Ecdysteroid compounds and their use

Abstract

This invention discloses a jugnitin compound and its applications. The invention provides a jugnitin compound, which is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; the compound provided by this invention has one or more effects selected from the group consisting of: (1) inhibitory activity against the in vitro proliferation of tumor cells; (2) in vivo tumor-suppressive effect; (3) in vivo tumor-targeting ability; and (4) good in vivo safety.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to sucrose compounds and their applications. Background Technology

[0002] Cancer is one of the most serious malignant diseases threatening human health, causing more than 5 million deaths worldwide each year. Moreover, the incidence of cancer has been rising annually in recent years, and its mortality rate ranks first among all diseases. Chemotherapy is currently a commonly used and effective treatment for cancer. However, due to the multidrug resistance of cancer cells and the serious toxic side effects of existing anticancer drugs, there is an urgent clinical need for new anticancer drugs with better efficacy and fewer side effects.

[0003] Et-743 (Trabectedin) is a highly effective antitumor agent isolated from the marine tunicate Ecteinascidiaturbinata, and has been approved by the European Union and the United States for the treatment of advanced soft tissue tumors.

[0004]

[0005] There is still a need to continue developing arachin compounds with better efficacy and lower toxicity to meet more clinical needs. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to overcome the shortcomings of existing drugs, thereby providing a sucrose compound and its application. The sucrose compound of the present invention has one or more effects selected from the group consisting of: (1) having inhibitory activity against the in vitro proliferation of tumor cells; (2) having in vivo tumor-suppressing effect; (3) having in vivo tumor-targeting ability; and (4) having good in vivo safety.

[0007] This invention provides a sucrose compound, which is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0008] in, Q 1 For N or CR 12 ; Q 2 For N or CR 11 ; R 1 R 11 R 12 and R 2 Independently hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, -OC1-6 Alkyl, -N(R) 1 -1 )-R 1-2 -N(R) 1-1 )-S(O)2-R 1-2 -C 1-6 Alkylene-N(R) 1-1 )-C(O)R 1-2 -OC 3-12 Cycloalkyl, -O- (4 to 12-membered heterocyclic alkyl), -O- (4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -OC 3-12 Cycloalkyl-N(R) 1-1 )-C(O)R 1-2 -N(R) 1 -1 )-C(O)R 1-2 -C(O)R 1-2 -OC(O)-N(R) 1-1 )R 1-2 -N(R) 1-1 )-C(O)-OR 1-2 -N(R) 1-1 )-C(O)-N(R 1-1 )R 1-2 -N(R) 1-1 )-(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -N(R) 1-1 )-C 3-12 Cycloalkyl-N(R) 1-3 )-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-N(R 1-1 )-C(O)R 1-2 or -N(R) 1-1 )C(O)-C 1-6 Alkylene-R 1-2 The C mentioned 1-6 Alkyl, C 1-6 Alkylene, C 3-12 cycloalkyl, C 3-12 Cycloalkylene, 4- to 12-membered heterocycloalkylene, and 4- to 12-membered heterocycloalkyl are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 alkylene -OH, -C 1-6 Alkylene -SH, -C 1-6 Alkylene-S(C 1-6alkyl) and -C 1-6 Substitution of alkylene-NH2; Or, R 1 With R 11 Together with their respective attached atoms, they are conceived as 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl; each of the cycloalkyl or heterocycloalkyl is optionally bonded by one or more atoms selected from halogens, -C 1-6 Alkyl substituents; R 3 For hydrogen, deuterium, -C 1-6 Alkyl, -CH2-NR 3-1 R 3-2 -CH2-NR 3-1 C(O)R 3-2 -CH2-OC(O)-NR 3-1 R 3-2 -CH2-NR 3-1 C(O)-OR 3-2 -CH2-NR 3-1 C(O)NR 3-1 R 3-2 -CH2-N(R) 3-1 )C(O)R 3-2 -CH2-N(R) 3-1 )C(O)-C 1-6 Alkylene-R 3-2 or -C(O)-R 3-2 The C mentioned 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -O-NH-CH3, -NHC 1-6 Alkyl and -SC 1-6 Alkyl substituents; R 4 For hydrogen, deuterium, -C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 3-12 Cycloalkyl or -C(O) (4 to 12-membered heterocycloalkyl), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents; Or R 3 With R 4Together with the atoms attached thereto, they form 5-12 membered heterocyclic alkyl groups; each of the 5-12 membered heterocyclic alkyl groups is optionally bonded by one or more groups selected from halogen, oxo group, -OH, -CN, -NH2, -NHC. 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -C 1-6 Alkyl, -C 1-6 Alkylene -OH, -C(O)C 1-6 Alkylene -OH, -C(O)-C 3-12 Substituents of cyclohexene alkyl-OH and -C(O)-(4 to 12-membered heterocyclohexene alkyl)-OH; R 1-1 R 3-1 Each is independently hydrogen, deuterium, and C. 1-6 Alkyl or halogenated C 1-6 alkyl; R 1-2 R 3-2 Each independently is C 1-6 Alkyl, C 3-12 Cycloalkyl or 4- to 12-membered heterocyclic alkyl; the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally selected independently from one or more halogens, -OH, -SH, -NH2, -O-NH-CH3, C 3-6 cycloalkyl, -NHC 1-6 Alkyl and -SC 1-6 Alkyl substituents; Y can be either -OH or -CN.

[0009] In some embodiments, certain groups in the sucrose compounds are defined as follows, and groups not mentioned are as described in any embodiment of this application (hereinafter referred to as "in some embodiments").

