Drug-loaded macromolecules, preparation method thereof and application of drug-loaded macromolecules in medicine

Abstract

The invention relates to a drug-loaded macromolecule, a preparation method thereof and application of the drug-loaded macromolecule in medicine. Specifically, the macromolecule is a dendritic polymer loaded with a drug and a pharmacokinetic modifier, and particularly relates to the connection of the drug to the dendritic polymer through a specific linker. The macromolecules can be used for adjusting the release rate of drugs, specifically through selection of linkers.

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine, and relates to a dendrimer loaded with a drug and a pharmacokinetic modifier, and in particular to connecting a drug to a dendrimer via a specific linker. Background Art

[0002] At present, although the research and development of drugs has made great progress, there are still many drugs that are difficult to be formulated into suitable preparations for administration during the clinical trial stage due to their physical properties (such as solubility), or fail due to the toxic effects and poor therapeutic index caused by the high drug concentration period after administration. In addition, other disadvantages such as poor absorption, low bioavailability, poor in vivo stability, systemic side effects caused by poor targeting, and inability to control its biodistribution, metabolism and kidney or liver clearance in the body after administration are also included. With the continuous progress of drug research, some new research fields and some technical methods with great potential have emerged to promote the development of drugs, such as preparing drug agents in liposomes, micelles or polymerized micelle preparations, and covalently attaching drug agents to hydrophilic polymer backbones. Although these strategies can solubilize drug active agents and improve bioavailability and targeting in some cases, the release of drug active agents is difficult. In some cases, before the drug molecules reach the target organ, the carrier will quickly degrade and release the drug active agent. In many cases, the release rate of the drug active agent from the carrier is variable, so that the drug cannot reach an effective therapeutic dose in the body or in the target organ.

[0003] In recent years, it has been found that dendritic polymers have made significant progress in the fields of biotechnology and drug applications (Xiangyang Shi et al., Sci China Mater, 2018, 61 (11), 1387-1403). Dendritic polymers are polymers of a specific type with dense branching structures. The structure obtained by continuously repeating branching growth outward from the core molecule is similar to a tree-like macromolecule, that is, the core is divided into two branches after the branch grows to a certain length, and so on is repeated until it grows dense enough to grow into a spherical bush (V Gajbhiye et al., Journal of Pharmacyand Pharmacology, 2009, 61, 989-1003), characterized by a higher concentration of functional groups / unit molecular volume than ordinary polymers. In particular, the unique properties of dendritic polymers, such as their high branching degree, multivalence, spherical structure and well-determined molecular weight, give them the hope of new stents for drug delivery. In the past decade, research on the design and synthesis of biocompatible dendritic polymers and their applications in many fields of biological sciences, including drug delivery, has also received increasing attention.

[0004] Starpahrma, an Australian company, uses its developed dendritic polylysine to load and transport anti-cancer drugs to enhance the pharmacological properties of drugs and ensure that the drugs are delivered to the right part of the body at the right time. This method is called "drug delivery". This technology is known as The trademark is launched. -Docetaxel, - Cabazitaxel and - Irinotecan is currently used by the company The technology focuses on the development of three anti-cancer drugs that are in the clinical research stage, showing good development prospects.

[0005] CN103796684A discloses macromolecules that link drugs to dendritic polymers via diacid linkers, particularly via C-terminal molecules interrupted by oxygen, nitrogen or sulfur atoms. 1-10 The compounds are connected by saturated branched or straight chain diacid linkers.

[0006] The related patents that have been disclosed so far include WO2007082331A1, WO2012167309A1, WO2018154004A1 and WO2022042583A1. Summary of the invention

[0007] The object of the present disclosure is to provide a macromolecule or a pharmaceutically acceptable salt thereof, comprising:

[0008] i) a dendrimer comprising a core and at least one generation of structural units, the outermost generation of the structural units having surface amino groups, wherein at least two different terminal groups are covalently attached to the surface amino groups of the dendrimer; ii) a first terminal group, which is a residue A of a pharmaceutically active agent containing a hydroxyl group;

[0009] iii) a second terminal group which is a pharmacokinetic modifier;

[0010] The first terminal group is connected to the linker L 0 covalently linked to the surface amino group of the dendrimer, the linker L 0 The structure is -C(O)-LC(O)-; wherein the linker forms an ester bond with the hydroxyl group of the pharmaceutically active agent and forms an amide bond with the surface amino group; L is an alkylene group, and the alkylene group is optionally substituted with one or more O, S, NR A or C(R x R y ) intermittent, R x , R y Together with the attached carbon atom, it forms a cycloalkyl or heterocyclic group; and the alkylene group is optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, nitro, cyano, -OR3 、-NR 1 R 2 、-C(O)R 3 、-C(O)OR 3 、-S(O) x R 4 、-C(O)NR 1 R 2 、-NR 0 C(O)NR 1 R 2 、-S(O) x NR 1 R 2 、-NR 0 S(O) x NR 1 R 2 , oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl; R A is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, -C(O)R 3 、-C(O)OR 3 and -S(O) x R 4 wherein the alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R b replace;

[0011] R 0 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a cycloalkylalkyl group;

[0012] R 1 and R 2 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclyl group, a heterocyclylalkyl group, an aryl group, a heteroaryl group, a -C(O)R 3 、-C(O)OR 3 and -S(O) x R 4 wherein the alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R b Replace; or R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, which is optionally substituted by one or more R b replace;

[0013] R 3is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl; wherein the alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R b replace;

[0014] R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl; wherein the alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R b replace;

[0015] R b are the same or different at each occurrence and are each independently selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, nitro, cyano, hydroxy, amino, -NHalkyl, -N(alkyl), oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0016] x is 0, 1, or 2;

[0017] The structure of the pharmaceutically active agent is shown in general formula (I):

[0018]

[0019] in:

[0020] R 5 is selected from the group consisting of a hydrogen atom, a halogen and an alkyl group;

[0021] R 6 and R 7 are the same or different and are each independently selected from hydrogen, halogen, alkyl and hydroxyalkyl; or, R 6 , R 7 Together with the carbon atoms to which they are attached, they form a heterocyclic group, which is optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl and hydroxyalkyl;

[0022] R 8 -S(O)R 8a or -S(O)2R 8a ;

[0023] R 8a is selected from the group consisting of alkyl, haloalkyl and cycloalkyl;

[0024] n is an integer from 1 to 10;

[0025] B is

[0026] R 9 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkyl group;

[0027] R 10 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkyl group;

[0028] Ring A is a heteroaryl group, which is optionally substituted by one or more substituents selected from halogen, alkyl, haloalkyl and alkoxy;

[0029] Ring B is a heterocyclic group, and the heterocyclic group is optionally substituted by one or more substituents selected from halogen, alkyl, haloalkyl and alkoxy.

[0030] In some embodiments of the present disclosure, the macromolecule or its pharmaceutically acceptable salt, wherein L is C 1-10 Alkylene, the C 1-10 The alkylene group is optionally substituted with one or more of O, S, NR A or C(R x R y ) intermittent, R x , R y Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group; and said C 1-10 The alkylene group is optionally selected from halogen, 3 to 6 membered heterocyclyl and -NR 1 R 2 is substituted by one or more substituents; R A C 1-6 Alkyl or -S(O) x R 4 ; R 1 and R 2 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 Hydroxyalkyl, 3 to 6 membered cycloalkyl C 1-6 Alkyl, -C(O)R 3 and -S(O) x R 4 ; or R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms a 5- or 6-membered heterocyclic group; R 3 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Haloalkyl; R 4 C 1-6 alkyl; x is 2; in some embodiments, L is C 1-6 Alkylene, the C 1-6 The alkylene group is optionally substituted with one or more O, S or NR A intermittent; and said C 1-6 The alkylene group is optionally substituted with one or more -NR1 R 2 Replaced by; R A C 1-6 Alkyl; R 1 and R 2 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 Hydroxyalkyl, 3 to 6 membered cycloalkyl C 1-6 Alkyl and -C(O)R 3 ; or R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms a 5- or 6-membered heterocyclic group; R 3 A hydrogen atom or C 1-6 alkyl.

[0031] In some embodiments of the present disclosure, the macromolecule or its pharmaceutically acceptable salt, wherein L is an alkylene group, the alkylene group is optionally substituted with one or more C(R x R y ) intermittent, R x , R y Together with the attached carbon atom, it forms a cycloalkyl or heterocyclic group; and the alkylene group is optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, nitro, cyano, -OR 3 、-NR 1 R 2 、-C(O)R 3 、-C(O)OR 3 、-S(O) x R 4 、-C(O)NR 1 R 2 、-NR 0 C(O)NR 1 R 2 、-S(O) x NR 1 R 2 、-NR 0 S(O) x NR 1 R 2 , oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein R 0 , R 1 , R 2 , R 3 , R 4 and x are as defined above; in some embodiments, wherein L is C 1-10 Alkylene, the C 1-10 The alkylene group is optionally substituted with one or more C(R x R y) intermittent, R x , R y Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group; and said C 1-10 The alkylene group is optionally selected from halogen, 3 to 6 membered heterocyclyl and -NR 1 R 2 is substituted by one or more substituents; R 1 and R 2 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 Hydroxyalkyl, 3 to 6 membered cycloalkyl C 1-6 Alkyl, -C(O)R 3 and -S(O) x R 4 ; or R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms a 5- or 6-membered heterocyclic group; R 3 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Haloalkyl; R 4 C 1-6 alkyl; x is 2; in some embodiments, L is C 1-6 Alkylene, the C 1-6 The alkylene group is optionally substituted with one or more -NR 1 R 2 Replaced by; R 1 and R 2 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 Hydroxyalkyl, 3 to 6 membered cycloalkyl C 1-6 Alkyl and -C(O)R 3 ; or R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms a 5- or 6-membered heterocyclic group; R 3 A hydrogen atom or C 1-6 In some embodiments, L is C 1-6 Alkylene, the C 1-6 The alkylene group is optionally substituted with one or more -NR 1 R 2 Replaced by; R 1 and R 2 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3 to 6 membered cycloalkyl C 1-6 Alkyl; or R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms a 5- or 6-membered heterocyclic group; in some embodiments, L is C 1-6Alkylene, the C 1-6 The alkylene group is optionally substituted with one or more -NR 1 R 2 Replaced by; R 1 and R 2 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3 to 6 membered cycloalkyl C 1-6 In some embodiments, L is C 1-6 Alkylene, the C 1-6 The alkylene group is optionally substituted with one or more -NR 1 R 2 Replaced by; R 1 and R 2 The same or different, and each independently is C 1-6 alkyl.

[0032] In some embodiments of the present disclosure, the macromolecule or its pharmaceutically acceptable salt, wherein L is selected from

[0033]

[0034]

[0035] In some embodiments, L is selected from

[0036]

[0037]

[0038] In some embodiments, L is selected from

[0039]

[0040]

[0041] In some embodiments, L is selected from

[0042] In some embodiments, L is selected from In some embodiments, L is selected from In some embodiments, L is The * bond is attached to the C(O) close to the dendrimer.

[0043] In some embodiments of the present disclosure, the macromolecule or a pharmaceutically acceptable salt thereof, wherein R A Selected from hydrogen atoms, C 1-6 Alkyl and -S(O) x R 4 ; R 4 and x are as defined above; in some embodiments, R A C 1-6 Alkyl or -S(O) x R 4 ; R 4 C 1-6 alkyl; x is 2; in some embodiments, R A is selected from methyl, isopropyl and -S(O)2CH3; in some embodiments, R A is a hydrogen atom; in some embodiments, R A C 1-6 alkyl; in some embodiments, R A It is methyl.

[0044] In some embodiments of the present disclosure, the macromolecule or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 Hydroxyalkyl, 3 to 6 membered cycloalkyl C 1-6 Alkyl, -C(O)R 3 and -S(O) x R 4 ; or R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms a 5- or 6-membered heterocyclic group; R 3 , R 4 and x are as defined above; in some embodiments, R 1 and R 2 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 Hydroxyalkyl, 3 to 6 membered cycloalkyl C 1-6 Alkyl, -C(O)R 3 and -S(O) x R 4 ; or R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms a 5- or 6-membered heterocyclic group; R 3 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Haloalkyl; R4 C 1-6 alkyl; x is 2; in some embodiments, R 1 and R 2 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 Hydroxyalkyl, 3 to 6 membered cycloalkyl C 1-6 Alkyl and -C(O)R 3 ; or R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms a 5- or 6-membered heterocyclic group; R 3 A hydrogen atom or C 1-6 alkyl; in some embodiments, R 1 and R 2 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3 to 6 membered cycloalkyl C 1-6 Alkyl; or R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms a 5- or 6-membered heterocyclic group; in some embodiments, R 1 and R 2 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3 to 6 membered cycloalkyl C 1-6 alkyl; in some embodiments, R 1 and R 2 The same or different, and each independently is C 1-6 alkyl; in some embodiments, R 1 and R 2 are the same or different and are each independently selected from methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, or R 1 , R 2 Together with the nitrogen atom to which it is attached, In some embodiments, R 1 and R 2 are the same or different and are each independently selected from methyl, ethyl, n-propyl, isopropyl, tert-butyl and isobutyl; in some embodiments, R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms a 5- or 6-membered heterocyclic group; in some embodiments, R 1 , R 2 Together with the nitrogen atom to which it is attached,

[0045] In some embodiments of the present disclosure, the macromolecule or a pharmaceutically acceptable salt thereof, wherein R3 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 3 A hydrogen atom or C 1-6 alkyl; in some embodiments, R 3 is a hydrogen atom; in some embodiments, R 3 C 1-6 alkyl; in some embodiments, R 3 is selected from a hydrogen atom, a methyl group and a trifluoromethyl group; in some embodiments, R 3 It is methyl.

[0046] In some embodiments of the present disclosure, the macromolecule or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 4 C 1-6 alkyl; in some embodiments, R 4 It is methyl.

[0047] In some embodiments of the present disclosure, the macromolecule or a pharmaceutically acceptable salt thereof, wherein x is 2.

[0048] In some embodiments of the present disclosure, the macromolecule or a pharmaceutically acceptable salt thereof, wherein R x , R y Together with the attached carbon atom, it forms a 3- to 6-membered cycloalkyl group; in some embodiments, R x , R y Together with the carbon atom to which it is attached it forms a cyclopropyl group.

[0049] In some embodiments of the present disclosure, the macromolecule or its pharmaceutically acceptable salt, wherein the linker L 0 Selected from

[0050]

[0051]

[0052] In some embodiments, the linker L 0 Selected from

[0053]

[0054]

[0055]

[0056]

[0057] In some embodiments, the linker L 0 Selected from

[0058]

[0059]

[0060] In some embodiments, the linker L 0 Selected from

[0061] In some embodiments, the linker L 0 Selected from

[0062] In some embodiments, the linker L 0 Selected from In some embodiments, the linker L 0 for *The terminal C(O) forms an amide bond with the surface amino group of the dendrimer.

[0063] In some embodiments of the present disclosure, the macromolecule or a pharmaceutically acceptable salt thereof, wherein R 5 is halogen; in some embodiments, R 5 is F or Cl; in some embodiments, R 5 For Cl.

[0064] In some embodiments of the present disclosure, the macromolecule or a pharmaceutically acceptable salt thereof, wherein R 6 C 1-6 Hydroxyalkyl, R 7 is a hydrogen atom; or, R 6 , R 7 Together with the carbon atoms to which they are attached, they form a 6-membered heterocyclic group; in some embodiments, R 6 is hydroxymethyl, R 7 is a hydrogen atom, or, R 6 , R 7 Together with the carbon atoms to which they are attached, they form a 6-membered oxygen-containing heterocyclic group.

[0065] In some embodiments of the present disclosure, the macromolecule or a pharmaceutically acceptable salt thereof, wherein for In some embodiments, for In some embodiments, for In some embodiments, for

[0066] In some embodiments of the present disclosure, the macromolecule or a pharmaceutically acceptable salt thereof, wherein R 8 is -S(O)2R 8a ; R 8a As defined in Formula (I); in some embodiments, R 8 It is -S(O)2CF3.

[0067] In some embodiments of the present disclosure, the macromolecule or a pharmaceutically acceptable salt thereof, wherein R 8a C 1-6 haloalkyl; in some embodiments, R 8a It is trifluoromethyl.

[0068] In some embodiments of the present disclosure, the macromolecule or a pharmaceutically acceptable salt thereof, wherein n is 3, 4, 5 or 6; in some embodiments, n is 4 or 5; in some embodiments, n is 4; in some embodiments, n is 5.

[0069] In some embodiments of the present disclosure, the macromolecule or a pharmaceutically acceptable salt thereof, wherein R 9 A hydrogen atom or C 1-6 alkyl; in some embodiments, R 9 A hydrogen atom.

[0070] In some embodiments of the present disclosure, the macromolecule or a pharmaceutically acceptable salt thereof, wherein R 10 C 1-6 alkyl; in some embodiments, R 10 is tert-butyl or isopropyl; in some embodiments, R 10 is tert-butyl; in some embodiments, R 10 It is isopropyl.

[0071] In some embodiments of the present disclosure, the macromolecule or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl group; in some embodiments, ring A is an isoxazolyl group; in some embodiments, ring A is The * terminal is connected to O.

[0072] In some embodiments of the present disclosure, in the macromolecule or a pharmaceutically acceptable salt thereof, ring B is a 6-membered heterocyclic group; in some embodiments, ring B is a 6-membered oxygen-containing heterocyclic group.

[0073] In some embodiments of the present disclosure, the macromolecule or a pharmaceutically acceptable salt thereof, wherein for

[0074] In some embodiments of the present disclosure, the macromolecule or its pharmaceutically acceptable salt, wherein B is selected from In some embodiments, B is selected from

[0075] In some embodiments, B is In some embodiments, B is In some embodiments, B is

[0076] In some embodiments of the present disclosure, the macromolecule or a pharmaceutically acceptable salt thereof, wherein R 5 is halogen; R 6 C 1-6 Hydroxyalkyl, R 7 is a hydrogen atom; or, R 6 , R 7 Together with the carbon atoms to which they are attached, they form a 6-membered heterocyclic group; R 8 is -S(O)2R 8a ; R 8a C 1-6 haloalkyl; n is 3, 4, 5 or 6; B is selected from

[0077]

[0078] In some embodiments of the present disclosure, the macromolecule or its pharmaceutically acceptable salt, wherein the pharmaceutically active agent is selected from the following compounds, or their structural modifications:

[0079]

[0080]

[0081] In some embodiments, the pharmaceutically active agent is selected from Compound 1w, Compound 7p-1 and Compound 7p-2, or structural modifications thereof; in some embodiments, the pharmaceutically active agent is Compound 1w; in some embodiments, the pharmaceutically active agent is Compound 7p-1; in some embodiments, the pharmaceutically active agent is Compound 7p-2.

[0082] In some embodiments of the present disclosure, the macromolecule or a pharmaceutically acceptable salt thereof, wherein the residue A of the pharmaceutically active agent is selected from the following structures:

[0083]

[0084] Where R 5 , R 8 , R 9 , R 10 , Ring A, Ring B and n are as defined in Formula (I); in some embodiments, the residue A of the pharmaceutically active agent is selected from the following structures:

[0085]

[0086] In some embodiments, the residue A of the pharmaceutically active agent is selected from the following structures:

[0087]

[0088] In some embodiments, the residue A of the pharmaceutically active agent is In some embodiments, the residue A of the pharmaceutically active agent is In some embodiments, the residue A of the pharmaceutically active agent is

[0089]

[0090] In some embodiments of the present disclosure, the release rate of the pharmaceutically active agent of the macromolecule is slower than the release of the drug that does not rely on the delivery of the macromolecule, and may be twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times or more than ten times, more than fifteen times, more than twenty times, more than thirty times. The macromolecule with low release rate is suitable for macromolecule to be formulated into a drug that is slowly released in the time of long time, for example, 1 week to 3 months, 1 month to 6 months, more than 6 months. The drug can be released from the macromolecule in the extended period (such as several days, weeks or months). The slow release is preferably more than 2 days, particularly 2 days to 6 months and especially greater than 50% release in 5 days to 30 days.

