, 3, 4, or 5 substituents. The compound according to claim 1,

42. E is represented by the following formula (E-1) to (E-12), (E-37), or (E-39) to (E 42. The compound of claim 41, wherein the cleavable moiety is any one of the following:

43. Before formula (E-1) to (E-12), (E-37), or (E-39) to (E-41) Any one of the phenyl rings is F, Cl, CN, acetyl, NO ２ , and C.F. ３ 43. The compound according to claim 42, optionally substituted with 1, 2, 3, or 4 substituents selected from The compounds listed above.

44. E is any one of groups represented by the following formulae (E-13) to (E-36): 【Chemistry 11】 【change】 【change】 In the formula, R is C １－６ A compound according to any one of claims 1 to 26, which is alkyl. 。

45. 45. The method according to claim 1, wherein D is a residue of a GLP-1 polypeptide. compound.

46. 45. The method according to claim 1, wherein D is a residue of a GLP-1 polypeptide analogue. The compound described.

47. The compound of claim 46, wherein the GLP-1 polypeptide analog is liraglutide. thing.

48. The compound of formula (I) has any one of the following formulae: 【Chemistry 12】 【change】 or a pharma- ceutically acceptable salt thereof. The compounds listed above.

49. The compound of formula (II) has the formula (II-2): 【Chemistry 13】 or a pharma- ceutically acceptable salt thereof. thing.

50. The compound of formula (II) has the formula (II-4): 【Chemistry 14】 or a pharma- ceutically acceptable salt thereof. thing.

51. The compound of formula (I) is 【Chemistry 15】 or a pharma- ceutically acceptable salt thereof, wherein liragluzide is a residue of liragluzide.

48. The compound according to any one of claims 1 and 3 to 47,

52. The compound of formula (I) is 【Chemistry 16】 or a pharma- ceutically acceptable salt thereof, wherein liragluzide is a residue of liragluzide.

48. The compound according to any one of claims 1 and 3 to 47,

53. The compound of formula (I) is 【Chemistry 17】 or a pharma- ceutically acceptable salt thereof, wherein liragluzide is a residue of liragluzide.

48. The compound according to any one of claims 1 and 3 to 47,

54. The compound of formula (I) is 【Chemistry 18】 or a pharma- ceutically acceptable salt thereof, wherein liragluzide is a residue of liragluzide.

48. The compound according to any one of claims 1 and 3 to 47,

55. The compound of formula (I) is 【Chemistry 19】 or a pharma- ceutically acceptable salt thereof, wherein liragluzide is a residue of liragluzide.

48. The compound according to any one of claims 1 and 3 to 47,

56. The compound of formula (I) is 【Chemistry 20】 or a pharma- ceutically acceptable salt thereof, wherein liragluzide is a residue of liragluzide.

48. The compound according to any one of claims 1 and 3 to 47,

57. The compound of formula (I) is 【Chemistry 21】 or a pharma- ceutically acceptable salt thereof, wherein liragluzide is a residue of liragluzide.

48. The compound according to any one of claims 1 and 3 to 47,

58. The compound is as follows: 【Chemical 22】 or a pharma- ceutically acceptable salt thereof, wherein U is uracil. Or a compound according to claim 2.

59. The compound of claim 1 or claim 2, wherein E is not (E-38).

60. The compound has the formula: 【Chemistry 23】 or a pharma- ceutically acceptable salt thereof. The compounds listed above.

61. The compound has the formula: 【Chemistry 24】 or a pharma- ceutically acceptable salt thereof. The compounds listed above.

62. The compound has the formula: 【Chemistry 25】 or a pharma- ceutically acceptable salt thereof. The compounds listed above.

63. The GLP-1 polypeptide of formula (I) or an analog thereof is When conjugated, the GLP-1 polysaccharide of formula (I) in free, unconjugated form Inactive or weakly biologically active compared to the peptide or its analogues The GLP-1 polypeptide of formula (I) or an analog thereof is released from the compound of formula (I). The method according to any one of claims 1 and 3 to 62, wherein the biological activity is restored after compound.

64. A compound according to any one of claims 1 to 63, or a pharma- ceutically acceptable salt thereof; and a pharma- ceutically acceptable carrier.

65. 1. A method of treating a disease or condition in a subject in need thereof, comprising administering to the subject: A therapeutically effective amount of a compound according to any one of claims 1 to 63 or a pharma- ceutically acceptable salt thereof.

65. A method comprising administering a compound according to claim 64, or a salt thereof, or a pharmaceutical composition according to claim 64.

66. 66. The method of claim 65, wherein the disease or condition is selected from diabetes and obesity.

67. A compound according to any one of claims 1 and 3 to 63, having the following formula: 【Chemistry 26】 or a pharma- ceutically acceptable salt thereof, said method comprising: (i) reacting a compound of the formula: 【Chemical 27】 The above formula HZ ３ -D or an analog thereof. Hmm, a method.

68. The compound of the formula: 【Chemistry 28】 (i) a compound of the formula: １ is a protecting group) and 【Chemical Formula 29】 Obtaining a compound of formula 【Chemistry 30】 (ii) reacting the compound obtained in step (i) with a compound containing a leaving group; 68. The method of claim 67, obtained by a method comprising:

69. The compound of the formula: 【Chemistry 31】 (i) reducing a compound of the formula: 【Chemistry 32】 Obtaining a compound of formula 【Chemistry 32】 (ii) reacting the compound obtained in step (i) with a compound containing a leaving group; 68. The method of claim 67, obtained by a method comprising:

70. 70. The method of any one of claims 67 to 69, wherein D is a residue of liraglutide.

Images