[0010] In some embodiments, the number of heteroatoms in the 4- to 12-membered heterocyclic alkyl group and the 4- to 12-membered heterocyclic alkyl group is one or more, and each heteroatom is independently selected from N, O, and S; preferably, the 4- to 12-membered heterocyclic alkyl group and the 4- to 12-membered heterocyclic alkyl group are 4- to 6-membered heterocyclic alkyl groups and 4- to 6-membered heterocyclic alkyl groups; the number of heteroatoms is one or two, and the heteroatoms are independently selected from N; for example, N-heterocyclic butyl ( , ), piperidinyl ( , ), piperazine group ( , ), or its divalent group.

[0011] In some implementation schemes, R 1 -NH2, -C1-6 Alkylene-N(R) 1-1 )-C(O)R 1-2 -N(R) 1-1 )-R 1-2 -O-(4 to 6-membered heterocyclic alkylene)-C(O)R 1-2 -OC 3-6 Cycloalkyl-N(R) 1-1 )-C(O)R 1-2 -N(R) 1-1 )-(4 to 6-membered heterocyclic alkylene)-C(O)R 1-2 -(4 to 6-membered heterocyclic alkylene)-C(O)R 1-2 -(4 to 6-membered heterocyclic alkylene)-N(R 1-1 )-C(O)R 1-2 or -N(R) 1-1 )-C(O)R 1-2 The C mentioned 1-6 Alkylene, C 3-6 The cycloalkyl group or 4- to 6-membered heteroalkyl group is optionally surrounded by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 alkylene -OH, -C 1-6 Alkylene -SH, -C 1-6 Alkylene-S(C 1-6 alkyl) and -C 1-6 Substituents of alkylene-NH2.

[0012] In some implementation schemes, R 1 -NH2, -C 1-6 Alkylene-N(R) 1-1 )-C(O)R 1-2 -N(R) 1-1 )-R 1-2 -O-(4 to 6-membered heterocyclic alkylene)-C(O)R 1-2 -OC 3-6 Cycloalkyl-N(R) 1-1 )-C(O)R 1-2 -N(R) 1-1 )-C(O)R 1-2 or -N(R) 1 -1 )-(4 to 6-membered heterocyclic alkylene)-C(O)R 1-2 The C mentioned 1-6 Alkylene, C 3-6 The cycloalkyl group or 4- to 6-membered heteroalkyl group is optionally separated by one or more elements selected from halogen, -OH, -NH2, -NHCH3, -C1-6 Alkylene-OH substitution.

[0013] In some implementation schemes, R 1 -NH2, -N(R) 1-1 )-R 1-2 or -N(R) 1-1 )-C(O)R 1-2 .

[0014] In some implementation schemes, R 1-1 It is hydrogen, deuterium or C 1-6 alkyl.

[0015] In some implementation schemes, R 1-1 It is hydrogen, deuterium, or -CH3; preferably, R 1-1 It is hydrogen or -CH3.

[0016] In some implementation schemes, R 1-2 C 1-6 Alkyl, C 3-6 Cycloalkyl or 4- to 6-membered heterocyclic alkyl; the C 1-6 Alkyl, C 3-6 The cycloalkyl group or 4- to 6-membered heterocycloalkyl group is optionally surrounded by one or more elements selected from halogen, -OH, -O-NHCH3, -SH, -NH2, cyclopropyl, -NHC 1-6 Alkyl and -SC 1-6 Alkyl substituents.

[0017] In some implementation schemes, R 1-2 C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted by one or more substituents selected from -OH, cyclopropyl, or -O-NHCH3.

[0018] In some implementation schemes, R 2 Hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, the C 1-6 Each alkyl group is optionally surrounded by one or more elements selected from halogens, -OH, -SH, -NH2, and -NHC. 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 alkylene -OH, -C 1-6 Alkylene -SH, -C 1-6 Alkylene-S(C 1-6 alkyl) and -C 1-6 Substituents of alkylene-NH2.

[0019] In some implementation schemes, R 2 It can be hydrogen, deuterium, halogen, -OH, -CN, -NH2, -CH3, -OCH3 or -NHCH3.

[0020] In some implementation schemes, R 2 It can be hydrogen, deuterium, or -OCH3; for example, hydrogen.

[0021] In some implementation schemes, R 3-1 It is hydrogen, deuterium or C 1-6 alkyl.

[0022] In some implementation schemes, R 3-1 It is hydrogen, deuterium, or -CH3; preferably, R 1-1 It is hydrogen or -CH3.

[0023] In some implementation schemes, R 3-2 C 1-6 Alkyl, C 3-6 Cycloalkyl or 4- to 6-membered heterocyclic alkyl; the C 1-6 Alkyl, C 3-6 The cycloalkyl group or 4- to 6-membered heterocycloalkyl group is optionally surrounded by one or more elements selected from halogen, -OH, -O-NHCH3, -SH, -NH2, cyclopropyl, -NHC 1-6 Alkyl and -SC 1-6 Alkyl substituents.

[0024] In some implementation schemes, R 3-2 -C 1-6 alkylene-OH; preferably, R 3-2 -C 1-3 Alkylene-OH.

[0025] In some implementation schemes, R 3 For hydrogen, deuterium, -C 1-6 Alkyl, -CH2-NH2, -CH2-NH-C 1-6 Alkyl group, -CH2-N(C) 1-6 alkyl)-C 1-6 Alkyl group, -CH2-NHC(O)-C 1-6 Alkyl or -CH2-N(C) 1-6 Alkyl)C(O)-C 1-6 Alkyl, the C 1-6 Each alkyl group is optionally surrounded by one or more elements selected from halogens, -OH, -SH, -NH2, and -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents.