[0091] The release rate of the pharmaceutically active agent can be controlled by selecting an appropriate linker, and the release rate also depends on the characteristics of the pharmaceutically active agent. In some embodiments, each pharmaceutically active agent is linked to the dendritic polymer via the same linker. In other embodiments, the pharmaceutically active agent is linked to the dendritic polymer via two or more different linkers so that the pharmaceutically active agent is released from the macromolecule at different release rates.

[0092] In some embodiments, the macromolecule comprises a third terminal group. The third terminal group is a blocking group for blocking the reactivity of the surface amino groups of the dendritic polymer. In some embodiments, the blocking group is an acyl group, such as a C2-C 10 Acyl groups, especially acetyl.

[0093] In some embodiments, not all surface amino groups of the dendrimer are bound to the first terminal group, the second terminal group or the third terminal group. In some embodiments, some surface amino groups remain free amino groups. When the dendrimer is a G5 polylysine dendrimer, the total number of pharmaceutically active agents is preferably 4 to 32, and in particular 4 to 22. When the dendrimer is a G5 polylysine dendrimer, the total number of pharmacokinetic modifiers is preferably 25 to 32, preferably 29.

[0094] In some embodiments of the present disclosure, the pharmaceutically active agent is slightly soluble or insoluble in aqueous solution.

[0095] The second end group is a pharmacokinetic modifier, which can be any molecule or residue thereof that modifies or regulates the pharmacokinetic characteristics of the pharmaceutically active agent or macromolecule, including absorption, distribution, metabolism and / or excretion. In a specific embodiment, the pharmacokinetic modifier extends the plasma half-life of the pharmaceutically active agent, such that the half-life of the macromolecule is longer than the half-life of the pharmaceutically active agent alone or on a non-dendritic polymer carrier. Preferably, the half-life of the macromolecule or composition is at least 2 times longer and more preferably at least 10 times longer than the half-life of the pharmaceutically active agent alone or on a non-dendritic polymer carrier.

[0096] In some embodiments of the present disclosure, the macromolecule or a pharmaceutically acceptable salt thereof, wherein the pharmacokinetic modifier is selected from polyethylene glycol (PEG), polyethyloxazoline (PEOX), polyvinyl pyrrolidone, polypropylene glycol, folate or a folate derivative of a ligand for a cell surface receptor; in some embodiments, the pharmacokinetic modifier is polyethylene glycol.

[0097] In some embodiments of the present disclosure, the macromolecule or its pharmaceutically acceptable salt, the polyethylene glycol has a molecular weight ranging from 220 to 5500Da, for example, it can be 220-2500Da, 570-2500Da, 220-1100Da, 570-1100Da, 1000-5500Da, 1000-2500Da, 1000-2300Da, 1800-2400, 2000-2200Da; in some embodiments, it has a molecular weight ranging from 1000-5500Da; in some embodiments, it has a molecular weight ranging from 1000-2500Da; in some embodiments, it has a molecular weight ranging from 1000-2300Da; in some embodiments, it has a molecular weight ranging from 2000-2200Da; in some embodiments, it has a molecular weight ranging from 1800-2200Da.

[0098] In some embodiments, the pharmacokinetic modifier forms an amide bond (-NHC(O)-) with the surface amino group of the dendrimer.

[0099] The macromolecules of the present disclosure include dendrimers in which the outermost generation of the structural unit has surface amino groups. The nature of the dendrimer of the macromolecule is not particularly important, provided that it has surface amino groups. For example, the dendrimer can be a polylysine, polylysine analog, polyamidoamine (PAMAM), polyethyleneimine (PEI) or polyetherhydroxylamine (PEHAM) dendrimer.

[0100] Dendrimers contain a core and one or more dendrons which consist of one or more structural units. The structural units can be built up in layers called generations.

[0101] In some embodiments, the dendritic polymer has 1 to 5 dendrons, particularly 2 to 4 dendrons, especially 2 or 3 dendrons attached to the core.

[0102] In some embodiments of the present disclosure, the dendritic polymer has 1 to 8 generations of structural units; in some embodiments, the dendritic polymer has 2 to 7 generations of structural units; in some embodiments, the dendritic polymer has 3 to 6 generations of structural units; in some embodiments, the dendritic polymer has 4 to 6 generations of structural units; in some embodiments, the dendritic polymer has 5 generations of structural units.

[0103] In some embodiments, the building block is lysine or a lysine analog.

[0104] In some embodiments, the macromolecule or a pharmaceutically acceptable salt thereof, wherein the dendrimer comprises a core and structural units of 2 to 7 generations of lysine or lysine analogs, for example, 2, 3, 4, 5, 6 or 7 generations of lysine or lysine analogs.

[0105] In some embodiments, the lysine has a structure as shown in 1:

[0106] In some embodiments, the lysine analog has the structure shown in 2:

[0107] In some embodiments, the lysine analog has the structure shown in 3: wherein a is 1 or 2; b and c are the same or different and are each independently an integer from 1 to 4.

[0108] In some embodiments, the lysine analog has the structure shown in 4: wherein a is an integer from 0 to 2; b and c are the same or different and are each independently an integer from 2 to 6.

[0109] In some embodiments, the lysine analog has the structure shown in 5: wherein a is an integer from 0 to 5; b and c are the same or different and are each independently an integer from 1 to 5.

[0110] In some embodiments, the lysine analog has the structure shown in 6: wherein a is an integer from 0 to 5; b and c are the same or different and are each independently an integer from 0 to 5.

[0111] In some embodiments, the lysine analog has the structure shown in 7: wherein a is an integer from 0 to 5; b and c are the same or different and are each independently an integer from 1 to 5.

[0112] In some embodiments, the lysine analog has the structure shown in 8: wherein a is an integer from 0 to 5; b, c and d are the same or different and are each independently an integer from 1 to 5.

[0113] In some embodiments, the lysine analog has the structure shown in 9: wherein a is an integer from 0 to 5; b and c are the same or different and are each independently an integer from 1 to 5.

[0114] In some embodiments, the core of the dendrimer described in the present disclosure is benzhydrylamine of lysine (BHALys).

[0115] In some embodiments of the present disclosure, the structure of the benzhydrylamine of lysine (BHALys) is In some embodiments, the structure of the benzhydrylamine of lysine (BHALys) is

[0116] In some embodiments, the core of the dendrimer described in the present disclosure can be selected from dibenzhydrylamine (BHA), dibenzhydrylamine of lysine (BHALys) and lysine analogs, or the following structures:

[0117] wherein a is an integer from 1 to 9, preferably from 1 to 5;

[0118] wherein a, b and c are the same or different and are each independently an integer from 1 to 5, and d is an integer from 0 to 100 (preferably an integer from 1 to 30);

[0119] wherein a and b are the same or different and are each independently an integer from 0 to 5;

[0120] wherein a and c are the same or different and are each independently an integer from 1 to 6, and b is an integer from 0 to 6;

[0121] wherein a and d are the same or different and are each independently an integer from 1 to 6, and b and c are the same or different and are each independently an integer from 0 to 6;

[0122] wherein a and b are the same or different and are each independently an integer from 1 to 5 (preferably an integer from 1 to 3, more preferably 1);

[0123] wherein a, b and c are the same or different and are each independently an integer from 1 to 6;

[0124] wherein a, b and c are the same or different and are each independently an integer from 0 to 6;

[0125] wherein a, b and c are the same or different and are each independently an integer from 0 to 6;

[0126] wherein a, b and c are the same or different and are each independently an integer from 0 to 6, and d, e and f are the same or different and are each independently an integer from 1 to 6;

[0127] wherein a, b and c are the same or different and are each independently an integer from 1 to 6;

[0128] wherein a, b, c and d are the same or different and are each independently an integer from 0 to 6;

[0129] wherein a, b, c and d are the same or different and are each independently an integer from 1 to 6; or

[0130] wherein a, b, c and d are the same or different and are each independently an integer from 0 to 6, and e, f, g and h are the same or different and are each independently an integer from 1 to 6.

[0131] In some embodiments of the present disclosure, the macromolecule or a pharmaceutically acceptable salt thereof, wherein the dendritic polymer is selected from BHALys[Lys] 16 , BHALys[Lys] 32 and BHALys[Lys] 64; In some embodiments, the dendrimer is BHALys[Lys] 32 .

[0132] In some embodiments of the present disclosure, the macromolecule or its pharmaceutically acceptable salt is a macromolecule or its pharmaceutically acceptable salt represented by general formula (II):

[0133]

[0134] in:

[0135] Y is PEG 220-5500 or H; Q is H or L 0 -A, where L 0 -A is selected from the following structures:

[0136]

[0137]

[0138] Wherein: L is as defined above; R 5 , R 8 , R 9 , R 10 , Ring A, Ring B and n are as defined in the general formula (I); provided that: at least one Q is L 0 -A.

[0139] In some embodiments of the present disclosure, the macromolecule or its pharmaceutically acceptable salt is a macromolecule or its pharmaceutically acceptable salt represented by general formula (III):

[0140]

[0141] in:

[0142] Y and Q are as defined in the general formula (II).

[0143] In some embodiments of the present disclosure, the macromolecule represented by the general formula (II) or the general formula (III) or a pharmaceutically acceptable salt thereof, wherein the macromolecule or a pharmaceutically acceptable salt thereof has 4 to 32 L 0 -A; In some embodiments, the macromolecule or a pharmaceutically acceptable salt thereof has 4 to 22 L 0 -A; In some embodiments, the macromolecule or a pharmaceutically acceptable salt thereof has 15 to 22 L 0 -A; In some embodiments, the macromolecule or a pharmaceutically acceptable salt thereof has 15 to 32 L 0 -A; In some embodiments, the macromolecule or a pharmaceutically acceptable salt thereof has 9 to 18 L 0-A; In some embodiments, the macromolecule or a pharmaceutically acceptable salt thereof has 4, 9, 13, 14, 15, 17, 18, 19, 21 or 22 L 0 -A; In some embodiments, the macromolecule or a pharmaceutically acceptable salt thereof has 9, 13, 15 or 18 L 0 -A; In some embodiments, the macromolecule or a pharmaceutically acceptable salt thereof has 9 L 0 -A; In some embodiments, the macromolecule or a pharmaceutically acceptable salt thereof has 13 L 0 -A; In some embodiments, the macromolecule or a pharmaceutically acceptable salt thereof has 15 L 0 -A; In some embodiments, the macromolecule or a pharmaceutically acceptable salt thereof has 18 L 0 -A.

[0144] In some embodiments of the present disclosure, the macromolecule represented by the general formula (II) or the general formula (III) or a pharmaceutically acceptable salt thereof has 25 to 32 PEG 220-5500 ; In some embodiments, it has 29 PEG 220-5500 .

[0145] In some embodiments of the present disclosure, the macromolecule represented by the general formula (II) or the general formula (III) or a pharmaceutically acceptable salt thereof, wherein the PEG 220-5500 Having a molecular weight of 1000-5500Da; in some embodiments, the PEG 220-5500 Having a molecular weight of 1000-2500Da; in some embodiments, the PEG 220-5500 Having a molecular weight of 1000-2300Da; in some embodiments, the PEG 220-5500 Having a molecular weight of 1800-2400Da; in some embodiments, the PEG 220-5500 Having a molecular weight of 2000-2200Da; in some embodiments, the PEG 220-5500 It has a molecular weight of 1800-2200 Da.

[0146] In some embodiments of the present disclosure, the macromolecule or a pharmaceutically acceptable salt thereof has a molecular weight between 60-120 kDa; in some embodiments, the macromolecule or a pharmaceutically acceptable salt thereof has a molecular weight between 73-106 kDa; in some embodiments, the macromolecule or a pharmaceutically acceptable salt thereof has a molecular weight between 80-100 kDa; in some embodiments, the macromolecule or a pharmaceutically acceptable salt thereof has a molecular weight of 74.0 kDa, 82.8 kDa, 89.6 kDa, 90.8 kDa, 91.1 kDa, 92.8 kDa, 93.3 kDa, 98.0 kDa, 100.5 kDa, 102.2 kDa or 105.8 kDa.

[0147] In some embodiments of the present disclosure, the macromolecule or its pharmaceutically acceptable salt has a drug loading of 5% to 35%; in some embodiments, the macromolecule or its pharmaceutically acceptable salt has a drug loading of 15% to 30%; in some embodiments, the macromolecule or its pharmaceutically acceptable salt has a drug loading of 8.3%, 17.0%, 22.8%, 23.8%, 25.5%, 25.6%, 28.4%, 28.6%, 29.8%, 32.3% or 32.8%.

[0148] In some embodiments of the present disclosure, the macromolecule represented by the general formula (II) or the general formula (III) or a pharmaceutically acceptable salt thereof, wherein L 0 -A is selected from the following structures:

[0149]

[0150]

[0151] ; L is as defined above.

[0152] In some embodiments of the present disclosure, the macromolecule represented by the general formula (II) or (III) or a pharmaceutically acceptable salt thereof, wherein A is a residue of the following compound:

[0153] ; In some embodiments, A is the residue of compound 1w; In some embodiments, A is the residue of compound 7p-1; In some embodiments, A is the residue of compound 7p-2.

[0154] In some embodiments of the present disclosure, the macromolecule or a pharmaceutically acceptable salt thereof comprises:

[0155] i) a dendrimer comprising a core and 2 to 7 generations of structural units of lysine or lysine analogs, the outermost generation of the structural units having surface amino groups, wherein at least two different end groups are covalently attached to the surface amino groups of the dendrimer;

[0156] ii) a first terminal group, which is a residue A of a pharmaceutically active agent containing a hydroxyl group, and the structure of A is as follows:

[0157]

[0158] iii) a second terminal group, which is a pharmacokinetic modifier, wherein the pharmacokinetic modifier is polyethylene glycol;

[0159] The first terminal group is connected to the linker L 0 covalently linked to the surface amino group of the dendrimer, the linker L 0 The structure is -C(O)-LC(O)-; wherein the linker forms an ester bond with the hydroxyl group of the pharmaceutically active agent and forms an amide bond with the surface amino group; L is C 1-6 Alkylene, the C 1-6 The alkylene group is optionally substituted with one or more O, S or NR A intermittent; and said C 1-6 The alkylene group is optionally substituted with one or more -NR 1 R 2 Replaced by; R A C 1-6 Alkyl; R 1 and R 2 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 Hydroxyalkyl, 3 to 6 membered cycloalkyl C 1-6 Alkyl and -C(O)R 3 ; or R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms a 5- or 6-membered heterocyclic group; R 3 A hydrogen atom or C 1-6 Alkyl; the dendrimer is BHALys[Lys] 32 ; The polyethylene glycol has a molecular weight ranging from 1800 to 2200 Da.

[0160] In some embodiments of the present disclosure, the macromolecule represented by the general formula (II) or the general formula (III) or a pharmaceutically acceptable salt thereof, wherein: Q is H or L 0 -A; Y is PEG 220-5500 or H; and the macromolecule has 4 to 32 L 0 -A; with 25 to 32 PEG 220-5500 , and the PEG 220-5500 With a molecular weight of 1800-2200Da; wherein L 0 -A is selected from the following structures:

[0161]

[0162] ; L is C 1-6 Alkylene, the C 1-6 The alkylene group is optionally substituted with one or more O, S or NR A intermittent; and said C 1-6 The alkylene group is optionally substituted with one or more -NR 1 R 2 Replaced by; R A C 1-6 Alkyl; R 1 and R 2 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 Alkyl, C 1-6 Hydroxyalkyl, 3 to 6 membered cycloalkyl C 1-6 Alkyl and -C(O)R 3 ; or R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms a 5- or 6-membered heterocyclic group; R 3 A hydrogen atom or C 1-6 alkyl.

[0163] Table A Typical macromolecules disclosed herein include, but are not limited to:

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170] Another aspect of the present disclosure also discloses the following compounds:

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185] Another aspect of the present disclosure relates to a pharmaceutical composition, which contains the macromolecule or a pharmaceutically acceptable salt thereof described in the present disclosure, and one or more pharmaceutically acceptable carriers, diluents or excipients. In some embodiments, the pharmaceutical composition does not contain a solubilizing excipient, such as polyethoxylated castor oil or polysorbate. In some embodiments, the pharmaceutical composition is administered transdermally, orally, or by injection.

[0186] The composition of the macromolecule of the present disclosure or its pharmaceutically acceptable salt is formulated, including those suitable for oral, rectal, topical, nasal, inhalation, aerosol, ocular, or parenteral (including intraperitoneal, intravenous, subcutaneous or intramuscular injection) administration. The composition can be conveniently presented in unit dosage form and can be prepared by any method well known in the pharmaceutical field. All methods include the step of associating the macromolecule with a carrier constituting one or more auxiliary components. Generally, the composition is prepared by associating the macromolecule with a liquid carrier to form a solution or suspension, or alternatively associating the macromolecule with a formulation component suitable for forming a solid, optionally a granular product, and then, if necessary, the product is molded into a desired delivery form. The solid preparation of the present disclosure, when it is a particle, will generally include a particle size range of about 1 nanometer to about 500 microns. Generally, for solid preparations intended for intravenous administration, the particle diameter range will generally be about 1nm to about 10 microns. The composition may contain a macromolecule of the present disclosure, which is a nanoparticle having a particle diameter of less than 1000 nm, for example, 5 to 1000 nm, particularly 5 to 500 nm, especially 5 to 400 nm (such as 5 to 50 nm and particularly 5 to 20 nm). In a particular embodiment, the composition contains a macromolecule with an average size of 5 to 20 nm. In some embodiments, the macromolecule is polydisperse in the composition, with a PDI of between 1.01 and 1.8, particularly between 1.01 and 1.5, and particularly between 1.01 and 1.2. In a particular embodiment, the macromolecule is monodisperse in the composition. Particularly preferred are sterile, lyophilized compositions that are reconstituted in an aqueous vehicle before injection.

[0187] In some embodiments of the present disclosure, the composition contains macromolecules having an average size of 5 to 20 nm. In some embodiments, the particle size D of the macromolecules is 90 or D 50 Less than 1000 nm, for example, 5 to 1000 nm, particularly 5 to 500 nm, especially 5 to 400 nm (such as 5 to 50 nm, particularly 5 to 20 nm). In a particular embodiment, the composition comprises a 50 It is a macromolecule ranging from 5 to 20 nm.

[0188] The macromolecules disclosed herein or their pharmaceutically acceptable salts can also be used to provide controlled release and / or sustained release formulations of pharmaceutically active agents. In sustained release formulations, formulation ingredients are selected to release macromolecules from formulations over extended periods of time (such as days, weeks or months). Such formulations include transdermal patches or in implantable devices that can be deposited subcutaneously or by intravenous, subcutaneous, intramuscular, intradural or intracranial injections. In controlled release formulations, diacid linkers are selected to release most of their pharmaceutically active agents in a given time window. For example, when it is known that most of the macromolecules accumulate in target organs, tissues or tumors, linkers can be selected to release most of their pharmaceutically active agents after the accumulation time has passed. This allows for the delivery of high drug loading at sites where it is needed to act at a given time point. Alternatively, linkers are selected to release pharmaceutically active agents at therapeutic levels over an extended period of time. In some embodiments, the formulation can have a variety of controlled release characteristics. For example, a formulation comprises a macromolecule in which the drug is connected by different linkers, which allows a burst of fast-release drug followed by a slower release at a lower but constant therapeutic level over an extended period. In some embodiments, the formulation may have sustained-release and controlled-release properties. For example, the formulation ingredients may be selected to release the macromolecule over an extended period and the linker may be selected to deliver a constant low therapeutic level of the pharmaceutically active agent. In some embodiments, the pharmaceutically active agent is connected to the same molecule by different linkers. In some embodiments, each drug-linker combination is connected to a different macromolecule in the same formulation.

[0189] In some embodiments, the macromolecule is formulated as a sustained release formulation. In some embodiments, the linker is selected to allow controlled release of the pharmaceutically active agent. In some embodiments, the macromolecule is formulated to release greater than 50% of the pharmaceutically active agent between 5 minutes and 60 minutes. In some embodiments, the macromolecule is formulated to release greater than 50% of the pharmaceutically active agent between 2 hours and 48 hours. In some embodiments, the macromolecule is formulated to release greater than 50% of the pharmaceutically active agent between 5 days and 30 days.

[0190] The present disclosure further relates to the use of the macromolecule of the present disclosure or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the preparation of a drug for treating and / or preventing a tumor; preferably, the tumor is selected from melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder cancer, gallbladder cancer, bile duct cancer, choriocarcinoma and pediatric tumors (Ewing's familial sarcoma, Wilms' sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testicular cancer, neuroblastoma, retinoblastoma, hepatoblastoma, Wilms' tumor, etc.).

[0191] The present disclosure further relates to use of the macromolecule of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and / or preventing myelofibrosis.

[0192] The present disclosure further relates to a method for treating and / or preventing tumors, which comprises administering to a patient in need thereof the macromolecule described in the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. The tumor is preferably selected from melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder cancer, gallbladder cancer, bile duct cancer, choriocarcinoma and pediatric tumors (Ewing's familial sarcoma, Wilms' sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testicular cancer, neuroblastoma, retinoblastoma, hepatoblastoma, Wilms' tumor, etc.).

[0193] The present disclosure further relates to a method for treating and / or preventing myelofibrosis, which comprises administering the macromolecule described in the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same to a patient in need thereof.

[0194] The present disclosure further relates to the macromolecule described in the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

[0195] The present disclosure also relates to the macromolecules described in the present disclosure or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same, which are used as drugs for treating and / or preventing tumors; wherein the tumors are preferably selected from melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder cancer, gallbladder cancer, bile duct cancer, choriocarcinoma and pediatric tumors (Ewing's familial sarcoma, Wilms' sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testicular cancer, neuroblastoma, retinoblastoma, hepatoblastoma, Wilms' tumor, etc.).

[0196] The present disclosure also relates to the macromolecule described in the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for treating and / or preventing myelofibrosis.

[0197] The present disclosure also relates to the macromolecules described in the present disclosure or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same, for use in treating and / or preventing tumors; wherein the tumors are preferably selected from melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder cancer, gallbladder cancer, bile duct cancer, choriocarcinoma and pediatric tumors (Ewing's familial sarcoma, Wilms' sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testicular cancer, neuroblastoma, retinoblastoma, hepatoblastoma, Wilms' tumor, etc.).

[0198] The present disclosure also relates to the macromolecule or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the macromolecule or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing myelofibrosis.

[0199] The present disclosure also relates to use of the macromolecule described in the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the macromolecule described in the present disclosure in the preparation of a drug for inhibiting BCL-2 and / or BCL-xL.

[0200] The present disclosure also relates to the macromolecule described in the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in inhibiting BCL-2 and / or BCL-xL.

[0201] The present disclosure further relates to a method for inhibiting BCL-2 and / or BCL-xL, which comprises administering the macromolecule described in the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same to a patient in need thereof.

[0202] The "tumor" described in the present disclosure is preferably cancer; wherein the cancer is preferably selected from melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder cancer, gallbladder cancer, bile duct cancer, choriocarcinoma and pediatric tumors (Ewing's familial sarcoma, Wilms' sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testicular cancer, neuroblastoma, retinoblastoma, hepatoblastoma, Wilms' tumor, etc.).

[0203] "Cancer" includes, but is not limited to, hematological malignancies (eg, lymphoma, leukemia) and solid malignancies.

[0204] "Cancer" includes, but is not limited to, T-cell leukemia, T-cell lymphoma, acute lymphoblastic lymphoma (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AML), multiple myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma, non-Hodgkin's lymphoma, follicular lymphoma, and solid tumors, e.g., non-small cell lung cancer (NSCLC, e.g., EGF mutant NSCLC, KRAS mutant NSCLC), small cell lung cancer (SCLC), breast cancer, neuroblastoma, ovarian cancer, prostate cancer, melanoma (e.g., BRAF mutant melanoma, KRAS mutant melanoma), pancreatic cancer, cervical cancer, endometrial cancer, and colon cancer (e.g., KRAS mutant colon cancer, BRAF mutant colon cancer).

[0205] In another aspect of the present disclosure, a method of reducing hypersensitivity after treatment with an oncology drug is provided, comprising administering a pharmaceutical composition of the present disclosure, wherein the composition is substantially free of solubilizing excipients such as Cremophor EL and polysorbate 80.

[0206] In another aspect of the present disclosure, a method for reducing the toxicity of an oncology drug or a formulation of an oncology drug is provided, comprising administering a macromolecule of the present disclosure. In some embodiments, the reduced toxicity is hematotoxicity, neurotoxicity, gastrointestinal toxicity, cardiotoxicity, hepatotoxicity, nephrotoxicity, ototoxicity, or brain virality.

[0207] In another aspect of the present disclosure, a method for reducing side effects associated with an oncology drug or a formulation of an oncology drug is provided, comprising administering a macromolecule of the present disclosure. In some embodiments, the reduced side effects are selected from neutropenia, leukopenia, thrombocytopenia, bone marrow toxicity, bone marrow suppression, neuropathy, fatigue, nonspecific neurocognitive problems, vertigo, encephalopathy, anemia, taste disorders, dyspnea, constipation, anorexia, nail disorders, fluid retention, weakness, pain, nausea, vomiting, mucositis, alopecia, skin reactions, myalgia, and allergies.

[0208] In some embodiments of the present disclosure, the macromolecules described herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same can reduce or eliminate the need for premedication with agents such as corticosteroids and antihistamines.

[0209] Terminology

[0210] Unless stated otherwise, the following terms used in the specification and claims have the following meanings.

[0211] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 Alkyl), further preferably an alkyl group having 1 to 10 carbon atoms (i.e., C 1-10 More preferably, the alkyl group has 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available attachment point, and the substituent is preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl. The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the alkyl group is defined as above, and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0212] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0213] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20-membered cycloalkyl). The cycloalkyl is preferably a cycloalkyl having 3 to 12 ring atoms (i.e., 3 to 12-membered cycloalkyl), further preferably a cycloalkyl having 3 to 8 ring atoms (i.e., 3 to 8-membered cycloalkyl), more preferably a cycloalkyl having 3 to 6 ring atoms (i.e., 3 to 6-membered cycloalkyl), and most preferably a cycloalkyl having 3 ring atoms (i.e., cyclopropyl).

[0214] The monocyclic cycloalkyl group includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl, and preferably cyclopropyl or cyclobutyl.

[0215] The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.

[0216] The term "spirocycloalkyl" refers to a polycyclic system with one carbon atom (called spiro atom) shared between the rings, which may contain one or more double bonds in the ring, or one or more heteroatoms selected from nitrogen, oxygen and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -OO-, -OS- or -SS-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon ring, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20-membered spirocycloalkyl). The spirocycloalkyl preferably has 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl). The spirocycloalkyl includes monospirocycloalkyl and polyspirocycloalkyl (such as bispirocycloalkyl, etc.), preferably monospirocycloalkyl or bispirocycloalkyl, more preferably 3-yuan / 4-yuan, 3-yuan / 5-yuan, 3-yuan / 6-yuan, 4-yuan / 4-yuan, 4-yuan / 5-yuan, 4-yuan / 6-yuan, 5-yuan / 3-yuan, 5-yuan / 4-yuan, 5-yuan / 5-yuan, 5-yuan / 6-yuan, 5-yuan / 7-yuan, 6-yuan / 3-yuan, 6-yuan / 4-yuan, 6-yuan / 5-yuan, 6-yuan / 6-yuan, 6-yuan / 7-yuan, 7-yuan / 5-yuan or 7-yuan / 6-yuan monospirocycloalkyl. Non-limiting examples include:

[0217] Its connection point can be at any position;

[0218]

[0219] The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20-membered fused cycloalkyl). The fused cycloalkyl preferably has 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl). The fused cycloalkyl includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic fused cycloalkyl. Non-limiting examples include: Its connection point can be at any position;

[0220]

[0221] wait.

[0222] The term "bridged cycloalkyl" refers to a full carbon polycyclic system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds in the ring and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl). The bridged cycloalkyl preferably has a bridged cycloalkyl of 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and more preferably has a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl. Non-limiting examples include:

[0223] Its connection point can be at any position.

[0224] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0225] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl), which contains at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-) in the ring, and has 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclic group), further preferably a heterocyclic group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclic group); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclic group); further preferably a heterocyclic group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclic group); most preferably a heterocyclic group having 6 ring atoms (i.e., a 6-membered heterocyclic group).

[0226] Non-limiting examples of the monocyclic heterocyclic group include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and homopiperazinyl.

[0227] The polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.

[0228] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroheterocyclyl). The spiro heterocyclic group preferably has a spiro heterocyclic group of 6 to 14 ring atoms (i.e., a 6 to 14-membered spiro heterocyclic group), and more preferably has a spiro heterocyclic group of 7 to 11 ring atoms (i.e., a 7 to 11-membered spiro heterocyclic group). The spiro heterocyclic group includes a monospiro heterocyclic group and a polyspiro heterocyclic group (such as a bispiro heterocyclic group, etc.), preferably a monospiro heterocyclic group or a bispiro heterocyclic group, more preferably a 3-yuan / 4-yuan, 3-yuan / 5-yuan, 3-yuan / 6-yuan, 4-yuan / 4-yuan, 4-yuan / 5-yuan, 4-yuan / 6-yuan, 5-yuan / 3-yuan, 5-yuan / 4-yuan, 5-yuan / 5-yuan, 5-yuan / 6-yuan, 5-yuan / 7-yuan, 6-yuan / 3-yuan, 6-yuan / 4-yuan, 6-yuan / 5-yuan, 6-yuan / 6-yuan, 6-yuan / 7-yuan, 7-yuan / 5-yuan or 7-yuan / 6-yuan monospiro heterocyclic group. Non-limiting examples include:

[0229] wait.

[0230] The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system which shares two adjacent atoms between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur within the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more of cycloalkyl, aryl, or heteroaryl, wherein the point of attachment is on the monocyclic heterocyclyl, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused heterocyclyl). The fused heterocyclic group preferably has a fused heterocyclic group of 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), more preferably a fused heterocyclic group of 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group), and further preferably a fused heterocyclic group of 9 ring atoms (i.e., a 9-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably a bicyclic fused heterocyclic group or a tricyclic fused heterocyclic group, more preferably a 3-yuan / 4-yuan, 3-yuan / 5-yuan, 3-yuan / 6-yuan, 4-yuan / 4-yuan, 4-yuan / 5-yuan, 4-yuan / 6-yuan, 5-yuan / 3-yuan, 5-yuan / 4-yuan, 5-yuan / 5-yuan, 5-yuan / 6-yuan, 5-yuan / 7-yuan, 6-yuan / 3-yuan, 6-yuan / 4-yuan, 6-yuan / 5-yuan, 6-yuan / 6-yuan, 6-yuan / 7-yuan, 7-yuan / 5-yuan or 7-yuan / 6-yuan bicyclic fused heterocyclic group. Non-limiting examples include:

[0231]

[0232] wait.

[0233] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic ring system which shares two atoms which are not directly connected between the rings, which may contain one or more double bonds in the ring, and which contains at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered bridged heterocyclic group). The bridged heterocyclic group preferably has a bridged heterocyclic group with 6 to 14 ring atoms (i.e., a 6 to 14-membered bridged heterocyclic group), more preferably a bridged heterocyclic group with 7 to 10 ring atoms (i.e., a 7 to 10-membered bridged heterocyclic group), and further preferably a bridged heterocyclic group with 7 to 8 ring atoms (i.e., a 7 to 8-membered bridged heterocyclic group). According to the number of constituent rings, it can be divided into a bicyclic bridged heterocyclic group and a polycyclic bridged heterocyclic group (such as a tricyclic bridged heterocyclic group, a tetracyclic bridged heterocyclic group, etc.), preferably a bicyclic bridged heterocyclic group or a tricyclic bridged heterocyclic group. Non-limiting examples include:

[0234]

[0235] wait.

[0236] The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic groupoxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl and heteroaryl.

[0237] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., a polycyclic aromatic group) having a conjugated π electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e., a 6- to 14-membered aromatic group). The aryl group is preferably an aromatic group having 6 to 10 ring atoms (i.e., a 6- to 10-membered aromatic group). The monocyclic aromatic group is, for example, phenyl. Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthryl, etc. The polycyclic aromatic group also includes a phenyl group fused with one or more heterocyclic groups or cycloalkyl groups, or a naphthyl group fused with one or more heterocyclic groups or cycloalkyl groups, wherein the connection point is on the phenyl group or the naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, and non-limiting examples include:

[0238] wait.

[0239] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0240] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but does not include -OO-, -OS- or -SS-) in the ring, and has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e., a 5- to 14-membered heteroaryl). The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e. a 5- to 10-membered heteroaryl group), more preferably a monocyclic heteroaryl group having 5 or 6 ring atoms (i.e. a 5- or 6-membered heteroaryl group) or a bicyclic heteroaryl group having 9 to 10 ring atoms (i.e. a 9- to 10-membered bicyclic heteroaryl group), most preferably a 5- or 6-membered monocyclic heteroaryl group containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur in the ring, or a 9- to 10-membered bicyclic heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and sulfur in the ring.

[0241] The monocyclic heteroaryl group includes, but is not limited to, furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, etc.

[0242] The polycyclic heteroaryl, non-limiting examples include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, etc. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aromatic groups, wherein the connection point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more cycloalkyl or heterocyclic groups, wherein the connection point is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include:

[0243]

[0244] wait.

[0245] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0246] The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein alkyl and cycloalkyl are as defined above.

[0247] The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, wherein alkyl and heterocyclyl are as defined above.

[0248] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0249] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0250] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy and butoxy, etc. Alkoxy can be substituted or unsubstituted, and when substituted, it can be substituted at any usable point of attachment, and the substituent is preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0251] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0252] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0253] The term "hydroxy" refers to -OH.

[0254] The term "amino" refers to -NH2.

[0255] The term "cyano" refers to -CN.

[0256] The term "nitro" refers to -NO2.

[0257] The term "oxo" or "oxo" refers to "=0".

[0258] The term "carbonyl" refers to C=O.

[0259] The term "carboxy" refers to -C(O)OH.

[0260] The term "acyl" refers to the atomic group remaining after removing one or more hydroxyl groups from an organic or inorganic oxygen-containing acid, and has the general formula -C(O)R; R can be selected from alkyl, halogenated alkyl, etc.; common ones include formyl and acetyl, etc.

[0261] The term "formyl" refers to -C(O)H.

[0262] The term "acetyl" refers to -C(O)CH3.

[0263] The term "alkylene" refers to a straight or branched divalent alkyl group, wherein alkyl is as defined above; preferably C 1-10 Alkylene, more preferably C 1-6 Alkylene; an alkylene group may be substituted or unsubstituted; non-limiting examples of "alkylene" include: -CH2-, -CH2CH2CH2-, and -CH2CH(CH3)CH2-.

[0264] The term "PEG 220-5500 ” refers to polyethylene glycol having a molecular weight ranging from 220 to 5500 Da.

[0265] The term "G5 polylysine dendrimer" refers to a dendrimer having a structural unit of 5 generations of lysine.

[0266] The macromolecules disclosed herein may exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). Substituents in the macromolecules disclosed herein may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers may be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomer salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art to obtain pure isomers. In addition, the separation of enantiomers and diastereoisomers is usually completed by chromatography.

[0267] In the chemical structure of the macromolecules disclosed in the present disclosure, the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or or include both and For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E configurations are included.

[0268] The macromolecules of the present disclosure may exist in different tautomeric forms, and all such forms are included in the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is easily converted from one isomeric form to another isomeric form. It includes all possible tautomers, that is, in the form of a single isomer or in the form of a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc. An example of a lactam-lactim equilibrium is shown below:

[0269]

[0270] For example, when referring to pyrazolyl, it is understood to include either or a mixture of two tautomers of the following two structures:

[0271]

[0272] All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomer.

[0273] The macromolecules of the present disclosure include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a macromolecule in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the macromolecules of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example, respectively. 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 p. 33 p. 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I.129 I and 131 I, etc., preferably deuterium.

[0274] Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic efficacy, and extending drug biological half-life. All isotopic composition changes of the macromolecules disclosed herein, whether radioactive or not, are included in the scope of the present disclosure. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.

[0275] For macromolecules disclosed herein, when a position is specifically designated as "deuterium" or "D", the position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).

[0276] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally (optionally) substituted with halogen or cyano" 1-6 The term "alkyl" means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted with halogen or cyano and the case where the alkyl is not substituted with halogen and cyano.

[0277] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, which are replaced independently of each other by a corresponding number of substituents. Those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0278] "Pharmaceutical composition" means a mixture containing one or more macromolecules described herein or their pharmaceutically acceptable salts and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0279] The macromolecules disclosed herein may be in the form of pharmaceutically acceptable salts. However, it should be understood that non-pharmaceutically acceptable salts also fall within the scope of the present disclosure, as these may be used as intermediates in the preparation of pharmaceutically acceptable salts or may be useful during storage or transportation. "Pharmaceutically acceptable salts" refer to salts of the macromolecules disclosed herein, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have the desired biological activity. They may be prepared separately during the final separation and purification of the macromolecules, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0280] As used herein, the singular form of "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0281] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given only for illustrative purposes and not for limitation.

[0282] "Dendrimer" refers to a molecule containing a core and at least one dendron attached to the core. Each dendron is composed of at least one layer or generation of branched building blocks, resulting in an increasingly branched structure with branches per generation of building blocks. The maximum number of dendrons attached to the core is limited by the number of functional groups on the core. The core may have one or more functional groups suitable for having a dendron and optionally additional functional groups for attaching agents suitable for targeting specific organs or tissues, signaling or imaging.

[0283] "Building block" refers to a branched molecule having at least three functional groups, one functional group for attachment to the core or the previous generation of building blocks and at least two functional groups for attachment to the next generation of building blocks or the surface of a dendrimer-forming polymer.

[0284] "Generation" refers to the number of layers of structural units that make up a dendron or dendrimer. For example, a dendrimer of one generation will have one layer of structural units with branches attached to the core, e.g., core-[[structural unit]] u , where u is the number of dendrons attached to the core. A two-generation dendrimer has two layers of structural units in each dendron attached to the core. When the structural unit has one branch point, the dendrimer may be: core [[structural unit] [structural unit] 2] u , the third generation dendrimers have three layers of building blocks in each dendron connected to the core, for example core-[[building block][building block]2[building block]4] u , the six-generation dendrimer has six layers of structural units connected to the core, for example, core-[[structural unit][structural unit]2[structural unit]4[structural unit]8[structural unit] 16 [Structural unit] 32 ] u etc. The last generation (outermost generation) of the building blocks provides the surface functionalization of the dendrimer and the number of functional groups available for attachment to end groups. For example, in a dendrimer with two dendrons attached to the core (u=2), if each building block has one branch point and there are six generations, then the outermost generation has 64 building blocks and 128 functional groups available for attachment to end groups.

[0285] The macromolecules of the present disclosure may have a loading of 2, 4, 8, 16, 32, 64 or 120 residues of the pharmaceutically active agent, particularly 16, 32 or 64 residues, more particularly 32 residues.

[0286] "Slightly soluble" refers to a drug or pharmaceutically active agent that has a solubility of 1 mg / mL to 10 mg / mL in water. A drug that has a solubility of less than 1 mg / mL in water is considered insoluble.

[0287] "Active pharmaceutical ingredient" (API) refers to a compound used to exert a therapeutic effect in vivo. This term is used interchangeably with the term "drug".

[0288] "Residue of a pharmaceutically active agent" refers to the portion of a macromolecule that is a pharmaceutically active agent when the pharmaceutically active agent is modified by attachment to the macromolecule.

[0289] “Drug loading” refers to the mass percentage of the pharmaceutically active agent loaded on the macromolecule described in the present disclosure to the macromolecule. For example, in Example 1, 28.6% wt% of compound 1w means a drug loading of 28.6%, i.e., the ratio of the mass of all 1w on compound 1 to the mass of compound 1 is 28.6%.

[0290] In the present disclosure, "residue of a pharmaceutically active agent", "residue A of a pharmaceutically active agent" and "A" are used interchangeably and, together with A in general formula (II) and general formula (III), refer to the residue of a molecule having pharmaceutical activity.

[0291] The term "linker" or "linker L" in this disclosure 0 ” and “L 0 " can be used interchangeably with L in formula (II) and formula (III) 0 , all refer to the connecting group that connects the first end group to the surface amino group of the dendrimer.