[0026] In some implementation schemes, R 3The CH3 group is hydrogen, deuterium, -CH3, -CH2-NH2, -CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-NHC(O)-CH3, or -CH2-N(CH3)C(O)-CH3, wherein each CH3 group is optionally replaced by one or more elements selected from halogens, -OH, -SH, -NH2, and -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents.

[0027] In some implementation schemes, R 3 It is hydrogen, deuterium, -CH3, -CH2-NHCH3; preferably, R 3 It is hydrogen.

[0028] In some implementation schemes, R 11 Hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl or -NHC 1-6 alkyl.

[0029] In some implementation schemes, R 11 It can be hydrogen, deuterium, -F, -Cl, -OH, -CH3, -OCH3, -NH2 or -NHCH3.

[0030] In some implementation schemes, R 11 It can be hydrogen, deuterium, or -OCH3.

[0031] In some implementation schemes, R 12 Hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl or -NHC 1-6 alkyl.

[0032] In some implementation schemes, R 12 It is hydrogen, deuterium, -F, -Cl, -OH, -CH3, -OCH3, -NH2 or -NHCH3; preferably, R 12 It is hydrogen.

[0033] In some implementation schemes, R 4 For hydrogen, deuterium, C 1-6 Alkyl or -C(O)C 1-6 Alkyl, the C 1-6 The alkyl group is optionally surrounded by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents.

[0034] In some implementation schemes, R 4It is hydrogen, deuterium, or -CH3; preferably, R 4 It is hydrogen.

[0035] In some implementations, Y is -CN.

[0036] In some embodiments, the compound shown in formula (I) is a compound shown in formulas (II) and (III):

[0037] Among them, R 1 R 11 R 2 R 3 R 4 Y is defined as described in any of the compounds shown in formula (I).

[0038] In some embodiments, the compounds shown in formulas (I), (II), and (III) are compounds with the structures shown in formulas (II-1) and (III-1).

[0039] Among them, R 1 -NH2, -N(R) 1-1 )-R 1-2 or -N(R) 1-1 )-C(O)R 1-2 ; R 1-1 It can be hydrogen, deuterium, or -CH3; R 1-2 C 1-6 Alkyl; the C 1-6 Each alkyl group may optionally be substituted by one or more substituents selected from -OH, cyclopropyl, or -O-NHCH3.

[0040] R 4 It can be hydrogen, deuterium, or -CH3; Y can be either -OH or -CN.

[0041] In some implementation schemes, R 1-2 C 1-6 Alkyl-OH, C 1-6 Alkyl-O-NHCH3 or C 1-6 Alkyl (C) 3-6 (cycloalkyl)-OH.

[0042] In some implementation schemes, R 1 -NH2, , , or ; In some embodiments, the compound of the present invention is: , , , , , , .

[0043] Those skilled in the art will understand that this invention covers compounds obtained by any combination of the various embodiments. Embodiments obtained by combining technical features or preferred technical features from one embodiment with technical features or preferred technical features from another embodiment are also included within the scope of this invention.

[0044] In another aspect, the present invention provides a compound with the following structure: .

[0045] In another aspect, the present invention provides a pharmaceutical composition comprising (a preventive or therapeutically effective amount) of the compounds described herein, and one or more pharmaceutically acceptable carriers.

[0046] A further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, the method comprising combining the compound of the present invention or a pharmaceutically acceptable form thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers.

[0047] The pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention are pharmaceutically acceptable carriers.

[0048] Pharmaceutical compositions can be administered in any form, as long as they achieve the purpose of preventing, alleviating, preventing, or curing symptoms in human or animal patients. For example, they can be formulated into various suitable dosage forms depending on the route of administration.

[0049] In other embodiments, the administration of the compounds or pharmaceutical compositions of the present invention may be combined with other treatment methods. These other treatment methods may be selected from, but are not limited to, radiotherapy, chemotherapy, immunotherapy, or combinations thereof.

[0050] This invention also relates to a pharmaceutical formulation comprising, as an active ingredient, a compound of the invention or a pharmaceutically acceptable form thereof, or a mixture thereof, a pharmaceutical composition of the invention. In some embodiments, the formulation is in the form of a solid dosage form, a semi-solid dosage form, a liquid dosage form, or a gaseous dosage form.

[0051] A further object of the present invention is to provide an article of manufacture, for example, in the form of a kit. The article of manufacture as used herein is intended to include, but is not limited to, medicine boxes and packaging. The article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition contained in the first container, wherein the composition comprises: a first therapeutic agent, the first therapeutic agent comprising: a compound of the present invention or a pharmaceutically acceptable form thereof, or a mixture thereof; (c) optionally present packaging instructions stating that the pharmaceutical composition may be used to treat oncological conditions (as defined below); and (d) a second container.

[0052] The first container is a container for containing a pharmaceutical composition. This container may be used for the preparation, storage, transportation, and / or individual / bulk sales. The first container is intended to encompass bottles, jars, vials, flasks, syringes, tubes (e.g. for cream products), or any other container for the preparation, containment, storage, or dispensing of pharmaceutical products.

[0053] The second container is a container for holding the first container and optional instruction manuals. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic boxes), cartons, cartons, bags (e.g., paper or plastic bags), sachets, and cloth bags. The instruction manuals may be physically attached to the outside of the first container by cable ties, glue, U-staples, or other adhesive methods, or they may be placed inside the second container without any physical means of attachment to the first container. Alternatively, the instruction manuals may be located outside the second container. When located outside the second container, it is preferable that the instruction manuals be physically attached by cable ties, glue, U-staples, or other adhesive methods. Alternatively, they may be adjacent to or in contact with the outside of the second container without physical attachment.

[0054] The packaging instructions, such as trademarks, labels, or markings, list information relating to the pharmaceutical composition contained within the first container. The listed information is typically determined by the regulatory authority governing the region where the product is to be sold (e.g., the U.S. Food and Drug Administration). Preferably, the packaging instructions specifically list the approved indications for which the pharmaceutical composition is used. The packaging instructions can be made of any material from which information contained therein or on the material can be read. Preferably, the packaging instructions are made of a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic) on which the desired information can be formed (e.g., printed or coated).

[0055] In another aspect, the present invention provides the use of the compounds described herein or in a pharmaceutically acceptable form thereof, or the pharmaceutical compositions of the present invention, in the preparation of a medicament.

[0056] In another aspect, the present invention provides the use of the compounds described herein or in a pharmaceutically acceptable form thereof, or the pharmaceutical compositions of the present invention, in the preparation of a medicament for the prevention or treatment of tumors or cancer.

[0057] In another aspect, the present invention provides a method for preventing or treating tumors, the method comprising administering to an individual in need (a preventive or therapeutically effective amount) of a compound as described herein or in a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention.

[0058] On the other hand, the present invention provides (preventive or therapeutically effective amounts) of the compounds described herein or their pharmaceutically acceptable forms, or pharmaceutical compositions of the present invention, for the prevention or treatment of tumors or cancer.

[0059] In another aspect, the present invention provides a method for preventing or treating tumors or cancer by combining (a preventive or therapeutically effective amount) of the compounds described herein or in a pharmaceutically acceptable form thereof, or by combining the pharmaceutical compositions of the present invention with other treatment methods, including but not limited to: radiotherapy, chemotherapy, immunotherapy, or combinations thereof.

[0060] In some implementations, the tumor or cancer includes, but is not limited to, breast cancer and ovarian cancer.

[0061] In a further preferred embodiment, the compounds of the present invention can be used in combination with radiotherapy, chemotherapy, or immunotherapy to prevent or treat tumors or cancer.

[0062] Dosing regimens can be adjusted to provide the optimal required response. For example, when administered in injectable form, a single bolus, bolus, and / or continuous infusion can be given, etc. For example, several fractions can be administered over time, or the dose can be reduced or increased proportionally as indicated by the urgency of the treatment situation. It should be noted that dosage values ​​can vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. Generally, the dosage of treatment is variable, depending on considerations such as: the age, sex, and general health of the patient to be treated; the frequency of treatment and the nature of the desired effect; the extent of tissue damage; the duration of symptoms; and other variables that can be adjusted by individual physicians. To further understand, for any particular individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the composition or supervising the administration of the composition. The dosage and administration regimen of the pharmaceutical composition can be readily determined by a person skilled in the clinical field. For example, the compositions or compounds of the present invention can be administered in fractions from four times daily to once every three days, with dosages ranging from, for example, 0.01 to 1000 mg per dose. The required dose can be administered once or multiple times to achieve the desired results. The pharmaceutical compositions according to the invention can also be provided in unit dose form.

[0063] General terms and definitions

[0064] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0065] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed. Those skilled in the art will understand that the foregoing term “comprising” encompasses the meaning of “consisting of.”

[0066] The term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0067] Unless otherwise stated, concentrations are by weight and proportions (including percentages) are by moles.

[0068] The term "one or more species" or similar expression "at least one species" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

[0069] When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. In particular, each range of values ​​disclosed herein (in the form of “about a to b”, or equivalently, “approximately a to b”, or equivalently, “about ab”) should be understood to represent each numerical value and range encompassed within a wider range.

[0070] For example, the expression "C1-6" should be understood as encompassing any subrange and each point value within it, such as C2-5, C3-4, C1-2, C1-3, C1-4, C1-5, etc., and C1, C2, C3, C4, C5, C6, etc. For example, the expression "C3- 10 "It should also be understood in a similar way, for example, it can encompass any subrange and point value contained within it, such as C3-9, C6-9, C6-8, C6-7, C7- 10 C7-9, C7-8, C8-9, etc., as well as C3, C4, C5, C6, C7, C8, C9, C 10For example, the expression "3-10 yuan" should be understood as encompassing any sub-range and each point value within it, such as 3-4 yuan, 3-5 yuan, 3-6 yuan, 3-7 yuan, 3-8 yuan, 3-9 yuan, 4-5 yuan, 4-6 yuan, 4-7 yuan, 4-8 yuan, 5-7 yuan, 5-8 yuan, 6-7 yuan, etc., as well as 3, 4, 5, 6, 7, 8, 9, 10 yuan, etc. Similarly, the expression "5-10 yuan" should also be understood in a similar way, for example, it can encompass any sub-range and point value included within it, such as 5-6 yuan, 5-7 yuan, 5-8 yuan, 5-9 yuan, 5-10 yuan, 6-7 yuan, 6-8 yuan, 6-9 yuan, 6-10 yuan, 7-8 yuan, etc., as well as 5, 6, 7, 8, 9, 10 yuan, etc.

[0071] In this specification, groups and their substituents may be selected by those skilled in the art to provide stable structural moieties and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left.

[0072] When used alone or in combination with other groups herein, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon group. As used herein, the term "C" refers to a saturated straight-chain or branched hydrocarbon group. 1-6 "Alkyl" refers to a saturated straight-chain or branched hydrocarbon group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms). "C" 1-6 "alkyl" can be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl. The alkyl group in this invention may optionally be substituted with one or more substituents described herein.

[0073] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl," then it should be understood that "alkyl" represents a linked alkylene group. For example, in some specific structures, when an alkyl group is clearly indicated as a linking group, then that alkyl group represents a linked alkylene group, for example, the group "halogenated-C". 1-6 C in "alkyl" 1-6 Alkyl should be understood as C 1-6 Alkylene.