[0292] "Oncology drug" refers to a pharmaceutically active agent used to treat cancer, such as a chemotherapeutic drug.

[0293] "Solubilizing excipients" refer to formulation additives used to dissolve insoluble or slightly soluble drugs in aqueous formulations. Examples include surfactants such as polyethoxylated castor oil including Cremophor EL, Cremophor RH40 and Cremophor RH60, D-α tocopherol-polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, solutol HS15, sorbitan monoleate, poloxamer 407, Labrasol, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0294] Figure 1 This is the drug PK curve in mouse plasma in Test Example 5. DETAILED DESCRIPTION

[0295] The present disclosure is further described and explained below in conjunction with embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0296] The experimental methods without specific conditions in the examples disclosed herein are usually carried out under conventional conditions or under conditions recommended by raw material or product manufacturers. Reagents without specific sources are conventional reagents purchased from the market.

[0297] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6The unit of (ppm) is given. NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measurement solvent, and tetramethylsilane (TMS) as the internal standard.

[0298] MS was measured using Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC / MS (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), Waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0299] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

[0300] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0301] High performance liquid chromatography was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

[0302] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0303] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0304] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0305] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0306] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0307] The known starting materials disclosed in the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Shanghai Titan Technology Co., Ltd., Shanghai Bid Pharmaceutical Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Darui Chemicals and other companies.

[0308] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0309] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0310] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0311] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0312] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0313] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0314] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0315] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0316] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0317] Referring to the synthesis method of patent CN 110312531A, the following type of dendritic polymers were synthesized, wherein the first amino end group is used to connect with the pharmaceutically active agent, and the second amino end group is used to connect with the pharmacokinetic modifier (such as PEG):

[0318]

[0319] The dendrimers represented in the examples below include the core of the reference dendrimer and the structural units in the outermost generation of the dendrimer. Generations 1 to subsurface generations are not depicted. Dendrimer BHALys[Lys] 32 represents a 5th generation dendrimer having the formula BHALys[Lys]2[Lys]4[Lys]8[Lys] 16 [Lys] 32 , 64 surface amino groups are available for binding end groups.

[0320] Dendrimer Scaffold BHALys[Lys] 32 [α-NH 2· TFA] 32 [ε-PEG 570 ] 32 , BHALys[Lys] 32 [α-NH 2· TFA] 32 [ε-PEG 1100 ] 32 , BHALys[Lys] 32 [α-NH 2· TFA] 32 [ε-t-PEG 2300 ] 32 , BHALys[Lys] 32 [α-4-HSBA] 32 [ε-PEG 1100 ] 32 , BHALys[Lys] 32 [α-GILGVP-NH2.TFA] 32 [ε-PEG 1100 ] 32 and BHALys[Lys] 32 [α-GILGVP-NH 2· TFA] 32 [ε-t-PEG 2300 ] 32 The preparation of can be found in Kaminskas et al., J Control. Release (2011) (doi: 10.1016 / j.jconrel.2011.02.005). Dendritic polymer scaffold 4-azidobenzamide-PEG 12 -NEOEOEN[Su(NPN)2][Lys] 16 [NH 2· TFA] 32The preparation of may be found in WO08 / 017122.

[0321] Dendrimer Scaffold BHALys[Lys] 32 [α-NH 2· TFA] 32 [ε-PEG 2100 ] 32 In the examples, it is referred to as the dendrimer scaffold 1-PEG2K, which was synthesized according to the method of Journal of Controlled Release, 2011, 152, 241-248.

[0322] Example 1

[0323]

[0324]

[0325] first step

[0326] 2-Bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)phenol 1b

[0327] 2-Bromo-5-(hydroxymethyl)phenol 1a (46.3 g, 0.228 mol) and imidazole (19 g, 0.279 mol) were dissolved in a mixed solvent of dichloromethane (400 mL) and tetrahydrofuran (800 mL), tert-butyldimethylsilyl chloride (42 g, 0.279 mol) was added in batches at 0°C, and then stirred at 0°C for 2 hours. Water (500 mL) was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate (200 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system C to obtain the title compound 1b (53.4 g, yield: 73.8%).

[0328] MS m / z(ESI):339.0[M+23].

[0329] Step 2

[0330] 4-((2-Bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)phenoxy)methyl)thiazole 1c

[0331] Compound 1b (30 g, 93.4 mmol), thiazol-4-ylmethanol (11 g, 95.5 mmol, Bid) and tri-n-butylphosphine (29 g, 0.143 mol) were dissolved in toluene (500 mL), and azodicarbonyl dipiperidine (36 g, 0.143 mol) was added under nitrogen atmosphere. After the addition was complete, the temperature was raised to 60°C and stirred for 0.5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system C to obtain the title compound 1c (37.4 g, yield: 95.4%).

[0332] MS m / z(ESI):414.2[M+1].

[0333] Step 3

[0334] 7-(((tert-Butyldimethylsilyl)oxy)methyl)-4H-chromeno[3,4-d]thiazole 1d

[0335] Compound 1c (32 g, 77.3 mmol), anhydrous potassium carbonate (32 g, 0.232 mol), triphenylphosphine (20.3 g, 77.3 mmol) and palladium acetate (8.7 g, 38.8 mmol) were dissolved in N,N-dimethylformamide (250 mL), heated to 100°C, and stirred for 12 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system C to obtain the title compound 1d (14.0 g, yield: 54.2%). MS m / z (ESI): 334.0 [M+1].

[0336] Step 4

[0337] (4H-chromeno[3,4-d]thiazol-7-yl)methanol 1e

[0338] Compound 1d (14.0 g, 0.67 mmol) was dissolved in tetrahydrofuran (150 mL), and 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (45 mL, 45.0 mmol) was added dropwise at room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 1e (9.0 g, yield: 97.7%).

[0339] MS m / z(ESI):220.1[M+1].

[0340] Step 5

[0341] 4H-chromeno[3,4-d]thiazole-7-carbaldehyde 1f

[0342] Compound 1e (9.0 g, 41.0 mmol) was dissolved in dichloromethane (150 mL), and Dess-Martin periodinane (23 g, 54.2 mmol) was added at room temperature and stirred for 1 hour. The reaction solution was filtered, and the filter cake was washed twice with dichloromethane, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system A to obtain the title compound 1f (8.0 g, yield: 89.7%).

[0343] MS m / z(ESI):218.0[M+1].

[0344] Step 6

[0345] (E)-N-((4H-chromeno[3,4-d]thiazol-7-yl)methylidene)-2-methylpropane-2-sulfenamide 1g

[0346] Compound 1f (8.0 g, 36.8 mmol), tert-butylsulfenamide (5.4 g, 44.6 mmol) and cesium carbonate (18.1 g, 55.5 mmol) were dissolved in dichloromethane (200 mL) and stirred at room temperature for 16 hours. The reaction solution was filtered, the filter cake was washed twice with dichloromethane, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system A to obtain the title compound 1g (9.0 g, yield: 76.3%).

[0347] MS m / z(ESI):321.2[M+1].

[0348] Step 7

[0349] N-((4H-chromeno[3,4-d]thiazol-7-yl)methyl)-2-methylpropane-2-sulfenamide 1h

[0350] Compound 1g (9.0g, 28.1mmol) was dissolved in a mixed solution of tetrahydrofuran (50mL) and methanol (50mL), sodium borohydride (1.1g, 29.1mmol) was added at 0°C, and the mixture was reacted at room temperature for 30 minutes. Water (200mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (100mL×3). The organic phase was collected and dried, filtered, and the filtrate was concentrated to obtain the crude title compound 1h (9.0g). The product was used directly in the next step without purification.

[0351] MS m / z(ESI):323.4[M+1].

[0352] Step 8: (2S,4R)-2-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester 1i

[0353] Compound 1h (4.4 g, 13.7 mmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (25 mL, 4.0 M), stirred for 0.5 hours, and concentrated to obtain a crude product. The crude product and (2S, 4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (3.2 g, 13.8 mmol, Shanghai Shaoyuan) were dissolved in N, N-dimethylformamide (50 mL), and N, N-diisopropylethylamine (9.0 g, 69.6 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (6.8 g, 17.9 mmol) were added respectively, and reacted at room temperature for 1 hour. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (100 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, the filtrate was collected by filtration, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent A to give the title compound 1i (5.8 g, yield: 97.8%).

[0354] MS m / z(ESI):432.3[M+1].

[0355] Step 9

[0356] ((S)-1-((2S,4R)-2-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-4-hydroxypyrrolidine-1-

[0357] tert-Butyl (3,3-dimethyl-1-oxobutan-2-yl)carbamate 1j

[0358] Compound 1i (5.8 g, 13.4 mmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (30 mL, 4.0 M), stirred for reaction for 0.5 hours, and concentrated to obtain a crude product. The crude product and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (3.1 g, 13.4 mmol, Shanghai Shaoyuan) were dissolved in N,N-dimethylformamide (60 mL), and N,N-diisopropylethylamine (8.6 g, 66.5 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (6.6 g, 17.4 mmol) were added respectively, and reacted at room temperature for 1 hour. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (10 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent A to obtain the title compound 1j (7.0 g, yield: 96.4%). MS m / z (ESI): 545.3 [M+1].

[0359] Step 10

[0360] 7-(((S)-1-((2S,4R)-2-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-4-hydroxypyrrolidine-1-

[0361] 3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoic acid methyl ester 1k

[0362] Compound 1j (4.2 g, 7.72 mmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (30 mL, 4.0 M), stirred for 0.5 hours, and concentrated to obtain a crude product. The crude product and 7-methoxy-7-oxoheptanoic acid (1.4 g, 8.03 mmol, Leyan) were dissolved in N,N-dimethylformamide (50 mL), and N,N-diisopropylethylamine (5.0 g, 38.7 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.8 g, 10.0 mmol) were added respectively, and reacted at room temperature for 1 hour. The reaction solution was poured into water (200 mL), extracted with ethyl acetate (100 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent A to give the title compound 1k (3.5 g, yield: 75.4%).

[0363] MS m / z(ESI):601.4[M+1].

[0364] Step 11

[0365] 7-(((S)-1-((2S,4R)-2-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-4-hydroxypyrrolidine-1-

[0366] (2-(4-(4-(4-nitro-2-nitro-3-yl)amino)-7-oxoheptanoic acid)

[0367] Compound 1k (3.5 g, 5.83 mmol) was added to a mixed solvent of water (20 mL) and methanol (40 mL), and lithium hydroxide monohydrate (1.3 g, 31.0 mmol) was added. The reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 4-5 with dilute hydrochloric acid. A white solid precipitated and was filtered. The filter cake was washed with water and dried to obtain a crude title compound 1l (3.1 g). The product was directly used in the next step without purification.

[0368] MS m / z(ESI):587.4[M+1].

[0369] Step 12

[0370] (S)-4-(4-Bromo-2-fluorophenyl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester 1n

[0371] 4-Bromo-1,2-difluorobenzene (8.9 g, 46.27 mmol, Shaoyuan) and (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester 1m (10 g, 46.23 mmol, Bid) were dissolved in dimethyl sulfoxide (100 mL), potassium hydroxide (3.9 g, 69.51 mmol) was added, and stirred at room temperature for 16 hours. The reaction solution was poured into 200 mL of water, extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered and the filtrate was collected, and concentrated under reduced pressure to obtain the crude title compound 1n (17.9 g), which was used directly in the next step without purification.

[0372] MS m / z(ESI):389.2[M+1].

[0373] Step 13

[0374] (S)-8-Bromo-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester

[0375] The crude compound 1n (19 g) was dissolved in tetrahydrofuran (200 mL) and protected by nitrogen. The reaction solution was cooled to 0°C, and 1M lithium bistrimethylsilylamide tetrahydrofuran solution (66.9 mL, 66.93 mmol) was added dropwise, and then the temperature was raised to 60°C for reaction for 1 hour. The reaction solution was cooled to room temperature, poured into water (200 mL) for quenching, extracted with ethyl acetate (200 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound 1o (1.2 g, yield: 6.7%). MS m / z (ESI): 369.2 [M+1].

[0376] Step 14

[0377] (S)-3-(tert-Butyloxycarbonyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxylic acid 1p

[0378] Compound 1o (1.2 g, 3.25 mmol) was dissolved in tetrahydrofuran (25 mL), and under nitrogen protection, 2.5 M n-butyl lithium hexane solution (2.6 mL, 6.51 mmol) was added dropwise at -78°C, and the reaction was stirred at -78°C for 0.5 hours, and carbon dioxide gas was passed for 2 hours. Water (30 mL) was added to the reaction solution to quench, and it was extracted with ethyl acetate (10 mL), and the aqueous phase was collected. The pH of the aqueous phase was adjusted to 4-5 with dilute hydrochloric acid (1 M), and it was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1p (230 mg), which was directly used in the next step without purification.

[0379] MS m / z(ESI):279.2[M-55].

[0380] Step 15

[0381] (S)-1,2,3,4,4a,5-Hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxylic acid methyl ester 1q

[0382] The crude compound 1p (230 mg) was dissolved in methanol (10 mL), thionyl chloride (1 g, 8.41 mmol) was added, and the mixture was heated to 50° C. and stirred for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 1q (164 mg), which was used directly in the next step without purification.

[0383] MS m / z(ESI):249.1[M+1].

[0384] Step 16 (S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxylic acid methyl ester 1s

[0385] (4'-Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methanol 1r (177 mg, 0.71 mmol, prepared by the method disclosed in Example 8, compound f on page 43 of the specification of patent application WO2008061208A2) and triethylamine (143 mg, 1.41 mmol) were dissolved in dichloromethane (10 mL), and methanesulfonyl chloride (121 mg, 1.06 mmol) was added dropwise under ice bath, and the reaction was stirred at room temperature for 2 hours. Add water (10 mL) to quench, extract with dichloromethane (10 mL×3), separate, combine the organic phases, add anhydrous sodium sulfate to dry, filter and concentrate the filtrate under reduced pressure, the residue is dissolved in N,N-dimethylformamide (5 mL), add compound 1q (100 mg, 0.35 mmol) and potassium carbonate (243 mg, 1.76 mmol), and heat to 75°C for 16 hours. The reaction solution is cooled to room temperature and concentrated under reduced pressure, and the residue is purified by silica gel column chromatography with elution system B to obtain the title compound 1s (139 mg, yield: 82.3%).

[0386] MS m / z(ESI):481.5[M+1].

[0387] Step 17 (S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carboxylic acid 1t

[0388] Compound 1s (139 mg, 0.29 mmol) was dissolved in a mixed solvent of water (2 mL), tetrahydrofuran (2 mL) and methanol (2 mL), and lithium hydroxide monohydrate (61 mg, 1.45 mmol) was added, and the mixture was heated to 70°C and stirred for 16 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent, and the resulting aqueous phase was adjusted to pH 5-6 with dilute hydrochloric acid (1 M), extracted with ethyl acetate (20 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1t (120 mg). The product was used directly in the next step without purification. MS m / z (ESI): 467.3 [M+1].

[0389] Step 18

[0390] tert-Butyl 4-((R)-3-((4-(N-((S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carbonyl)aminosulfonyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazine-1-carboxylate 1v

[0391] The crude compound 1t (120 mg), (R)-4-(4-(phenylthio)-3-((4-aminosulfonyl-2-((trifluoromethyl)sulfonyl)phenyl)amino)butyl)piperazine-1-carboxylic acid tert-butyl ester 1u (118 mg, 0.19 mmol, prepared by the method disclosed in Intermediate 9 on page 65 of the specification of patent application CN114144411A) were dissolved in dichloromethane (10 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (148 mg, 0.77 mmol), triethylamine (133 mg, 1.29 mmol) and 4-dimethylaminopyridine (32 mg, 0.26 mmol) were added respectively, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system A to obtain the title compound 1v (136 mg, yield: 48.0%).

[0392] MS m / z(ESI):1101.3[M+1].

[0393] Step 19: (S)-N-((4-(((R)-4-(4-(7-(((S)-1-((2S,4R)-2-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoyl)piperazine-1-yl

[0394] 1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-3-((4'-chloro-4,4-dichloro

[0395] methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino

[0396] [1,2-d][1,4]oxazine-8-carboxamide 1w

[0397] Compound 1v (50 mg, 0.045 mmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (2 mL, 4.0 M), stirred for reaction for 0.5 hour, and concentrated to obtain a crude product. The crude product and compound 1l (30 mg, 0.051 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), and N,N-diisopropylethylamine (30 mg, 0.232 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (20 mg, 0.053 mmol) were added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (instrument model: Gilson 281, chromatographic column: X-Bridge, Prep 30×150 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-60%, flow rate: 30 mL / min) to obtain the title compound 1w (25 mg, yield: 35.1%).

[0398] MS m / z(ESI):1569.5[M+1].

[0399] 1 H NMR (500MHz, CDCl3): δ8.70(s,1H),8.39(d,1H),8.08(dd,1H),7.68(d,2H),7.45-7.22(m,4H),7.21(d,1H),7.16(d,1H ),7.11(d,1H),6.99(d,2H),6.92-6.86(m,2H),6.69(d,1H),6.66(d,1H),6.37(d,1H),5.44(s,2H),4.75(t,1H),4.59(d ,1H),4.55-4.51(m,1H),4.47(dd,1H),4.26(dd,1H),4.14(t,2H),3.95-3.91(m,1H),3.86(t,1H),3.77-3.56(m,3H),3. 48-3.19(m,4H),3.17-2.99(m,2H),2.90-2.76(m,3H),2.75-2.66(m,1H),2.58-1.21(m,34H),1.00(s,6H),0.97(s,9H).

[0400] Step 20

[0401] 1-((3R,5S)-5-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-1-((S)-2-(7-(4-((R)-3-((4-(N-((S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a, 5-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptylamido)-3,3-dimethylbutanoyl)pyrrolidin-3-yl)5-(2-(trimethylsilyl)ethyl)-N,N-dimethyl-L-glutamic acid 1y

[0402] Compound 1w (200 mg, 0.127 mmol) and compound 1x (175 mg, 0.635 mmol, prepared by the method disclosed in Example 9 on page 37 of the specification of patent application WO2022042583 A1, intermediate 1-Z01-J-TMS) were dissolved in N,N-dimethylformamide (4.0 mL), 4-dimethylaminopyridine (80 mg, 0.649 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (122 mg, 0.638 mmol) were added, and the reaction was carried out at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to obtain the title compound 1y (210 mg, yield: 90.2%).

[0403] MS m / z(ESI):1826.7[M+1].

[0404] Step 21

[0405] (S)-5-(((3R,5S)-5-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-1-((S)-2-(7-(4-((R)-3-((4-(N-((S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2, 3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carbonyl)aminosulfonyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptylamido)-3,3-dimethylbutanoyl)pyrrolidin-3-yl)oxy)-4-(dimethylamino)-5-oxopentanoic acid 1z

[0406] Compound 1y (210 mg, 0.115 mmol) was dissolved in dichloromethane (3.0 mL), trifluoroacetic acid (1.0 mL) was added, and the mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent A to obtain the title compound 1z (190 mg, yield: 95.7%).

[0407] MS m / z(ESI):1727.0[M+1].

[0408] Step 22

[0409] Compound 1

[0410] Under nitrogen atmosphere, compound 1z (160 mg, 0.0926 mmol) and benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate (60 mg, 0.115 mmol, Shanghai Shaoyuan) were dissolved in N,N-dimethylformamide (4.0 mL), and a solution of the dendritic polymer scaffold 1-PEG2K (138 mg, 1.94 μmol, synthesized according to the literature Journal of Controlled Release, 2011, 152, 241-248) and N-methylmorpholine (40 mg, 0.395 mmol) in anhydrous N,N-dimethylformamide (1.0 mL) was added dropwise, and the reaction was carried out at room temperature for 16 hours.

[0411] The reaction solution was diluted with acetonitrile (50 mL) and filtered. The filtrate was passed through an ultrafiltration device (10KD, Pellicon) and purified by ultrafiltration with acetonitrile. After concentration, the product was freeze-dried to obtain 200 mg of the title compound 1 with a yield of 87.9%.

[0412] 19 F NMR (500 MHz, CD3OD): δ -108.94 ppm (2.66 mg p-fluorobenzoic acid, calibrated at 1.00), -80.15 ppm (34.72 mg compound 1, 1.00).