[0074] When used alone or in combination with other groups herein, the term "alkylene" refers to a saturated straight-chain or branched divalent hydrocarbon group. As used herein, the term "C 1-6 "Alkylene" refers to a saturated, straight-chain or branched divalent hydrocarbon group having 1-6 carbon atoms. 1-6"alkylene" includes, but is not limited to, methylene, ethylene, propylene, or butylene. The alkylene groups in this invention may optionally be substituted with one or more substituents described in this invention.

[0075] In this application, the term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group. For example, "C 3-12 "Cycloalkyl" or "3-12 membered cycloalkyl" refers to a cycloalkyl group having 3-12 ring carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12). Common cycloalkyl groups include (but are not limited to) monocyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutene, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkyl groups, including fused rings, bridged rings, or spirocyclic groups, such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, bicyclic [5.2.0]nonyl, decahydronaphthyl, etc. In one embodiment, the cycloalkyl group is preferably a saturated cycloalkyl group.

[0076] In this application, the term "cycloalkylene" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic dicyclic group. For example, "C 3-12 "Cycloalkylene" or "3-12-membered cycloalkylene" refers to a cycloalkylene compound having 3-12 ring carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12). Common cycloalkylene compounds include (but are not limited to) monocyclic cycloalkylene compounds, such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclobutene, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkylene compounds, including fused rings, bridged rings, or spirocyclic compounds, such as bicyclic[1.1.1]pentylene, bicyclic[2.2.1]heptylene, bicyclic[3.2.1]octylene, bicyclic[5.2.0]nonylene, decahydronaphthylene, etc. In one embodiment, the cycloalkylene compound is preferably a saturated cycloalkylene compound.

[0077] The term "heterocyclic alkyl" refers to a saturated or partially saturated non-aromatic cyclic group containing at least one heteroatom selected from N, O, P, and S as a ring member. Preferably, the number of heteroatoms is 1, 2, 3, or 4 (e.g., 1 or 2 heteroatoms independently selected from N). Examples include 3-8-membered, 3-6-membered, 4-12-membered, and 4-6-membered heterocyclic alkyl groups. Furthermore, the heterocyclic alkyl group may contain 0, 1, 2, or 3 oxo groups. Specific examples include, but are not limited to, ethylene oxide, oxocyclobutane, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, homopiperazinyl, and pyrrolidoneyl. In one embodiment, the heterocyclic alkyl group is preferably a saturated heterocyclic alkyl group.

[0078] The term "heterocyclic alkylene" refers to a saturated or partially saturated, non-aromatic divalent cyclic group containing at least one heteroatom selected from N, O, P, and S as a ring member. Preferably, the number of heteroatoms is 1, 2, 3, or 4 (e.g., 1 or 2 heteroatoms independently selected from N). Examples include 3-8-membered, 3-6-membered, 4-12-membered, and 4-6-membered heterocyclic alkylene groups. Furthermore, the heterocyclic alkylene group may contain 0, 1, 2, or 3 oxo groups. Specific examples include, but are not limited to, ethylene oxide, cyclobutane, pyrrolidine, tetrahydrofuranyl, piperidinyl, piperazine, tetrahydropyranyl, homopiperazine, and pyrrolidone. In one embodiment, the heterocyclic alkylene group is preferably a saturated heterocyclic alkylene group.

[0079] In this application, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0080] In this application, the term "hydroxyl group" refers to -OH.

[0081] In this application, the term "cyano" refers to -CN.

[0082] In this application, the term "nitro" refers to -NO2.

[0083] In this application, the term "amino" refers to -NH2.

[0084] In this application, "oxo" refers to C(O), i.e., carbonyl group.

[0085] When used alone or in combination with other groups in this application, the term "haloalkyl" refers to the alkyl group described above, wherein one or more hydrogen atoms are replaced by a halogen. For example, the term "C 1-6 "Halogenated alkyl" or "halogenated C" 1-6 "Alkyl" refers to a C-aryl group that is optionally substituted with one or more (e.g., 1-3) halogens. 1-6 Alkyl groups. Those skilled in the art will understand that when there is more than one halogen substituent, the halogens can be the same or different, and can be located on the same or different C atoms. Examples of alkyl halogens include, for example, -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl, or -CH2CH2CF3. The alkyl halogens in this invention are optionally substituted with one or more substituents described in this invention.

[0086] When used alone or in combination with other groups in this application, the term "alkoxy" means an alkyl group to which an oxygen atom is attached as described above to the parent molecule. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, and pentoxy.

[0087] As used in this application, the term "each independently" means that at least two groups (or segments) in a structure with the same or similar value ranges can have the same or different meanings under specific circumstances. For example, if substituent A and substituent B are each independently hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl, then when substituent A is hydrogen, substituent B can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl; similarly, when substituent B is hydrogen, substituent A can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl.

[0088] As used herein, the term "substitution" and its other variations refer to the replacement of one or more (e.g., 1, 2, 3, or 4) atoms or groups of atoms (e.g., hydrogen atoms) on a specified atom with other equivalents, provided that the replacement does not exceed the normal valence of the specified atom or group of atoms in the present case and is capable of forming a stable compound. If an atom or group of atoms is described as "optionally substituted," it may or may not be substituted. Unless otherwise stated, the linking site of a substituent herein may be any suitable position of the substituent. When the linking bond in a substituent is shown as a chemical bond through two atoms connected to each other in a ring system, it indicates that the substituent may be linked to any one of the cyclic atoms in the ring system.

[0089] When any variable (e.g., R) a When a variable appears multiple times in the definition of a compound, the definition at each position is independent of the definitions at the other positions; their meanings are independent and do not affect each other. Therefore, if a group is surrounded by one, two, or three R... a Group substitution, meaning that the group can be replaced by up to 3 R groups. a Replacement, where a certain position R a Definition and other positions R a The definitions are independent of each other. Furthermore, combinations of substituents and / or variables are only permitted if the combination produces a stable compound. The term "optionally substituents" is used in conjunction with one or more R... a "Replace" indicates that it was not replaced by R a Replaced and by one or more R a Replaces both scenarios. For example, "the C..." 1-6 Alkyl groups are optionally surrounded by one or more R a "Replace" means C 1-6 Alkyl and (by one or more R) a (replaced) C 1-6 alkyl.

[0090] When a listed group does not explicitly indicate that it has a substituent, the group refers only to the unsubstituted group. For example, when "C 1-6When "alkyl" is not specified as "substituted or unsubstituted," it refers only to "C". 1-6 "alkyl" itself or "unsubstituted C" 1-6 alkyl".

[0091] As used herein, the compounds of this invention may contain one or more chiral centers and exist in different optically active forms. When a compound contains one chiral center, the compound comprises enantiomers. This invention includes both isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When the compound of Formula I contains more than one chiral center, diastereomers may be present. This invention includes resolved optically pure specific isomers and mixtures of diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and chiral chromatography.

[0092] The term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. The compounds described in this invention can exist in stereoisomer form, and therefore encompass all possible stereoisomer forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, and transisomers. The compounds described in this invention can also exist in any combination or mixture of the aforementioned stereoisomers, such as equal mixtures of meso, racemic, and transisomers, or, for example, a single enantiomer, a single diastereomer or a mixture of more than one, or a single transisomer or a mixture thereof.

[0093] The term "tautomer" refers to a functional group isomer that is produced by the rapid movement of an atom in two positions within a molecule.

[0094] Solid lines may be used in this application ( ), solid wedge ( ) or virtual wedge ( The carbon-carbon bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) are included at that carbon atom. Solid or imaginary wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and imaginary wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of the present invention may exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0095] The wavy line may be used in this application. The description of the bond connecting to the asymmetric carbon atom indicates that the bond at that carbon atom is a real wedge ( ) or virtual wedge ( ( ) represents one of the absolute configurations of the stereoisomers shown.

[0096] In this application, unless otherwise specified, the structures described herein may also include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, compounds whose structures are identical to those of this application except that hydrogen atoms are replaced by deuterium or tritium, or carbon atoms are replaced by carbon-13 or carbon-14, are within the scope of this application.

[0097] This invention also covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0098] Unless otherwise stated, the word “or” or “and” in this article refers to “and / or”.

[0099] Unless otherwise specified, the "" appearing in the specific groups mentioned in this article "or" "" refers to the connection position; the two can be interchanged.

[0100] The term “pharmaceutically acceptable form” refers to, but is not limited to, its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug.

[0101] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites. Therefore, when referring to "compounds of the present invention" herein, it is also intended to encompass the various derivative forms of the compounds described above.

[0102] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts. Suitable acid addition salts are formed by acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed by bases that form pharmaceutically acceptable salts. Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0103] As used herein, the term "ester" means an ester derived from the compounds described herein, including physiologically hydrolyzable esters (the compounds of the present invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of the present invention may themselves also be esters.

[0104] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0105] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form nitrogen oxides because nitrogen requires available lone pairs of electrons to be oxidized. Those skilled in the art will identify nitrogen-containing heterocycles capable of forming nitrogen oxides. They will also recognize that tertiary amines can form nitrogen oxides. Synthetic methods for preparing nitrogen oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, sodium perborate, and dioxiranes such as dimethyldioxyethylene. These methods for preparing nitrogen oxides have been extensively described and reviewed in the literature.

[0106] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body upon administration of the compounds of this invention. Metabolites of the compounds can be identified using techniques known in the art, and their activity can be characterized by experimental methods. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[0107] The present invention further includes, within its scope, prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity, and which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the present invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds, which are readily converted in vivo into the desired therapeutically active compounds. The prodrugs of the present invention can be prepared, for example, by replacing suitable functional groups present in the compounds of the present invention with certain portions known to those skilled in the art as "pro-moiety".

[0108] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved using conventional protecting groups. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0109] This invention also covers methods for preparing the compounds described herein. It should be understood that the compounds of this invention can be synthesized using the methods described below, as well as synthetic methods known in the field of synthetic organic chemistry or variations thereof understood by those skilled in the art. Preferred methods include (but are not limited to) those described below. The reaction can be carried out in a solvent or solvent mixture suitable for the reagents and materials used and suitable for achieving the conversion.

[0110] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat one or more symptoms of a target condition or disease.

[0111] As used herein, the term "effective amount" (e.g., "therapeutic effective amount" or "preventive effective amount") refers to the amount of active ingredient that, when administered, will achieve the desired effect to a certain extent, such as relieving one or more symptoms of the treated condition or preventing the occurrence of the condition or its symptoms.

[0112] Unless otherwise stated, as used herein, the term “treatment” means to reverse, alleviate, or inhibit the progression of a disease or condition to which such term applies, or one or more symptoms of such a disease or condition, or to prevent such a disease or condition, or one or more symptoms of such a disease or condition.

[0113] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0114] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0115] The reagents and raw materials used in this invention are all commercially available.

[0116] The positive and progressive effects of the present invention are as follows: the novel highly active seasedge derivative provided by the present invention can achieve at least one of the following technical effects: (1) high inhibitory activity against tumor cells; (2) excellent physicochemical properties (e.g., solubility, physical and / or chemical stability); (3) excellent safety (lower toxicity and / or fewer side effects, wider therapeutic window), etc. Detailed Implementation

[0117] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0118] Mass spectrometry (MS) measurements were performed using an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.