[0413] 19 F NMR indicated 18 Compound 1w / Compound 1. The actual molecular weight was approximately 98.0 kDa (28.6% wt% Compound 1w).

[0414] 1H NMR (500MHz, MeCN-d3): δ8.91-8.72(m,44H),8.42-7.89(m,132H),7.70-6.59(m,492H),5.60-5.16(m,108H),4.99- 3.35(m,5410H),3.31(s,89H),3.23-2.97(m,136H),2.86-2.61(m,127H),2.51-2.06(m,366H),1.66-1.10(m,416H).

[0415] Example 2

[0416]

[0417]

[0418] first step

[0419] 2-((2-(((3R,5S)-5-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamide

[0420] 2-((S)-2-(7-(4-((R)-3-((4-(N-((S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carbonyl)aminosulfonyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptamido)-3,3-dimethylbutanoyl)pyrrolidin-3-yl)oxy)-2-oxoylideneethyl)thio)acetic acid 2b

[0421] Compound 1w (200 mg, 0.127 mmol) and thiohydroxyacetic anhydride 2a (50 mg, 0.378 mmol, Shanghai Bid Pharmaceutical) were dissolved in dichloromethane (10 mL), 4-dimethylaminopyridine (30 mg, 0.246 mmol) and pyridine (50 mg, 0.632 mmol) were added, and the mixture was reacted at 50°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 2b (200 mg, yield: 92.2%).

[0422] MS m / z(ESI):1701.6[M+1].

[0423] Step 2

[0424] Compound 2

[0425] Under nitrogen atmosphere, compound 2b (200 mg, 0.117 mmol) and benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate (75 mg, 0.144 mmol, Shanghai Shaoyuan) were dissolved in N,N-dimethylformamide (3.0 mL), and a solution of dendritic polymer scaffold 1-PEG2K (130 mg, 1.83 μmol) and N-methylmorpholine (50 mg, 0.494 mmol) in anhydrous N,N-dimethylformamide (1.0 mL) was added dropwise, and the reaction was carried out at room temperature for 16 hours.

[0426] The reaction solution was diluted with acetonitrile (50 mL) and filtered. The filtrate was passed through an ultrafiltration device (10KD, Pellicon) and purified by ultrafiltration with acetonitrile. After concentration, lyophilization was performed to obtain 180 mg of the title compound 2 with a yield of 84.5%.

[0427] 19 F NMR (500 MHz, CD3OD): δ -108.83 ppm (2.66 mg p-fluorobenzoic acid, calibrated at 1.00), -80.18 ppm (35.86 mg compound 2, 0.86).

[0428] 19 F NMR indicated 14 Compound 1w / Compound 2. The actual molecular weight was approximately 90.8 kDa (23.8% wt. % Compound 1w).

[0429] 1 H NMR (500MHz, MeCN-d3): δ8.92-8.73(m,41H),8.43-7.91(m,121H),7.67-6.61(m,415H),5.63-5.07(m,108H),4.88- 3.34(m,5331H),3.31(s,89H),3.25-2.97(m,182H),2.89-2.56(m,166H),2.52-2.06(m,256H),1.73-1.09(m,432H).

[0430] Example 3

[0431]

[0432]

[0433] first step

[0434] 5-Benzyl-1-(tert-butyl) N,N-dimethyl-L-glutamic acid 3b

[0435] (S)-5-Benzyl 1-(tert-butyl) L-glutamic acid hydrochloride 3a (2.0 g, 6.06 mmol, Shanghai Bid Pharmaceutical) and formaldehyde aqueous solution (2.3 g, 30.6 mmol, 40% purity) were dissolved in methanol (20 mL), sodium triacetoxyborohydride (6.5 g, 30.6 mmol) was added, and the reaction was carried out at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to obtain the title compound 3b (1.6 g, yield: 82.1%).

[0436] MS m / z(ESI):266.1[M-55].

[0437] Step 2

[0438] (S)-5-(tert-Butoxy)-4-(dimethylamino)-5-oxopentanoic acid 3c

[0439] Under nitrogen atmosphere, compound 3b (1.5 g, 4.67 mmol) was dissolved in tetrahydrofuran (20 mL), palladium / carbon (200 mg, 10 wt.%) was added, hydrogen was replaced three times, and the reaction was carried out at room temperature for 16 hours. Filtered and concentrated under reduced pressure to obtain the crude title compound 3c (1.1 g). The product was used directly in the next step without purification.

[0440] MS m / z(ESI):176.0[M-55].

[0441] Step 3

[0442] 5-((3R,5S)-5-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamide

[0443] 1-((S)-2-(7-(4-((R)-3-((4-(N-((S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carbonyl)aminosulfonyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptamido)-3,3-dimethylbutanoyl)pyrrolidin-3-yl)1-(tert-butyl)N,N-dimethyl-L-glutamic acid 3d

[0444] Compound 1w (200 mg, 0.127 mmol) and compound 3c (150 mg, 0.648 mmol) were dissolved in N,N-dimethylformamide (4.0 mL), and 4-dimethylaminopyridine (80 mg, 0.649 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (125 mg, 0.654 mmol) were added respectively, and the mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to obtain the title compound 3d (220 mg, yield: 96.8%).

[0445] MS m / z(ESI):1782.7[M+1].

[0446] Step 4

[0447] (S)-5-(((3R,5S)-5-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamide

[0448] 3e-((S)-2-(7-(4-((R)-3-((4-(N-((S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carbonyl)aminosulfonyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptamido)-3,3-dimethylbutanoyl)pyrrolidin-3-yl)oxy)-4-(dimethylamino)-5-oxopentanoic acid

[0449] Compound 3d (220 mg, 0.123 mmol) was dissolved in dichloromethane (3.0 mL), trifluoroacetic acid (1.0 mL) was added, and the mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent A to obtain the title compound 3e (107 mg, yield: 50.7%).

[0450] MS m / z(ESI):1726.7[M+1].

[0451] Step 5

[0452] Compound 3

[0453] Under nitrogen atmosphere, compound 3e (107 mg, 61.9 μmol) and benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate (40 mg, 76.8 μmol, Shanghai Shaoyuan) were dissolved in N,N-dimethylformamide (3.0 mL), and a solution of dendritic polymer scaffold 1-PEG2K (90 mg, 1.21 μmol) and N-methylmorpholine (30 mg, 0.297 mmol) in anhydrous N,N-dimethylformamide (1.0 mL) was added dropwise, and the reaction was carried out at room temperature for 16 hours.

[0454] The reaction solution was diluted with acetonitrile (50 mL) and filtered. The filtrate was passed through an ultrafiltration device (10KD, Pellicon) and purified by ultrafiltration with acetonitrile. After concentration, it was lyophilized to obtain the title compound 3 (100 mg, yield 67.4%).

[0455] 19 F NMR (500 MHz, CD3OD): δ -108.92 ppm (2.43 mg p-fluorobenzoic acid, calibrated at 1.00), -80.12 ppm (39.04 mg compound 3, 1.10).

[0456] 19 F NMR indicated 15 Compound 1w / Compound 3. The actual molecular weight was approximately 92.8 kDa (25.5% wt. % Compound 1w).

[0457] 1 H NMR (500MHz, MeCN-d3): δ8.95-8.68(m,60H),8.42-7.90(m,140H),7.58-6.75(m,482H),5.60-5.13(m,11 8H),4.94-3.35(m,5159H),3.31(s,89H),3.20-2.58(m,419H),2.52-2.06(m,386H),1.65-1.44(m,422H).

[0458] Example 4

[0459]

[0460] first step

[0461] N-(2-(Benzyloxy)-2-oxyylideneethyl)-N-methylglycine 4b

[0462] Dissolve 4-methylmorpholine-2,6-dione 4a (5.0 g, 38.7 mmol, Shanghai Shaoyuan) and benzyl alcohol (4.6 g, 42.5 mmol, Sinopharm) in tetrahydrofuran (10 mL), add pyridine (2.0 mL), and react at room temperature for 24 hours. Add 10 mL of water, extract with ether (50 mL × 3), collect the aqueous phase, and concentrate under reduced pressure to obtain a crude product. Add dichloromethane (20 mL) to the crude product and stir for 24 hours, filter, and concentrate the filtrate to obtain the crude title compound 4b (6.5 g). The product is not purified and used directly in the next step.

[0463] MS m / z(ESI):238.4[M+1].

[0464] Step 2

[0465] N-Methyl-N-(2-oxo-2-(2-(trimethylsilyl)ethoxy)ethyl)glycine benzyl ester 4c

[0466] Compound 4b (2.0 g, 8.43 mmol) and trimethylsilyl alcohol (1.2 g, 10.1 mmol, Shanghai Bid Pharmaceutical) were dissolved in dichloromethane (30 mL), and 4-dimethylaminopyridine (105 mg, 0.852 mmol), N,N-diisopropylethylamine (3.3 g, 25.5 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.1 g, 10.8 mmol) were added respectively, and the mixture was reacted at room temperature for 16 hours. Water (100 mL) was added, and the mixture was extracted with dichloromethane (50 mL×3), the organic phases were combined, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to obtain the title compound 4c (2.0 g, yield: 70.3%).

[0467] MS m / z(ESI):338.4[M+1].

[0468] Step 3

[0469] N-Methyl-N-(2-oxo-2-(2-(trimethylsilyl)ethoxy)ethyl)glycine 4d

[0470] Under nitrogen atmosphere, compound 4c (1.8 g, 5.33 mmol) was dissolved in tetrahydrofuran (20 mL), palladium / carbon (200 mg, 10 wt.%) was added, hydrogen was replaced three times, and the reaction was carried out at room temperature for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude title compound 4d (1.3 g). The product was used directly in the next step without purification.

[0471] MS m / z(ESI):246.0[M-1].

[0472] Step 4

[0473] (3R,5S)-5-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamide

[0474] 4-((S)-2-(7-(4-((R)-3-((4-(N-((S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carbonyl)aminosulfonyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptylamido)-3,3-dimethylbutanoyl)pyrrolidin-3-yl N-methyl-N-(2-oxo-2-(2-(trimethylsilyl)ethoxy)ethyl)glycinate 4e

[0475] Compound 1w (160 mg, 0.102 mmol) and compound 4d (130 mg, 0.525 mmol) were dissolved in N,N-dimethylformamide (4.0 mL), and 4-dimethylaminopyridine (65 mg, 0.532 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (100 mg, 0.524 mmol) were added respectively, and the mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to obtain the title compound 4e (165 mg, yield: 90.0%).

[0476] MS m / z(ESI):1798.8[M+1].

[0477] Step 5

[0478] N-(2-(((3R,5S)-5-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamide

[0479] 4f)-1-((S)-2-(7-(4-((R)-3-((4-(N-((S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carbonyl)aminosulfonyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptamido)-3,3-dimethylbutanoyl)pyrrolidin-3-yl)oxy)-2-oxoylideneethyl)-N-methylglycine

[0480] Compound 4e (110 mg, 0.123 mmol) was dissolved in dichloromethane (2.0 mL), trifluoroacetic acid (1.0 mL) was added, and the mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent A to obtain the title compound 4f (60 mg, yield: 57.7%).

[0481] MS m / z(ESI):1698.6[M+1].

[0482] Step 6

[0483] Compound 4

[0484] Under nitrogen atmosphere, compound 4f (190 mg, 0.111 mmol) and benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate (72 mg, 0.138 mmol, Shanghai Shaoyuan) were dissolved in N,N-dimethylformamide (3.0 mL), and a solution of dendritic polymer scaffold 1-PEG2K (150 mg, 2.12 μmol) and N-methylmorpholine (50 mg, 0.494 mmol) in anhydrous N,N-dimethylformamide (1.0 mL) was added dropwise, and the reaction was carried out at room temperature for 16 hours.

[0485] The reaction solution was diluted with acetonitrile (50 mL) and filtered. The filtrate was purified by ultrafiltration using acetonitrile through an ultrafiltration device (10KD, Pellicon). After concentration, the product was lyophilized to obtain the title compound 4 (200 mg, yield 81.5%).

[0486] 19 F NMR (500 MHz, CD3OD): δ -64.34 ppm (5.73 mg of p-trifluoromethylbenzoic acid, calibrated at 1.00), -80.14 ppm (36.60 mg of compound 4, 0.22).

[0487] 19 F NMR indicated 17 Compound 1w / Compound 4. The actual molecular weight was approximately 92.8 kDa (28.4% wt% Compound 1w).

[0488] 1 H NMR (500MHz, MeCN-d3): δ8.89-8.71(m,61H),8.38-8.10(m,95H),7.71-6.75(m,596H),5.65-5.19(m,16 3H),4.17-3.40(m,5413H),3.31(s,89H),3.21-3.02(m,73H),2.89-2.11(m,523H),1.72-1.16(m,458H).

[0489] Example 5

[0490]

[0491]

[0492] first step

[0493] 1-((3R,5S)-5-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-1-((S)-2-(7-(4-((R)-3-((4-(N-((S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5- (hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carbonyl)aminosulfonyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptylamido)-3,3-dimethylbutanoyl)pyrrolidin-3-yl)-5-(2-(trimethylsilyl)ethyl)N-isopropyl-N-methyl-L-glutamic acid 5b

[0494] Compound 1w (200 mg, 0.127 mmol) and (S)-2-(isopropyl(methyl)amino)-5-oxo-5-(2-(trimethylsilyl)ethoxy)pentanoic acid 5a (200 mg, 0.659 mmol, prepared by the method disclosed in Example 13 on page 46 of the specification of patent application WO2022042583 A1, intermediate 1-Z01-P-TMS) were dissolved in N,N-dimethylformamide (4.0 mL), 4-dimethylaminopyridine (80 mg, 0.649 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (125 mg, 0.654 mmol) were added, and the reaction was carried out at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to obtain the title compound 5b (180 mg, yield: 76.1%).

[0495] MS m / z(ESI):1854.6[M+1].

[0496] Step 2

[0497] (S)-5-(((3R,5S)-5-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamide

[0498] 5c)-1-((S)-2-(7-(4-((R)-3-((4-(N-((S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carbonyl)aminosulfonyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptamido)-3,3-dimethylbutanoyl)pyrrolidin-3-yl)oxy)-4-(isopropyl(methyl)amino)-5-oxopentanoic acid

[0499] Compound 5b (180 mg, 97.0 μmol) was dissolved in tetrahydrofuran (2.0 mL), tetrabutylammonium fluoride (1.0 mL, 1.0 mmol, 1.0 M) was added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 5c (170 mg, yield: 99.8%).

[0500] MS m / z(ESI):1754.6[M+1].

[0501] Step 3

[0502] Compound 5

[0503] Under nitrogen atmosphere, compound 5c (200 mg, 113.9 μmol) and benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate (71 mg, 136 μmol, Shanghai Shaoyuan) were dissolved in N,N-dimethylformamide (3.0 mL), and a solution of dendritic polymer scaffold 1-PEG2K (121 mg, 1.71 μmol) and N-methylmorpholine (58 mg, 0.57 mmol) in anhydrous N,N-dimethylformamide (1.0 mL) was added dropwise, and the reaction was carried out at room temperature for 16 hours.

[0504] The reaction solution was diluted with acetonitrile (50 mL) and filtered. The filtrate was passed through an ultrafiltration device (10KD, Pellicon) and purified by ultrafiltration with acetonitrile. After concentration, it was lyophilized to obtain the title compound 5 (160 mg, yield 79.6%).

[0505] 19 F NMR (500 MHz, CD3OD): δ -64.30 ppm (4.41 mg of p-trifluoromethylbenzoic acid, calibrated at 1.00), -80.21 ppm (38.41 mg of compound 5, 0.27).

[0506] 19F NMR indicated 15 Compound 1w / Compound 5. The actual molecular weight was approximately 93.3 kDa (25.6% wt% Compound 1w).

[0507] 1 H NMR(500MHz,MeCN-d3): δ8.98-8.74(m,97H),7.62-6.77(m,487H),5.61-5.25(m,14 0H),4.66-3.34(m,5121H),3.32(s,89H),2.65-2.12(m,635H),1.60-1.13(m,407H).

[0508] Example 6

[0509]

[0510] first step

[0511] 2-(2-(((3R,5S)-5-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-1-((S)-2-(7-(4-((R)-3-((4-(N-((S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1, 2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carbonyl)aminosulfonyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptylamido)-3,3-dimethylbutanoyl)pyrrolidin-3-yl)oxy)-2-oxoethoxy)acetic acid 6b

[0512] Compound 1w (200 mg, 0.127 mmol) and 1,4-dioxane-2,6-dione 6a (47 mg, 0.404 mmol, Alfa) were dissolved in dichloromethane (5.0 mL), 4-dimethylaminopyridine (34 mg, 0.276 mmol) and pyridine (54 mg, 0.682 mmol) were added, and the mixture was reacted at 50°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 6b (200 mg, yield: 93.1%).

[0513] MS m / z(ESI):1685.4[M+1].

[0514] Step 2

[0515] Compound 6

[0516] Under nitrogen atmosphere, compound 6b (210 mg, 124.5 μmol) and benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate (80 mg, 0.154 mmol, Shanghai Shaoyuan) were dissolved in N,N-dimethylformamide (3.0 mL), and a solution of dendritic polymer scaffold 1-PEG2K (150 mg, 2.12 μmol) and N-methylmorpholine (65 mg, 0.643 mmol) in anhydrous N,N-dimethylformamide (1.0 mL) was added dropwise, and the reaction was carried out at room temperature for 16 hours.

[0517] The reaction solution was diluted with acetonitrile (50 mL) and filtered. The filtrate was passed through an ultrafiltration device (10KD, Pellicon) and purified by ultrafiltration with acetonitrile. After concentration, it was lyophilized to obtain the title compound 6 (200 mg, yield 81.7%).

[0518] 19 F NMR (500 MHz, CD3OD): δ -64.29 ppm (4.46 mg p-trifluoromethylbenzoic acid, calibrated at 1.00), -80.15 ppm (42.20 mg dendrimer final product, 0.37).

[0519] 19 F NMR indicated 21 Compound 1w / dendrimer. Actual molecular weight was approximately 102.2 kDa (32.3% wt.% Compound 1w).

[0520] 1 H NMR (500MHz, MeCN-d3): δ8.85-8.73(m,39H),8.32-7.96(m,119H),7.62-6.52(m,594H),5.54- 5.16(m,107H),4.69-3.35(m,5191H),3.31(s,89H),2.85-2.08(m,580H),1.67-1.14(m,446H).

[0521] Example 7-1 or 7-2

[0522]

[0523]

[0524]

[0525]

[0526]

[0527] first step

[0528] Tert-butyl 5-((5-(1-methoxy-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)pentanoate 7b

[0529] 2-(3-hydroxyisoxazol-5-yl)-3-methylbutyric acid methyl ester 7a (1.00g, 5.02mmol, prepared by the method disclosed in Example 3, intermediate 3 on page 226 of the specification of patent application WO2019084030A1) was dissolved in N,N-dimethylformamide (5mL), tert-butyl 5-bromovalerate (1.78g, 7.50mmol, Shanghai Shaoyuan) and anhydrous potassium carbonate (2.08g, 15.05mmol) were added respectively, and the temperature was raised to 70°C and stirred for 2 hours. The reaction solution was cooled to room temperature, water (30mL) was added, extracted with ethyl acetate (15mL×3), the organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound 7b (1.00g, yield: 56.0%).

[0530] MS m / z(ESI):354.1[M-1].

[0531] Step 2

[0532] 2-(3-((5-(tert-Butyloxy)-5-oxopentyl)oxy)isoxazol-5-yl)-3-methylbutanoic acid 7c

[0533] Compound 7b (1.00 g, 2.81 mmol) was dissolved in a mixed solvent of methanol (5 mL), water (5 mL) and tetrahydrofuran (5 mL), and lithium hydroxide monohydrate (590 mg, 14.1 mmol) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent, and the obtained aqueous phase was adjusted to pH 3-4 with 1M dilute hydrochloric acid, extracted with ethyl acetate (30 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 7c (900 mg). The product was used directly in the next step without purification. MS m / z (ESI): 340.1 [M-1].