[0119] Preparative high performance liquid chromatography (HPLC) was performed using a Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250 × 20 mm column).

[0120] Thin-layer chromatography purification was performed using GF 254 (0.4 ~ 0.5 nm) silica gel plates produced in Yantai.

[0121] The reaction was monitored using thin-layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS). The developing solvent systems used included, but were not limited to, dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and petroleum ether and ethyl acetate systems. The volume ratio of the solvent was adjusted according to the polarity of the compound, or by adding triethylamine, etc.

[0122] Column chromatography typically uses Qingdao Ocean 200-300 mesh silica gel as the stationary phase. Eluent systems include, but are not limited to, dichloromethane and methanol systems and n-hexane and ethyl acetate systems. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

[0123] Unless otherwise specified in the examples, the reaction temperature is room temperature (20°C~30°C).

[0124] Unless otherwise specified, the reagents used in the examples were purchased from Acros Organics, Aldrich Chemical Company, Nanjing Yaoshi Technology, Anaiji, or Shanghai Shuya Pharmaceutical Technology, etc.

[0125] In the conventional synthesis methods, preparation examples, and intermediate synthesis examples, the starting materials were commercially feasible and purchased from Shanghai Leyan, Shanghai Shaoyuan, Bid Biotechnology, Aladdin Reagent, etc. The key starting material M24 and the control compound trabectedine were both purchased from Zhejiang Zhongke Chuangyue. The meanings of the abbreviations are shown in the table below.

[0126]

[0127] Synthesis of intermediates: Example 1: Preparation of intermediate 1

[0128] Step 1: Preparation of compound Int1-2

[0129] Compound Int1-1 (1.4 g, 5.68 mmol) was dissolved in anhydrous DMF (6 mL), stirred until homogeneous, and then sodium azide (0.74 g, 11.4 mmol) was added. The reaction mixture was heated to 70 °C and reacted for 8 h. The reaction was monitored by TLC until complete. After cooling to room temperature, water and methyl tert-butyl ether were added, and the mixture was stirred and separated. The organic phase was separated and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The residue was purified by column chromatography to give compound Int1-2 (0.8 g, 68% yield).

[0130] Step 2: Preparation of compound Int1

[0131] Compound Int1-2 (0.8 g, 3.84 mmol) and Pd / C (10%, 0.08 g) were added to methanol (10 mL) at room temperature. After purging with hydrogen three times, the mixture was reacted under a hydrogen atmosphere for 5 h. LC-MS showed that the reaction was complete. The mixture was diluted with ethyl acetate, stirred, filtered, and the filtrate was concentrated under reduced pressure to give compound Int1 (0.4 g, yield: 69%).

[0132] Example 1: Preparation of Compound 1 and Compound 2

[0133] Step 1: Preparation of Compound 1-1

[0134] Sodium acetate (98.96 mg, 1.21 mmol) was added to a 5 mL acetic acid solution of compound M24 (50.00 mg, 0.08 mmol) and compound Int1 (39.17 mg, 0.26 mmol), and the mixture was stirred at 65 °C for 2 hours. The reaction solution was concentrated and purified by reverse-phase MPLC to give compound 1-1 (27.0 mg, 45% yield).

[0135] MS m / z (ESI): 756.3 [M+H] +

[0136] 1 HNMR (400 MHz, DMSO- d 6 ) δ 8.74 (d, J = 5.6 Hz, 1H), 6.71-6.38 (m, 3H), 6.32-6.22 (m, 2H), 6.15 (s, 1H), 5.13-4.57 (m, 4H), 4.45-4.42 (m, 2H), 4.19-3.93 (m, 4H), 3.63 (d, J = 5.9 Hz, 3H), 3.23-2.92 (m, 3H), 2.85-2.60 (m,3H), 2.39-2.23 (m, 8H), 2.09 -1.90 (m, 7H).

[0137] Step 2: Preparation of compounds 1-2

[0138] Compound 1-1 (400.0 mg, 0.53 mmol) was dissolved in THF (7.5 mL), and saturated NaHCO3 aqueous solution (1.5 mL) and Boc2O (40 drops) were added. The reaction solution was heated to 20 °C. oStir overnight at C. Extract with aqueous NH4Cl and ethyl acetate, separate the layers, dry the organic phase with anhydrous sodium sulfate, filter and evaporate to dryness. Purify the residue by column chromatography to give compounds 1-2 (400 mg, yield: 87.8%).

[0139] Step 3: Preparation of compounds 1-3

[0140] Compounds 1-2 (400.0 mg, 0.47 mmol) were dissolved in ethanol (8.0 mL), and 32 drops of 37% formaldehyde aqueous solution and NaBH3CN (160.0 mg, 2.58 mmol) were added. The reaction solution was heated to 25 °C. o C. Stir for 1 hour. Monitor the reaction for completeness by LCMS. Add ethyl acetate and water, stir, and separate the liquids. Dry the organic phase, concentrate under reduced pressure, and purify the residue by reverse MPLC to obtain compounds 1-3 (300.0 mg, yield: 71.1%).

[0141] Step 4: Preparation of compounds 1-4

[0142] Iodine (600.0 mg, 2.37 mmol), imidazole (600.0 mg, 8.82 mmol), and triphenylphosphine (900.0 mg, 3.44 mmol) were dissolved in dichloromethane (15.0 mL). The reaction mixture was stirred at 0 °C for 15 minutes, and then compounds 1-3 (300.0 mg, 0.35 mmol) were added. The mixture was allowed to warm to room temperature and stirred for another 2 hours. LC-MS showed that the reaction was complete. Ethyl acetate and water were added, and the mixture was stirred and separated. The organic phase was dried and concentrated under reduced pressure. The residue was purified by reverse-phase MPLC to give compounds 1-4 (70 mg, 23% yield).