[0534] Step 3

[0535] 5-((5-((S)-1-((2S,4R)-2-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-4-hydroxypyrrolidine

[0536] -1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)pentanoic acid tert-butyl ester 7d-1

[0537] and

[0538] 5-((5-((R)-1-((2S,4R)-2-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-4-hydroxypyrrolidine

[0539] -1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)pentanoic acid tert-butyl ester 7d-2

[0540] Compound 1i (655 mg, 1.52 mmol) was dissolved in a solution of hydrogen chloride in dioxane (10 mL, 4.0 M), stirred for reaction for 1 hour, and concentrated to obtain a crude product.

[0541] The above crude product and compound 7c (400 mg, 1.17 mmol) were dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (454 mg, 3.51 mmol) was added. After the solution was clarified, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (890 mg, 2.34 mmol) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to obtain the crude title compound, which was separated by chiral preparative column (instrument model: Gilson-281 chromatographic column: ChiralPak IE, 5 μm, 20 mm*250 mm; mobile phase: A-n-hexane; B-ethanol, (40% ethanol and 60% n-hexane) proportional elution, flow rate: 15 mL / min) to obtain the title compounds 7d-1 and 7d-2 (110 mg, yield 14.3%; 160 mg, yield 20.8%).

[0542] Single configuration compound (short retention time): 110 mg, yield: 14.3%;

[0543] MS m / z(ESI):655.1[M+1].

[0544] Chiral HPLC analysis: retention time 8.849 minutes, purity: 100% (chromatographic column: CHIRALPAK IE 150*4.6 mm, 5 μm; mobile phase: ethanol, n-hexane, gradient ratio: ethanol: n-hexane = 40%: 60%). Single configuration compound (longer retention time): 160 mg, yield: 20.8%.

[0545] MS m / z(ESI):655.1[M+1].

[0546] Chiral HPLC analysis: retention time 16.75 minutes, purity: 99.5% (chromatographic column: CHIRALPAK IE 150*4.6 mm, 5 μm; mobile phase: ethanol, n-hexane, gradient ratio: ethanol: n-hexane = 40%: 60%).

[0547] Step 4

[0548] 5-((5-((S)-1-((2S,4R)-2-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-4-hydroxypyrrolidine

[0549] -1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)pentanoic acid 7e-1

[0550] 5-((5-((R)-1-((2S,4R)-2-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-4-hydroxypyrrolidine

[0551] -1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)pentanoic acid 7e-2

[0552] The compound with shorter retention time (350 mg, 0.53 mmol) of compound 7d-1 or 7d-2 was added to a 4M solution of hydrogen chloride in 1,4-dioxane (5 mL), stirred at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain the crude title compound 7e-1 or 7e-2 (320 mg), which was used directly in the next step without purification. MS m / z (ESI): 599.4 [M+1].

[0553] Chiral HPLC analysis: retention time 7.709 minutes, purity: 98.2% (chromatographic column: CHIRALPAK IK 150*4.6 mm, 5 μm; mobile phase: ethanol + 0.1% trifluoroacetic acid, n-hexane, gradient ratio: ethanol 0.1% trifluoroacetic acid: n-hexane = 40%: 60%).

[0554] The compound with a longer retention time (160 mg, 0.27 mmol) of compound 7d-1 or 7d-2 was added to a 4M hydrogen chloride solution in 1,4-dioxane (5 mL), stirred at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain a crude title compound 7e-1 or 7e-2 (140 mg). The product was used directly in the next step without purification. MS m / z (ESI): 599.4 [M+1].

[0555] Chiral HPLC analysis: retention time 9.684 minutes, purity: 96.6% (chromatographic column: CHIRALPAK IK 150*4.6 mm, 5 μm; mobile phase: ethanol + 0.1% trifluoroacetic acid, n-hexane, gradient ratio: ethanol + 0.1% trifluoroacetic acid: n-hexane = 40%: 60%).

[0556] Step 5

[0557] (S)-tert-Butyl 3-(((tert-Butyldiphenylsilyl)oxy)methyl)piperazine-1-carboxylate 7f

[0558] Compound 1m (4 g, 18.49 mmol) was dissolved in tetrahydrofuran (60 mL), sodium hydride (2 g, 46.13 mmol, 60% purity) was added in batches at room temperature, stirred at room temperature for 1 hour, and then tert-butyldiphenylsilyl chloride (10.2 g, 37.11 mmol, 9.65 mL) was added dropwise, and stirred at room temperature for 3 hours. Ice saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system A to obtain the title compound 7f (8.0 g, yield: 95.2%).

[0559] MS m / z(ESI):455.2[M+1].

[0560] Step 6: tert-butyl (S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate 7 g

[0561] Methyl p-bromobenzoate (5.3 g, 24.65 mmol, Bid), compound 7f (8.5 g, 18.69 mmol), chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (1.5 g, 1.87 mmol), methanesulfonic acid(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (1.6 g, 1.88 mmol) and cesium carbonate (18.3 g, 56.17 mmol) were dissolved in 1,4-dioxane (100 mL), replaced with nitrogen, and the reaction solution was stirred at 90°C under nitrogen atmosphere for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain 7 g (10 g, yield: 90.8%) of the title compound.

[0562] MS m / z(ESI):589.2[M+1].

[0563] Step 7

[0564] (S)-methyl 4-(2-(((tert-butyldiphenylsilyl)oxy)methyl)piperazin-1-yl)benzoate 7h

[0565] Compound 7g (10 g, 16.98 mmol) was dissolved in dichloromethane (80 mL), p-toluenesulfonic acid hydrate (8.1 g, 42.58 mmol) was added at room temperature, and the reaction was stirred at room temperature for 4 hours. Ice water (80 mL) was added to the reaction solution, and it was extracted with dichloromethane (50 mL×3), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system A to obtain the title compound 7h (8.0 g, yield: 96.4%).

[0566] MS m / z(ESI):489.1[M+1].

[0567] Step 8

[0568] 4'-Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carbaldehyde 7i

[0569] Compound 1r (1.9 g, 7.42 mmol) was dissolved in dichloromethane (40 mL), and Dess-Martin periodinane (4.4 g, 10.37 mmol) was added at room temperature, and the reaction was stirred at room temperature for 1 hour. Water (40 mL) was added to the reaction solution, and it was extracted with dichloromethane (30 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound 7i (1.7 g, yield: 92.1%).

[0570] MS m / z(ESI):249.1[M+1].

[0571] Step 9: (S)-4-(2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid methyl ester 7j

[0572] Compound 7h (2.4 g, 4.91 mmol) and compound 7i (1.5 g, 6.03 mmol) were dissolved in 1,2-dichloroethane (60 mL), sodium triacetoxyborohydride (1.7 g, 7.88 mmol) was added, and the reaction was stirred at 60°C for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 7j (2.5 g, yield: 70.6%).

[0573] MS m / z(ESI):721.3[M+1].

[0574] Step 10 (S)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(hydroxymethyl)piperazine-1-

[0575] Benzoic acid 7k

[0576] Compound 7j (2.5 g, 3.47 mmol) and lithium hydroxide (1.2 g, 27.88 mmol) were dissolved in a mixed solvent of tetrahydrofuran (25 mL), methanol (25 mL) and water (25 mL), and the reaction solution was stirred at 75°C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and the obtained aqueous phase was adjusted to pH 2-3 with dilute hydrochloric acid (1 M), extracted with ethyl acetate (50 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography with elution system A to obtain the title compound 7k (640 mg, yield: 39.4%).

[0577] MS m / z(ESI):469.2[M+1].

[0578] Step 11

[0579] tert-Butyl 4-((R)-3-((4-(N-(4-((S)-4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)benzoyl)aminosulfonyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazine-1-carboxylate

[0580] Compound 7k (620 mg, 1.32 mmol) and compound 1u (600 mg, 0.92 mmol) were dissolved in dichloromethane (20 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (690 mg, 3.98 mmol), triethylamine (670 mg, 6.62 mmol) and 4-dimethylaminopyridine (163 mg, 1.32 mmol) were added respectively, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to obtain the title compound 7l (590 mg, yield: 40.4%).

[0581] MS m / z(ESI):1103.2[M+1].

[0582] Step 12

[0583] 1-(((S)-1-(4-(((4-(((R)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)-1-(phenylthio)butyl-2-yl)amino

[0584] 4-((4'-chloro-4,4-dimethyl)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)formamido)phenyl)-4-((4'-chloro-4,4-dimethyl)

[0585] -3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-2-yl)methyl)-5-(2-(trimethylsilyl)ethyl)

[0586] N,N-Dimethyl-L-glutamate 7m

[0587] Compound 7l (1.2 g, 1.09 mmol) and compound 1x (890 mg, 3.23 mmol) were dissolved in N,N-dimethylformamide (10.0 mL), 4-dimethylaminopyridine (400 mg, 3.26 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (622 mg, 3.26 mmol) were added, and the mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to obtain the title compound 7m (900 mg, yield: 60.1%).

[0588] MS m / z(ESI):1360.5[M+1].

[0589] Step 13

[0590] 1-(((S)-1-(4-(((4-(((R)-4-(4-(5-((5-((S)-1-((2S,4R)-2-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-4-hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)pentanoyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)formamido)phenyl)-4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-2-yl)methyl)

[0591] 5-(2-(Trimethylsilyl)ethyl)N,N-dimethyl-L-glutamic acid 7n-1

[0592] or

[0593] 1-(((S)-1-(4-(((4-(((R)-4-(4-(5-((5-((R)-1-((2S,4R)-2-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-4-hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)pentanoyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)formamido)phenyl)-4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-2-yl)methyl)

[0594] 5-(2-(Trimethylsilyl)ethyl)N,N-dimethyl-L-glutamic acid 7n-2

[0595] Compound 7m (300 mg, 0.220 mmol) was dissolved in dichloromethane (10 mL), and a solution of hydrogen chloride in 1,4-dioxane (0.16 mL, 4.0 M) was added dropwise. The mixture was stirred at room temperature for 16 hours. Triethylamine was added to the reaction solution under ice bath for neutralization, and the mixture was concentrated to obtain a crude product.

[0596] The above crude product and compound 7e-1 or 7e-2 (obtained from the compound with a longer retention time among compounds 7d-1 and 7d-2, 127 mg, 0.212 mmol) were dissolved in N,N-dimethylformamide (5.0 mL), and triethylamine (64 mg, 0.632 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (122 mg, 0.321 mmol) were added respectively, and the mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to obtain the title compound 7n-1 or 7n-2 (200 mg, yield: 50.8%).

[0597] MS m / z(ESI):1840.5[M+1].

[0598] Step 14 (S)-5-(((S)-1-(4-(((4-(((R)-4-(4-(5-((5-((S)-1-((2S,4R)-2-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-4-hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)pentanoyl 1-((phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)formamido)phenyl)-4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-2-yl)methoxy)-4-(dimethylamino)-5-oxopentanoic acid 7o-1

[0599] or (S)-5-(((S)-1-(4-(((4-(((R)-4-(4-(5-((5-((R)-1-((2S,4R)-2-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-4-hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)pentanoyl 2-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-2-yl)methoxy)-4-(dimethylamino)-5-oxopentanoic acid 7o-2

[0600] Compound 7n-1 or 7n-2 (200 mg, 0.108 mmol, prepared from the intermediate with a longer retention time in compound 7d-1 or 7d-2) was dissolved in hydrogen chloride / dioxane (2.0 mL, 4.0 M) and reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude title compound 7o-1 or 7o-2 (200 mg), which was used directly in the next step without purification.

[0601] MS m / z(ESI):1740.8[M+1].

[0602] Step 15

[0603] Compound 7-1 or 7-2

[0604] Under nitrogen atmosphere, compound 7o-1 or 7o-2 (190 mg, 0.106 mmol, prepared from the intermediate with longer retention time in compound 7d-1, 7d-2) and benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate (70 mg, 0.134 mmol, Shanghai Shaoyuan) were dissolved in N,N-dimethylformamide (3.0 mL), and a solution of dendritic polymer scaffold 1-PEG2K (130 mg, 1.83 μmol) and N-methylmorpholine (55 mg, 0.543 mmol) in anhydrous N,N-dimethylformamide (1.0 mL) was added dropwise, and the reaction was carried out at room temperature for 16 hours.

[0605] The reaction solution was diluted with acetonitrile (50 mL) and filtered. The filtrate was passed through an ultrafiltration (10KD, Pellicon) device and purified by ultrafiltration with acetonitrile. After concentration, lyophilization was performed to obtain the title compound 7-1 or 7-2 (150 mg, yield 69.8%).

[0606] 19 F NMR (500 MHz, CD3OD): δ -64.38 ppm (8.00 mg of p-trifluoromethylbenzoic acid was dissolved in 1500 μL CD3OD, 40 μL was taken, and the calibration was 1.00), -80.07 ppm (30.73 mg of compound 7-1 or 7-2 was dissolved in 410 μL CD3OD, 160 μL was taken, 1.54).

[0607] 19 F NMR indicated 13 Compound 7p-1 or 7p-2 / Compound 7-1 or 7-2. The actual molecular weight was approximately 89.6 kDa (22.8% wt. % Compound 7p-1 or 7p-2).

[0608] 1 H NMR(500MHz,MeCN-d3): δ8.94-8.66(m,24H),8.48-6.37(m,526H),6.09-5.84(m,20H),5.55- 5.19(m,43H),4.92-3.34(m,5405H),3.31(s,89H),2.60-1.84(m,710H),1.82-1.22(m,472H).

[0609] Step 16

[0610] 4-((S)-4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)-N-((4-(((R)-1-(phenylthio)-4-(piperazin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide 7ll

[0611] Compound 71 (590 mg, 0.53 mmol) was added to a 4M hydrogen chloride 1,4-dioxane solution (20 mL), and the reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude title compound 711 (560 mg), which was used directly in the next step without purification.

[0612] MS m / z(ESI):1003.3[M+1].

[0613] Step 17

[0614] (2S,4R)-N-((4H-chromeno[3,4-d]thiazol-7-yl)methyl)-1-((S)-2-(3-((5-(4-((R)-3-((4-(N-(4-((S)-4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)benzoyl)aminosulfonyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-5-oxopentyl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide 7p-1

[0615] or

[0616] (2S,4R)-N-((4H-chromeno[3,4-d]thiazol-7-yl)methyl)-1-((R)-2-(3-((5-(4-((R)-3-((4-(N-(4-((S)-4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)benzoyl)aminosulfonyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-5-oxopentyl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide 7p-2

[0617] Compound 7e-1 or 7e-2 (325 mg, 0.54 mmol) (prepared from the compound with longer retention time among compounds 7d-1 and 7d-2) and compound 7ll (570 mg, 0.57 mmol) were dissolved in dichloromethane (20 mL), and triethylamine (576 mg, 5.69 mmol) was added. After all the raw materials were dissolved, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (283 mg, 0.74 mmol) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was purified by preparative HPLC (instrument model: Waters-2555; chromatographic column: SharpSil-T, Prep 50×250 mm; 7 μm; C18 mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 55%-70%, flow rate: 80 mL / min) to give the title compound 7p-1 or 7p-2 (250 mg, yield: 27.8%).

[0618] MS m / z(ESI):1583.3[M+1].

[0619] 1 H NMR (500MHz, CDCl3): δ8.66(s,1H),8.35(d,1H),8.13-8.03(m,1H),7.65(d,2H),7.45-7.26(m,7 H),7.12(d,1H),7.07(d,1H),6.98(d,2H),6.91-6.83(m,2H),6.70(d,2H),6.63(d,1H),5.81(s, 1H),5.45-5.37(m,2H),4.68-4.52(m,2H),4.43-4.29(m,2H),4.25-4.09(m,2H),4.00-3.29(m,1 4H),3.17-2.76(m,7H),2.58-1.58(m,24H),1.47(t,2H),0.99(d,6H),0.94(d,3H),0.85(d,3H).

[0620] Example 8-1 or 8-2

[0621]

[0622]

[0623]

[0624]

[0625] first step

[0626] tert-Butyl 4-((R)-3-((4-(N-(4-((S)-4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-2-(5,11,11-trimethyl-3,7-dioxo-2,8-dioxa-5-aza-11-silanol)piperazin-1-yl)benzoyl)aminosulfonyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazine-1-carboxylate 8a

[0627] Compound 71 (300 mg, 0.271 mmol) and compound 4d (200 mg, 0.808 mmol) were dissolved in N,N-dimethylformamide (4.0 mL), and 4-dimethylaminopyridine (100 mg, 0.820 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (160 mg, 0.838 mmol) were added respectively, and the mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to obtain the title compound 8a (360 mg, yield: 99.3%).

[0628] MS m / z(ESI):1332.5[M+1].

[0629] The second step is ((S)-1-(4-(((4-(((R)-4-(4-(5-((5-((S)-1-((2S,4R)-2-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-4-hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)pentanoyl)piperazin-1-yl)-1- 1-((phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)formamido)phenyl)-4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-2-yl)methyl N-methyl-N-(2-oxo-2-(2-(trimethylsilyl)ethoxy)ethyl)glycinate 8b-1

[0630] or ((S)-1-(4-(((4-(((R)-4-(4-(5-((5-((R)-1-((2S,4R)-2-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-4-hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)pentanoyl)piperazin-1-yl)-1-( phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)formamido)phenyl)-4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-2-yl)methyl N-methyl-N-(2-oxo-2-(2-(trimethylsilyl)ethoxy)ethyl)glycinate 8b-2

[0631] Compound 8a (340 mg, 0.255 mmol) was dissolved in dichloromethane (4.0 mL), and a solution of hydrogen chloride in 1,4-dioxane (0.4 mL, 4.0 M) was added dropwise. The mixture was stirred at room temperature for 2 hours. Triethylamine was added to the reaction solution under ice bath to neutralize it, and the mixture was concentrated to obtain a crude product.

[0632] The crude product and compound 7e-1 or 7e-2 (obtained from the compound with a longer retention time among compounds 7d-1 and 7d-2, 155 mg, 0.259 mmol) were dissolved in N,N-dimethylformamide (5.0 mL), and triethylamine (120 mg, 1.19 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (130 mg, 0.342 mmol) were added, and the mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system A to obtain the title compound 8b-1 or 8b-2 (300 mg, yield: 65.6%).

[0633] MS m / z(ESI):1812.7[M+1].

[0634] Step 3

[0635] N-(2-(((S)-1-(4-(((4-(((R)-4-(4-(5-((5-((S)-1-((2S,4R)-2-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-4-hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)pentanoyl) piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)formamido)phenyl)-4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-2-yl)methoxy)-2-oxyylideneethyl)-N-methylglycine 8c-1

[0636] or

[0637] N-(2-(((S)-1-(4-(((4-(((R)-4-(4-(5-((5-((R)-1-((2S,4R)-2-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-4-hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)oxy)pentanoyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)formamido)phenyl)-4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-2-yl)methoxy)-2-oxoylideneethyl)-N-methylglycine

[0638] 8c-2

[0639] Compound 8b-1 or 8b-2 (285 mg, 0.157 mmol, prepared from the intermediate with a longer retention time in compound 7d-1, 7d-2) was dissolved in dichloromethane (3.0 mL), added to a solution of hydrogen chloride in 1,4-dioxane (1.0 mL, 4.0 M), and reacted at room temperature for 48 hours. The reaction solution was concentrated under reduced pressure to obtain a crude title compound 8c-1 or 8c-2 (270 mg), which was used directly in the next step without purification.

[0640] MS m / z(ESI):1712.5[M+1].

[0641] Step 4

[0642] Compound 8-1 or 8-2

[0643] Under nitrogen atmosphere, compound 8c-1 or 8c-2 (260 mg, 0.152 mmol, prepared from the intermediate with longer retention time in compound 7d-1, 7d-2) and benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate (1100 mg, 0.211 mmol, Shanghai Shaoyuan) were dissolved in N,N-dimethylformamide (3.0 mL), and a solution of dendritic polymer scaffold 1-PEG2K (150 mg, 2.12 μmol) and N-methylmorpholine (80 mg, 0.791 mmol) in anhydrous N,N-dimethylformamide (1.0 mL) was added dropwise, and the reaction was carried out at room temperature for 16 hours.

[0644] The reaction solution was diluted with acetonitrile (50 mL) and filtered. The filtrate was passed through an ultrafiltration (10KD, Pellicon) device and purified by ultrafiltration with acetonitrile. After concentration, it was lyophilized to obtain the title compound 8-1 or 8-2 (160 mg, yield 64.9%).

[0645] 19 F NMR (500 MHz, CD3OD): δ -64.37 ppm (5.52 mg of p-trifluoromethylbenzoic acid, calibrated at 1.00), -80.10 ppm (38.94 mg of compound 8-1 or 8-2, 0.07).

[0646] 19 F NMR indicated 4 compounds 7p-1 or 7p-2 / compound 8-1 or 8-2. The actual molecular weight was approximately 74.0 kDa (8.3% wt.% compound 7p-1 or 7p-2).

[0647] 1 H NMR (500MHz, MeCN-d3): δ8.91-8.76(m,48H),8.34-8.25(m,30H),7.86-7.68(m,63H),7.55-6.84(m,270H),6.08-5.94(m,37 H),5.54-5.30(m,71H),4.86-3.35(m,5186H),3.31(s,89H),2.59-2.17(m,235H),1.73-1.35(m,222H),1.03-0.81(m,137H).

[0648] Example 9

[0649]

[0650]

[0651] first step

[0652] 1-Benzyl 5-(tert-butyl)(S)-2-morpholinoglutarate 9c

[0653] 1-Benzyl 5-(tert-butyl) L-glutamic acid hydrochloride 9b (600 mg, 1.82 mmol, Shanghai Bid Pharmaceutical) and 2,2'-oxydiacetaldehyde 9a (1.0 g, crude product, prepared by the method disclosed in 0081 on page 8 of the specification of patent application US2019135778A1) were dissolved in a mixed solvent of acetonitrile (20 mL) and water (20 mL), sodium cyanoborohydride (240 mg, 3.81 mmol) was added, and the mixture was reacted at room temperature for 16 hours. The acetonitrile was removed by concentration under reduced pressure, and the aqueous phase was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system C to obtain the title compound 9c (480 mg, yield: 72.6%). MS m / z(ESI):364.2[M+1].

[0654] Step 2

[0655] (S)-5-(tert-Butoxy)-2-morpholinyl-5-oxopentanoic acid 9d

[0656] Under nitrogen atmosphere, compound 9c (480 mg, 1.32 mmol) was dissolved in tetrahydrofuran (10 mL), palladium / carbon (100 mg, 10 wt.%) was added, hydrogen was replaced three times, and the reaction was carried out at room temperature for 16 hours. Filter, collect the filtrate and concentrate under reduced pressure to obtain the crude title compound 9d (190 mg). The product was used directly in the next step without purification. MS m / z (ESI): 274.1 [M+1].

[0657] Step 3

[0658] 1-((3R,5S)-5-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamide

[0659] 1-((S)-2-(7-(4-((R)-3-((4-(N-((S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carbonyl)aminosulfonyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptamido)-3,3-dimethylbutanoyl)pyrrolidin-3-yl)5-(tert-butyl)(S)-2-morpholinyl glutarate 9e

[0660] Compound 1w (150 mg, 95.5 μmol) and compound 9d (150 mg, 0.549 mmol) were dissolved in N,N-dimethylformamide (3.0 mL), 4-dimethylaminopyridine (60 mg, 0.487 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (100 mg, 0.524 mmol) were added, and the mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 9e (140 mg, yield: 80.2%).

[0661] MS m / z(ESI):1824.7[M+1].

[0662] Step 4

[0663] (S)-5-(((3R,5S)-5-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamide

[0664] 9f

[0665] Compound 9e (140 mg, 76.7 μmol) was dissolved in dichloromethane (4.0 mL), trifluoroacetic acid (1.0 mL) was added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent A to obtain the title compound 9f (130 mg, yield: 95.8%).

[0666] MS m / z(ESI):1768.7[M+1].

[0667] Step 5

[0668] Compound 9

[0669] Under nitrogen atmosphere, compound 9f (130 mg, 73.5 μmol) and benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate (50 mg, 96.1 μmol, Shanghai Shaoyuan) were dissolved in N,N-dimethylformamide (3.0 mL), and a solution of dendritic polymer scaffold 1-PEG2K (100 mg, 1.41 μmol) and N-methylmorpholine (40 mg, 0.395 mmol) in anhydrous N,N-dimethylformamide (1.0 mL) was added dropwise, and the reaction was carried out at room temperature for 16 hours.

[0670] The reaction solution was diluted with acetonitrile (50 mL) and filtered. The filtrate was passed through an ultrafiltration device (10KD, Pellicon) and purified by ultrafiltration with acetonitrile. After concentration, it was lyophilized to obtain the title compound 9 (160 mg, yield 96.0%).

[0671] 19 F NMR (500 MHz, CD3OD): δ -64.27 ppm (4.61 mg of p-trifluoromethylbenzoic acid, calibrated at 1.00), -80.16 ppm (43.46 mg of compound 9, 0.34).

[0672] 19 F NMR indicated 19 Compound 1w / Compound 9. The actual molecular weight was approximately 100.5 kDa (29.8% wt. % Compound 1w).

[0673] 1 H NMR (500MHz, MeCN-d3): δ9.01-8.67(m,99H), 8.40-7.93(m,153H),7.68-6.62(m,586H),4.24- 3.36(m,5127H),3.32(s,89H),2.84-2.65(m,110H),2.53-2.12(m,394H),1.69-1.17(m,430H).

[0674] Example 10

[0675]

[0676]

[0677] first step

[0678] 3-Oxo-1-phenyl-2,5,8,11-tetraoxatridecan-13-oic acid 10b

[0679] 2,2'-((oxybis(ethane-2,1-diyl))bis(oxy))diacetic acid 10a (3.89 g, 17.51 ​​mmol, Leyan) was dissolved in N,N-dimethylformamide (100 mL). Triethylamine (3.25 g, 32.12 mmol) was added under ice bath, and benzyl bromide (2.50 g, 14.62 mmol) was slowly added dropwise for about 2 hours. The reaction mixture was reacted at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was dissolved in dichloromethane (100 mL) and washed with 1M dilute hydrochloric acid and saturated sodium chloride solution, respectively. The obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound 10b (1.8 g, yield: 39.4%).

[0680] MS m / z(ESI):313.3[M+1].

[0681] Step 2

[0682] Benzyl 2-((2,2-dimethyl-6-oxo-5,8,11-trioxa-2-silantridec-13-yl)oxy)acetate 10c

[0683] Compound 10b (900 mg, 2.88 mmol) and trimethylsilyl alcohol (510 mg, 4.31 mmol, Shanghai Bid Pharmaceutical) were dissolved in dichloromethane (20 mL), and 4-dimethylaminopyridine (18 mg, 0.15 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (828 mg, 4.31 mmol) were added respectively, and the mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound 10c (1.0 g, yield: 84.1%).

[0684] MS m / z(ESI):430.2[M+18].

[0685] Step 3

[0686] 2,2-Dimethyl-6-oxo-5,8,11,14-tetraoxa-2-silahexadecane-16-oic acid 10d

[0687] Compound 10c (1.0 g, 2.42 mmol) was dissolved in tetrahydrofuran (20 mL), palladium hydroxide (200 mg, 1.42 mmol) was added, hydrogen was replaced three times, and the reaction was stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude title compound 10d (780 mg). The product was used directly in the next step without purification.

[0688] MS m / z(ESI):321.1[M-1].

[0689] Step 4

[0690] (3R,5S)-5-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamide

[0691] 1-((S)-2-(7-(4-((R)-3-((4-(N-((S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carbonyl)aminosulfonyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptylamido)-3,3-dimethylbutanoyl)pyrrolidin-3-yl 2-((2,2-dimethyl-6-oxo-5,8,11-trioxa-2-silantridecane

[0692] -13-yl)oxy)acetate 10e

[0693] Compound 1w (300 mg, 0.19 mmol) and compound 10d (307 mg, 0.525 mmol) were dissolved in N,N-dimethylformamide (5.0 mL), 4-dimethylaminopyridine (129 mg, 1.05 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (200 mg, 1.05 mmol) were added, and the mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 10e (250 mg, yield: 69.8%).

[0694] MS m / z(ESI):1874.0[M+1].

[0695] Step 5

[0696] 2-(2-(2-(((3R,5S)-5-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-1-((S)-2-(7-(4-((R)-3-((4-(N-((S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2 ,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carbonyl)aminosulfonyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptylamido)-3,3-dimethylbutanoyl)pyrrolidin-3-yl)oxy)-2-oxoethoxy)ethoxy)ethoxy)acetic acid 10f

[0697] Compound 10e (180 mg, 0.096 mmol) was dissolved in tetrahydrofuran (2.0 mL), and tetrabutylammonium fluoride (0.2 mL, 0.2 mmol, 1.0 M) was added and reacted at room temperature for 2 hours. Under ice bath, the reaction solution was adjusted to neutrality with 1 M dilute hydrochloric acid, concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (instrument model: Waters-2545 chromatographic column: YMC Triart-Exrs, Prep 30×150 mm; 5 μm; C18, mobile phase: water (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-75%, flow rate: 30 mL / min) to obtain the title compound 10f (150 mg, yield: 88.1%).

[0698] MS m / z(ESI):1773.8[M+1].

[0699] Step 6

[0700] Compound 10

[0701] Under nitrogen atmosphere, compound 10f (150 mg, 0.085 mmol) and benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate (54 mg, 0.103 mmol, Shanghai Shaoyuan) were dissolved in N,N-dimethylformamide (3.0 mL), and a solution of the dendritic polymer scaffold 1-PEG2K (101 mg, 1.42 μmol) and N-methylmorpholine (44 mg, 0.435 mmol) in anhydrous N,N-dimethylformamide (1.0 mL) was added dropwise, and the reaction was carried out at room temperature for 16 hours.

[0702] The reaction solution was diluted with acetonitrile (50 mL) and filtered. The filtrate was passed through an ultrafiltration device (10KD, Pellicon) and purified by ultrafiltration with acetonitrile. After concentration, it was lyophilized to obtain the title compound 10 (160 mg, yield 95.0%).

[0703] 19 F NMR (500 MHz, CD3OD): δ -64.38 ppm (4.19 mg of p-trifluoromethylbenzoic acid, calibrated at 1.00), -80.18 ppm (35.92 mg of compound 10, 0.34).

[0704] 19 F NMR indicated 22 Compound 1w / Compound 10. The actual molecular weight was approximately 105.8 kDa (32.8% wt. % Compound 1w).

[0705] 1H NMR (500MHz, MeCN-d3): δ8.91-8.74(m,58H),8.34-8.21(m,53H),8.12-7.91(m,79H),7.63-6.72(m,599H),5.56-5.19(m,127 H),4.86-3.36(m,5399H),3.32(s,89H),3.19-2.99(m,150H),2.95-2.51(m,402H),2.46-2.07(m,333H),1.66-1.12(m,470H).

[0706] Embodiment 11

[0707]

[0708]

[0709] first step

[0710] 5-Benzyl 1-(tert-butyl)formyl-L-glutamate 11a

[0711] Compound 3a (2.0 g, 6.06 mmol, Shanghai Bid Pharmaceutical) and formic acid (837 mg, 18.19 mmol) were dissolved in dichloromethane (20 mL), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.18 g, 13.64 mmol) and N,N-diisopropylethylamine (6.26 g, 48.51 mmol) were added, and the reaction was carried out at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to obtain the title compound 11a (1.8 g, yield: 92.4%).

[0712] MS m / z(ESI):266.3[M-55].

[0713] Step 2

[0714] (S)-5-(tert-Butoxy)-4-(formamido)-5-oxopentanoic acid 11b

[0715] Under nitrogen atmosphere, compound 11a (1.2 g, 3.73 mmol) was dissolved in tetrahydrofuran (20 mL), palladium / carbon (397 mg, 10 wt.%) was added, hydrogen was replaced three times, and the reaction was carried out at room temperature for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude title compound 11b (800 mg). The product was used directly in the next step without purification.

[0716] MS m / z(ESI):230.2[M-1].

[0717] Step 3

[0718] 5-((3R,5S)-5-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamide

[0719] 1-((S)-2-(7-(4-((R)-3-((4-(N-((S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carbonyl)aminosulfonyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptylamido)-3,3-dimethylbutanoyl)pyrrolidin-3-yl)1-(tert-butyl)formyl-L-glutamate 11c

[0720] Compound 1w (220 mg, 0.14 mmol) and compound 11b (162 mg, 0.70 mmol) were dissolved in N,N-dimethylformamide (5.0 mL), 4-dimethylaminopyridine (88 mg, 0.71 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (136 mg, 0.71 mmol) were added, and the mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 11c (120 mg, yield: 48.0%).

[0721] MS m / z(ESI):1782.8[M+1].

[0722] Step 4

[0723] (S)-5-(((3R,5S)-5-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamide

[0724] 1-((S)-2-(7-(4-((R)-3-((4-(N-((S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carbonyl)aminosulfonyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptamido)-3,3-dimethylbutanoyl)pyrrolidin-3-yl)oxy)-2-formamido-5-oxopentanoic acid 11d

[0725] Compound 11c (200 mg, 0.112 mmol) was dissolved in dichloromethane (8.0 mL), trifluoroacetic acid (2.0 mL) was added, and the mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent A to obtain the title compound 11d (155 mg, yield: 80%).

[0726] MS m / z(ESI):1726.7[M+1].

[0727] Step 5

[0728] Compound 11

[0729] Under nitrogen atmosphere, compound 11d (146 mg, 84.5 μmol) and benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate (52.8 mg, 101.4 μmol, Shanghai Shaoyuan) were dissolved in N,N-dimethylformamide (3.0 mL), and a solution of dendritic polymer scaffold 1-PEG2K (107.8 mg, 1.52 μmol) and N-methylmorpholine (42.7 mg, 0.423 mmol) in anhydrous N,N-dimethylformamide (1.0 mL) was added dropwise, and the reaction was carried out at room temperature for 16 hours.

[0730] The reaction solution was diluted with acetonitrile (50 mL) and filtered. The filtrate was passed through an ultrafiltration device (10KD, Pellicon) and purified by ultrafiltration with acetonitrile. After concentration, it was lyophilized to obtain the title compound 11 (160 mg, yield 86.9%).

[0731] 19 F NMR (500 MHz, CD3OD): δ -64.29 ppm (4.45 mg of p-trifluoromethylbenzoic acid, calibrated at 1.00), -80.18 ppm (40.86 mg of compound 11, 0.265).

[0732] 19 F NMR indicated 14 Compound 1w / Compound 11. The actual molecular weight was approximately 91.1 kDa (23.8% wt. % Compound 1w).

[0733] 1 H NMR (500MHz, MeCN-d3): δ8.97-8.68(m,30H),8.45-6.43(m,442H),5.60-5.11(m,78H),3.85- 3.40(m,5618H),3.32(s,89H),3.23-2.99(m,93H),2.67-2.16(m,546H),1.68-1.15(m,361H).

[0734] Example 12

[0735]

[0736] first step

[0737] 1-((3R,5S)-5-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamido)-1-((S)-2-(7-(4-((R)-3-((4-(N-((S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5 1-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptylamido)-3,3-dimethylbutanoyl)pyrrolidin-3-yl)5-(2-(trimethylsilyl)ethyl)N,N-diethyl-L-glutamate 12b

[0738] Compound 1w (200 mg, 0.127 mmol) and (S)-2-(diethylamino)-5-oxo-5-(2-(trimethylsilyl)ethoxy)pentanoic acid 12a (115 mg, 0.379 mmol, prepared by the method disclosed in Example 11 on page 42 of the specification of patent application WO2022042583 A1, intermediate 1-Z01-L-TMS) were dissolved in N,N-dimethylformamide (5.0 mL), 4-dimethylaminopyridine (16 mg, 0.127 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (73 mg, 0.38 mmol) were added, and the reaction was carried out at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to obtain the title compound 12b (200 mg, yield: 84.6%).

[0739] MS m / z(ESI):1854.7[M+1].

[0740] Step 2

[0741] (S)-5-(((3R,5S)-5-(((4H-chromeno[3,4-d]thiazol-7-yl)methyl)formamide

[0742] 1-((S)-2-(7-(4-((R)-3-((4-(N-((S)-3-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-8-carbonyl)aminosulfonyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptamido)-3,3-dimethylbutanoyl)pyrrolidin-3-yl)oxy)-4-(diethylamino)-5-oxopentanoic acid 12c

[0743] Compound 12b (200 mg, 0.107 mmol) was dissolved in tetrahydrofuran (5.0 mL), tetrabutylammonium fluoride (0.866 mL, 0.866 mmol, 1.0 M) was added, and the mixture was reacted at room temperature for 16 hours. Water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 12c (180 mg, yield: 95.1%).

[0744] MS m / z(ESI):1754.8[M+1]

[0745] Step 3

[0746] Compound 12

[0747] Under nitrogen atmosphere, compound 12c (200 mg, 0.113 mmol) and benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate (71 mg, 0.136 mmol, Shanghai Shaoyuan) were dissolved in N,N-dimethylformamide (5.0 mL), and a solution of dendritic polymer scaffold 1-PEG2K (120 mg, 1.693 μmol) and N-methylmorpholine (58 mg, 0.573 mmol) in anhydrous N,N-dimethylformamide (1.0 mL) was added dropwise, and the reaction was carried out at room temperature for 16 hours.

[0748] The reaction solution was diluted with acetonitrile (50 mL) and filtered. The filtrate was passed through an ultrafiltration (10KD, Pellicon) device and purified by ultrafiltration with acetonitrile. After concentration, it was lyophilized to obtain the title compound 12 (160 mg, yield: 78.0%).

[0749] 19 F NMR (500 MHz, CD3OD): δ -64.34 ppm (3.43 mg of p-trifluoromethylbenzoic acid, calibrated at 1.000), -80.26 ppm (35.78 mg of compound 12, 0.215).

[0750] 19 F NMR indicated 9 Compound 1w / Compound 12. The actual molecular weight was approximately 82.8 kDa (17.0% wt.% Compound 1w).

[0751] 1 H NMR (500MHz, MeCN-d3): δ8.99-8.82(m,89H),8.32-8.09(m,135H),7.65-7.07(m,428H),5.55- 5.25(m,173H),4.68-3.35(m,5290H),3.32(s,89H),2.64-2.16(m,769H),1.63-1.13(m,476H).

[0752] Biological evaluation

[0753] Test Example 1: Inhibitory effect of the compounds of the present invention on the binding between BCL-xL and Bim.

[0754] The following method is used to determine the inhibitory effect of the compounds of the present invention on the binding between BCL-xL and Bim. The experimental method is briefly described as follows:

[0755] 1. Experimental Materials and Instruments

[0756] 1.Recombinant Human Bcl-xL (minus C-Terminus), CF (R&D, 894-BX-050)

[0757] 2.BIM, biotinylated (APExBIO, A4463)

[0758] 3.MAb Anti 6His-Eu cryptate Gold (cisbio, 61HI2KLA)

[0759] 4.High grade XL665-conjugated streptavidin (cisbio, 611SAXLA)

[0760] 5.Binding Domain Detection buffer (cisbio, 62DB1FDG)

[0761] 6.Binding Domain diluent buffer (cisbio, 62DLBDDF)

[0762] 7.384-well plate (Corning, 4513)

[0763] 8. Microplate reader (BMG labtech, PHERAstar FS)

[0764] 9. Micro-oscillator (IKA, Germany, MTS2 / 4S25)

[0765] 2. Experimental steps

[0766] Dilute the sample to be tested to 0.2mM with DMSO, then dilute it 3-fold to 10 concentrations, and set up a blank plate with DMSO. Take 1μL of the compound solution prepared in gradient concentration and add it to 99μL of Binding Domaindiluent buffer to prepare the experimental concentration containing the compound. Dilute BCL-xL protein to 0.5nM with Binding Domaindiluent buffer and add 4μL / well to a 384-well plate. Then take 2μL of the compound at the experimental concentration and add it to the 384-well plate, shake and mix well, centrifuge, apply a sealing film, and pre-incubate in a 25℃ incubator for 60 minutes.

[0767] Dilute BIM to 5 nM with Binding Domain diluent buffer, add 4 μL / well to the above 384-well plate, shake and mix, centrifuge, apply sealing film, and incubate in a 25°C incubator for 120 minutes.

[0768] Dilute XL665-conjugated streptavidin to 2nM and EU-anti-His to 1test concentration (1nM) with Binding Domain Detection buffer, then add 5μL / well of each to a 384-well plate. Mix by shaking, centrifuge, apply sealing film, and incubate in a 25℃ incubator for 120 minutes.

[0769] The signal values ​​were read using the HTRF program of the PHERAstar microplate reader, and the data were processed using Graphpad Prism 9 software.

[0770] 3. Experimental Data

[0771] Table 1 Inhibitory effect of the disclosed compounds on the binding between BCL-xl and Bim

[0772]

[0773]

[0774] Conclusion: The disclosed compounds have a significant inhibitory effect on the binding between BCL-xl and Bim.

[0775] Test Example 2: Inhibitory effect of the compounds of the present invention on the binding between BCL-2 and Bim.

[0776] The following method is used to determine the inhibitory effect of the compounds of the present invention on the binding between BCL-2 and Bim. The experimental method is briefly described as follows:

[0777] 1. Experimental Materials and Instruments

[0778] 1. Bcl-2 Protein, Human, Recombinant (His Tag) (Beijing Sino Biological Technology Co., Ltd., 10195-H08E)

[0779] 2.BIM, biotinylated (APExBIO, A4463)

[0780] 3.MAb Anti 6His-Eu cryptate Gold (cisbio, 61HI2KLA)

[0781] 4.High grade XL665-conjugated streptavidin (cisbio, 611SAXLA)

[0782] 5.Binding Domain Detection buffer (cisbio, 62DB1FDG)

[0783] 6.Binding Domain diluent buffer (cisbio, 62DLBDDF)

[0784] 7.384-well plate (Corning, 4513)

[0785] 8. Microplate reader (BMG labtech, PHERAstar FS)

[0786] 9. Micro-oscillator (IKA, Germany, MTS2 / 4S25)

[0787] 2. Experimental steps

[0788] Dilute the sample to be tested to 0.2mM with DMSO, then dilute it 3-fold to 10 concentrations, and set up blank wells with DMSO. Take 1μL of the compound solution prepared in gradient concentrations and add it to 99μL of Binding Domain diluent buffer to prepare the experimental concentration containing the compound. Dilute BCL-2protein to 1nM with Binding Domain diluent buffer and add 4μL / well to a 384-well plate. Take 2μL of the compound at the experimental concentration and add it to the 384-well plate, shake and mix well, centrifuge, apply a sealing film, and incubate in a 25°C incubator for 60 minutes.

[0789] BIM was diluted to 2.5 nM with Binding Domain diluent buffer, and 4 μL / well was added to the above 384-well plate. After oscillation and mixing, centrifugation was performed, and the plate was sealed with a film and incubated in a 25°C incubator for 120 minutes.

[0790] Dilute XL665-conjugated streptavidin to 1nM and EU-anti-His to 1test concentration (1nM) with Binding Domain Detection buffer, then add 5μL / well to a 384-well plate. Mix by oscillation and centrifuge, apply sealing film, and incubate in a 25°C incubator for 120 minutes.

[0791] The signal values ​​were read using the HTRF program of the PHERAstar microplate reader, and the data were processed using Graphpad Prism 9 software.

[0792] 3. Experimental Data

[0793] Table 2 Inhibitory effect of the disclosed compounds on the binding between BCL-2 and Bim

[0794]

[0795]

[0796] Conclusion: The disclosed compounds have a significant inhibitory effect on the binding between BCL-2 and Bim.

[0797] Test Example 3: Proliferation inhibitory effect of the compounds of the present invention on MOLT-4 cells.

[0798] The following method is used to determine the inhibitory effect of the compounds of the present invention on MOLT-4 cell proliferation. The experimental method is briefly described as follows:

[0799] 1. Experimental Materials and Instruments

[0800] 1.MOLT-4 cells (Nanjing Kebai Biotechnology Co., Ltd., CBP60525)

[0801] 2.96-well cell culture plate (Corning, 3903)

[0802] 3. U-bottom 96-well plate (Corning, 3795)

[0803] 4.Fetal Bovine Serum (Corning, 35-081-CV)

[0804] 5. RPMI 1640 culture medium (Gibco, 11875093)

[0805] 6.CellTiter- Luminescent Cell Assay (Promega, G7571)

[0806] 7.White Adhesive Bottom Seal for 96-well(PerkinElmer,6005199)

[0807] 8. Carbon dioxide incubator (Thermo, i160)

[0808] 9. Cell counter (Shanghai Ruiyu Biotechnology Co., Ltd., IC1000)

[0809] 10. Microplate reader (BMG labtech, PHERAstar FS)

[0810] 2. Experimental steps

[0811] MOLT-4 cells were cultured in complete medium (RPMI1640 medium containing 10% FBS) and passaged 2-3 times a week at a passage ratio of 1:5. During passage, the cells were transferred to a centrifuge tube, centrifuged at 1200 rpm for 3 minutes, the supernatant medium was discarded, and the cells were resuspended in complete medium.

[0812] During the experiment, transfer the cells to a centrifuge tube and centrifuge at 1200 rpm for 3 minutes. Discard the supernatant and resuspend the cells in complete medium. Count the cells using a cell counter and adjust the density to 2.2 × 10 5 cells / mL, 90 μL / well were added to a 96-well plate and cultured overnight in a 37°C constant temperature 5% CO2 incubator.

[0813] The sample to be tested was diluted to 0.2 mM with DMSO, and then diluted 3-fold to 10 concentrations, and blank wells were set. 5 μL of the compound solution prepared in gradient concentrations was added to 95 μL of complete culture medium and diluted 20 times. 10 μL of the above culture medium containing the compound was added to a 96-well plate and cultured in a 37°C constant temperature 5% CO2 incubator for 72 hours.

[0814] 50 μL CellTiter-Glo solution was added to each well, incubated at room temperature for 10 minutes, and the plate was read using the chemiluminescence program of the PHERAstar microplate reader. The data were processed using Graphpad Prism 9 software.

[0815] 3. Experimental Data

[0816] Table 3 Inhibitory effect of the disclosed compounds on MOLT-4 cell proliferation

[0817]

[0818]

[0819] Conclusion: The disclosed compounds have a significant inhibitory effect on the proliferation of MOLT-4 cells.

[0820] Test Example 4: Degradation effect of the compounds of the present invention on BCL-xL protein in MOLT-4 cells.

[0821] The following method was used to determine the degradation effect of the compound of the present invention on BCL-xL protein in MOLT-4 cells. The experimental method is briefly described as follows:

[0822] 1. Experimental Materials and Instruments

[0823] 1.MOLT-4 cells (Nanjing Kebai Biotechnology Co., Ltd., CBP60525)

[0824] 2. RPMI1640 culture medium (Gibco, 11875093)

[0825] 3. Fetal Bovine Serum (Corning, 35-081-CV)

[0826] 4. U-bottom 96-well plate (Corning, 3795)

[0827] 5. V-bottom 96-well plate (Axygen, AXYP96450VCS)

[0828] 6.48-well cell culture plate (Corning, 3548)

[0829] 7.BCA protein assay kit(ThermoFisher,23225)

[0830] 8.Human / Mouse Total Bcl-xL DuoSet IC ELISA(R&D,DYC894-5)

[0831] 9.DuoSet ELISA Ancillary Reagent Kit 2(R&D,DY008)

[0832] 10.EDTA (Invitrogen, AM9260G)

[0833] 11.TritonTM X-100 (Sigma, T8787-100ML)

[0834] 12. PBS (meilunbio, PWL050)

[0835] 13. Carbon dioxide incubator (Thermo, i160)

[0836] 14. Constant temperature incubator (ThermoFisher, NAPCO 6500TC)

[0837] 15. Centrifuge (ThermoFisher, ST16)

[0838] 16. Microplate reader (BMG labtech, PHERAstar FS)

[0839] 17. Cell counter (Shanghai Ruiyu Biotechnology Co., Ltd., IC1000)

[0840] 2. Experimental steps

[0841] MOLT-4 cells were cultured in complete medium (RPMI1640 medium containing 10% FBS) and passaged 2-3 times a week at a passage ratio of 1:5. During passage, the cells were transferred to a centrifuge tube, centrifuged at 1200 rpm for 3 minutes, the supernatant medium was discarded, and the cells were resuspended in complete medium.

[0842] During the experiment, the cells were transferred to a centrifuge tube, centrifuged at 1200 rpm for 3 minutes, the supernatant was discarded, and the cells were resuspended in complete medium. The density was adjusted to 1.78×106 cells / mL after counting with a cell counter, and 225 μL / well was added to a 48-well cell culture plate (400,000 cells per well), and placed in a 37°C constant temperature 5% CO2 incubator.

[0843] The sample to be tested was diluted to 0.1 mM with DMSO, and then diluted 3-fold to 8 concentrations in a U-bottom 96-well plate, and a blank well was set with DMSO. 5 μL of the compound solution prepared in gradient concentrations was added to 95 μL of complete culture medium and diluted 20 times. 25 μL of the above compound-containing culture medium was added to a 48-well cell culture plate and cultured in a 37°C constant temperature 5% CO2 incubator for 16 hours.

[0844] Transfer the cells to a 96-well V-bottom plate, centrifuge at 2000 rpm for 3 minutes, discard the supernatant, add pre-cooled PBS to wash once, centrifuge at 2000 rpm for 3 minutes, discard the supernatant, then add 130uL / well of cell lysis buffer (1mM EDTA, 0.5% Triton X-100in PBS, pH 7.2-7.4), and place on ice for 20 minutes.

[0845] After lysis, centrifuge at 2000g for 5 minutes at 4℃, and then determine the protein concentration by BCA method according to the instructions of "BCA protein assay kit". Then take 20μg protein from each well and add it to the ELISA plate for ELISA detection. The ELISA experiment was performed according to the instructions of the "Human / Mouse Total Bcl-xL DuoSet IC ELISA" kit. Finally, the signal value was read using the OD450 / OD540 program of the PHERAstar microplate reader, and the data was processed using Graphpad Prism 9 software.

[0846] 3. Experimental Data

[0847] Table 4 Degradation effect of the disclosed compounds on BCL-xL protein in MOLT-4 cells

[0848]

[0849] Conclusion: The disclosed compounds have a significant degradation effect on BCL-xL protein in MOLT-4 cells.

[0850] Test Example 5: Pharmacokinetic Evaluation

[0851] 1. Mouse Experiment

[0852] 1. Summary

[0853] Using mice as test animals, the concentrations of compound 1w, compound 7p-1 or compound 7p-2 (prepared from the compound with a longer retention time among compounds 7d-1 and 7d-2) in the plasma of mice at different times after intravenous (iv) administration of the test compound were determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compounds in mice was studied and their pharmacokinetic characteristics were evaluated.

[0854] 2. Experimental plan

[0855] 2.1 Trial Drugs

[0856] Compound 1w, compound 7p-1 or compound 7p-2 (prepared from the compound with a longer retention time among compounds 7d-1 and 7d-2, and the "compound 7p-1 or compound 7p-2" appearing later in this test example refers to the compound prepared from the compound with a longer retention time among compounds 7d-1 and 7d-2), the compound of Example 1, the compound of Example 5, the compound of Example 7 and the compound of Example 12.

[0857] 2.2 Experimental animals

[0858] 54 female mice were equally divided into 6 groups, provided by Weitonglihua Experimental Animal Technology Co., Ltd. and administered intravenously.

[0859] 2.3 Drug preparation

[0860] Preparation of compound 1w, compound 7p-1 or compound 7p-2: Weigh a certain amount of each compound, add 5% DMSO + 5% Tween 80 + 90% saline to prepare a 0.1 mg / mL solution.

[0861] Preparation of Example 1, Example 5, Example 7 and Example 12: Weigh a certain amount of each of the example compounds, add 5% DMSO + 95% saline to prepare 2.0 mg / mL, 1.0 mg / mL or 0.5 mg / mL solutions.

[0862] 2.4 Grouping and Dosage Regimen

[0863] Table 5 Grouping and dosing regimen

[0864]

[0865] 3. Operation

[0866] G1-G2 group: Before administration and at 0.083, 0.25, 0.5, 1, 2, 4, 8, 11 and 24 hours after administration, 0.1 mL of blood was collected from the eye socket, placed in an EDTA-K2 anticoagulant tube, centrifuged at 10000 rpm for 2 minutes (4°C), and plasma was separated within 1 hour and stored at -80°C for testing. The blood collection and centrifugation process was carried out under ice bath conditions.

[0867] G3-G6 group: Before administration and 0.25, 0.5, 1, 2, 4, 8, 24, 48, 72, 96, 120, 144 and 168 hours after administration, 0.1 mL of blood was collected from the eye socket, placed in an EDTA-K2 anticoagulant tube, centrifuged at 10000 rpm for 1 minute (4°C), and plasma was separated within 1 hour and stored at -20°C for testing. The blood collection and centrifugation process was operated under ice bath conditions. (Prepare 10% FA and add it to plasma at a ratio of 1:49).

[0868] The LC / MS / MS method was used to determine the content of compound 1w, compound 7p-1 or compound 7p-2 in mouse plasma after administration of different concentrations of the drug.

[0869] 4. Pharmacokinetic parameter results

[0870] Table 6 Pharmacokinetic parameters of the disclosed compounds in mice

[0871]

[0872] Conclusion: As shown in Table 6, the exposure level of the disclosed compound in mice is stable and long-lasting, and has obvious pharmacokinetic advantages; Figure 1 It is shown that compared with compound 1w, compound 7p-1 or compound 7p-2, the compound disclosed in the present invention has a stronger sustained-release effect on blood drug concentration, lower toxicity and can maintain efficacy, and has a safety advantage.

Claims

1. A macromolecule or a pharmaceutically acceptable salt thereof, comprising: i) a dendrimer comprising a core and at least one generation of structural units, the outermost generation of the structural units having surface amino groups, wherein at least two different end groups are covalently attached to the surface amino groups of the dendrimer; ii) a first terminal group, which is a residue A of a pharmaceutically active agent comprising a hydroxyl group; iii) a second terminal group which is a pharmacokinetic modifier; The first terminal group is connected to the linker L 0 covalently linked to the surface amino group of the dendrimer, the linker L 0 The structure is -C(O)-LC(O)-; wherein the linker forms an ester bond with the hydroxyl group of the pharmaceutically active agent and forms an amide bond with the surface amino group; L is an alkylene group, and the alkylene group is optionally substituted with one or more O, S, NR A or C(R x R y ) intermittent, R x , R y Together with the attached carbon atom, it forms a cycloalkyl or heterocyclic group; and the alkylene group is optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, nitro, cyano, -OR 3 、-NR 1 R 2 、-C(O)R 3 、-C(O)OR 3 、-S(O) x R 4 、-C(O)NR 1 R 2 、-NR 0 C(O)NR 1 R 2 、-S(O) x NR 1 R 2 、-NR 0 S(O) x NR 1 R 2 , oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl; R A is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, -C(O)R 3 、-C(O)OR 3 and -S(O) x R 4 wherein the alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R b replace; R 0 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a cycloalkylalkyl group; R 1 and R 2 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclyl group, a heterocyclylalkyl group, an aryl group, a heteroaryl group, a -C(O)R 3 、-C(O)OR 3 and -S(O) x R 4 wherein the alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R b Replace; or R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, which is optionally substituted by one or more R b replace; R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl; wherein the alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R b replace; R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl; wherein the alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R b replace; R b are the same or different at each occurrence and are each independently selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, nitro, cyano, hydroxy, amino, -NHalkyl, -N(alkyl), oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl; x is 0, 1, or 2; The structure of the pharmaceutically active agent is shown in general formula (I): in: R 5 is selected from the group consisting of a hydrogen atom, a halogen and an alkyl group; R 6 and R 7 are the same or different and are each independently selected from hydrogen, halogen, alkyl and hydroxyalkyl; or, R 6 , R 7 Together with the carbon atoms to which they are attached, they form a heterocyclic group, which is optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl and hydroxyalkyl; R 8 is -S(O)R 8a or -S(O)2R 8a ; R 8a is selected from the group consisting of alkyl, haloalkyl and cycloalkyl; n is an integer from 1 to 10; B is R 9 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkyl group; R 10 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkyl group; Ring A is a heteroaryl group, which is optionally substituted by one or more substituents selected from halogen, alkyl, haloalkyl and alkoxy; Ring B is a heterocyclic group, and the heterocyclic group is optionally substituted by one or more substituents selected from halogen, alkyl, haloalkyl and alkoxy.

2. The macromolecule according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L is C 1-6 Alkylene, the C 1-6 The alkylene group is optionally substituted with one or more O, S or NR A intermittent; and said C 1-6 The alkylene group is optionally substituted with one or more -NR 1 R 2 Replaced by; R A C 1-6 Alkyl; R 1 and R 2 are the same or different and are each independently selected from a hydrogen atom, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, 3 to 6 membered cycloalkyl C 1-6 Alkyl and -C(O)R 3 ; or R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms a 5- or 6-membered heterocyclic group; R 3 A hydrogen atom or C 1-6 alkyl.

3. The macromolecule according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the linker L 0 Selected from: Preferably, the linker L 0 Selected from More preferably, the linker L 0 Selected from *The terminal C(O) forms an amide bond with the surface amino group of the dendrimer.

4. The macromolecule or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 5 is halogen; R 6 C 1-6 Hydroxyalkyl, R 7 is a hydrogen atom; or, R 6 , R 7 Together with the carbon atoms to which they are attached, they form a 6-membered heterocyclic group; R 8 is -S(O)2R 8a ; R 8a C 1-6 haloalkyl; n is 3, 4, 5 or 6; B is selected from 5. The macromolecule or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the pharmaceutically active agent is selected from the following compound 1w, compound 7p-1 and compound 7p-2, or structural modifications thereof:

6. The macromolecule or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the residue A of the pharmaceutically active agent is selected from the following structures:

7. The macromolecule or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein the pharmacokinetic modifier is selected from polyethylene glycol, polyethyloxazoline, polyvinylpyrrolidone, polypropylene glycol, folate or a folate derivative for a ligand of a cell surface receptor; preferably polyethylene glycol.

8. The macromolecule or pharmaceutically acceptable salt thereof according to claim 7, wherein the polyethylene glycol has a molecular weight in the range of 220 to 5500 Da, preferably in the range of 1000-2500 Da, more preferably in the range of 1800-2200 Da.

9. The macromolecule or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein the dendrimer comprises a core and 2 to 7 structural units of lysine or lysine analogs.

10. The macromolecule according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein the dendritic polymer is selected from BHALys[Lys] 16 , BHALys[Lys] 32 and BHALys[Lys] 64 ; preferably BHALys[Lys] 32 .

11. The macromolecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, which is a macromolecule or a pharmaceutically acceptable salt thereof represented by the general formula (II): in: Y is PEG 220-5500 or H; Q is H or L 0 -A, where L 0 -A is selected from the following structures: Where: L, R 5 , R 8 , R 9 , R 10 , Ring A, Ring B and n are as defined in claim 1; provided that: at least one Q is L 0 -A.

12. The macromolecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, which is a macromolecule or a pharmaceutically acceptable salt thereof represented by the general formula (III): in: Y and Q are as defined in claim 11.

13. The macromolecule or pharmaceutically acceptable salt thereof according to claim 11 or 12, wherein the macromolecule or pharmaceutically acceptable salt thereof has 4 to 32 L 0 -A; Preferably, the macromolecule or its pharmaceutically acceptable salt has 4 to 22 L 0 -A.

14. The macromolecule according to any one of claims 11 to 13 or a pharmaceutically acceptable salt thereof, wherein the PEG 220-5500 Having a molecular weight of 1000-2500Da; preferably, the PEG 220-5500 It has a molecular weight of 1800-2200 Da.

15. The macromolecule according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein the macromolecule is selected from:

16. A pharmaceutical composition comprising the macromolecule according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

17. Use of a macromolecule according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, in the preparation of a medicament for treating and / or preventing a tumor; preferably, the tumor is selected from melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder cancer, gallbladder cancer, bile duct cancer, choriocarcinoma and pediatric tumor.

18. Use of the macromolecule or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, or the pharmaceutical composition according to claim 16, in the preparation of a medicament for treating and / or preventing myelofibrosis.

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