[0143] Step 5: Preparation of Compound 1

[0144] Compounds 1-4 (70.0 mg, 82.26 µmol) were dissolved in dichloromethane (2.0 mL), and trifluoroacetic acid (1.5 mL) was added. The reaction solution was heated to 25 °C. o C. Stir for 10 minutes. Adjust the pH of the reaction mixture to 7 with saturated sodium bicarbonate solution, and then extract with dichloromethane. Dry the organic phase with anhydrous sodium sulfate, filter and evaporate to dryness, and purify the residue by reverse HPLC to give compound 1 (40 mg, 65%).

[0145] MS m / z (ESI): 752.4 [M+H] +

[0146] Step 6: Preparation of Compound 2

[0147] Glycolic acid (35.0 mg, 460.53 µmol), HATU (100.0 mg, 263.16 µmol), HOAT (100.0 mg, 735.29 µmol), and TMP (20 drops) were dissolved in DMF (2.5 mL), and compound 1 (40.0 mg, 53.20 µmol) was added. The reaction mixture was stirred at room temperature for 20 minutes. The reaction was confirmed to be complete by LCMS. Ethyl acetate and water were added, and the mixture was stirred and separated. The organic phase was dried and concentrated under reduced pressure. The residue was purified by reverse HPLC to give compound 2 (20 mg, yield: 46%).

[0148] MS m / z (ESI): 810.3 [M+H] +

[0149] 1 HNMR (400 MHz, DMSO- d 6 ) δ 9.43 (s, 1H), 8.78 (s, 1H), 7.07 (s, 1H), 7.00-6.94 (m, 1H), 6.36 (s, 1H), 6.19-6.15 (m, 3H), 6.06 (s, 2H), 5.58 (t, J = 5.8 Hz, 1H), 4.98 (d, J = 7.3 Hz, 1H), 4.80-4.77 (m, 1H), 4.62-4.45 (m, 3H), 4.16-4.09 (m, 3H), 3.91 (d, J = 5.8 Hz, 2H), 3.72-3.64 (m, 1H), 3.64 (s,3H), 3.28 (d, J = 4.0 Hz, 1H), 2.88-2.79 (m, 1H), 2.56-2.53 (m, 1H), 2.48 (s,3H), 2.39 (s, 3H), 2.13 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H).

[0150] Example 2: Preparation of Compound 3

[0151] Iodine (5 mg, 0.02 mmol), triphenylphosphine (5 mg, 0.02 mmol), and imidazole (5 mg, 0.07 mmol) were dissolved in anhydrous tetrahydrofuran (1 mL) at 0 °C. After reacting the solution at 0 °C for 15 min, compound 1-1 (5 mg, 0.007 mmol) was added, and the reaction solution was stirred in an ice bath for 20 min. After filtration, the reaction solution was directly purified by reverse-phase MPLC to obtain compound 3 (1.1 mg, yield 22.4%).

[0152] MS m / z (ESI): 738.2 [M+H] +

[0153] 1 HNMR (400 MHz, DMSO- d 6 ) δ 8.87 (s, 1H), 7.21 (s, 1H), 6.67 (s, 1H),6.54 – 6.35 (m, 2H), 6.24 (s, 1H), 6.15 – 6.04 (m, 2H), 6.01 – 5.85 (m, 2H),5.33 (s, 1H), 5.13 (d, J = 11.7 Hz, H), 4.93 (d, J = 7.2 Hz, H), 4.89 (s, H), 4.45 (s, H), 4.21 (s, H), 4.05 (d, J = 7.8 Hz, 2H), 3.91 (d, J = 6.0 Hz, 1H), 3.64 (s, 3H), 3.20 (s, 2H), 2.36 – 2.23 (m, 6H), 2.00 (dd, J = 21.7, 14.2 Hz, 8H).

[0154] Example 1 of efficacy test: In vitro proliferation inhibition test of compounds on OVCAR-3 and BT474 tumor cells

[0155] Test objective

[0156] To detect the inhibitory activity of the drug compound on the in vitro proliferation of OVCAR-3 and BT474 tumor cells, cells were treated with different concentrations of the compound in vitro. After 6 days of culture, cell proliferation was detected using the CTG (CellTiter-Glo® Luminescent CellViability Assay, Promega, catalog number: G7558) reagent, and the results were analyzed based on the IC50 value. 50 The value is used to evaluate the in vitro activity of the compound.

[0157] Experimental methods (using OVCAR3 as an example)

[0158] 1. Cell culture: OVCAR-3 cells were cultured in 10% FBS RPMI-1640 medium.

[0159] 2. Cell preparation: Take OVCAR-3 cells in the logarithmic growth phase, wash them once with PBS, add 2-3 ml of trypsin to digest for 2-3 min. After the cells are completely digested, add 10-15 ml of cell culture medium to wash off the digested cells, centrifuge at 1000 rpm for 5 min, discard the supernatant, and then add 10-20 ml of cell culture medium to resuspend the cells to prepare a single-cell suspension.

[0160] 3. Cell plating: Mix the OVCAR-3 single-cell suspension thoroughly, and adjust the viable cell density to 6 × 10⁶ cells / year using cell culture medium. 4 Cells / ml: After adjusting the cell density, mix the cell suspension thoroughly and add 50 μL / well to a 96-well cell culture plate. Incubate the plate in an incubator for 18 hours (37°C, 5% CO2).

[0161] 4. Compound preparation: Dissolve the compound in DMSO to prepare a stock solution with an initial concentration of 10 mM. There are 9 concentrations of small molecule compounds, with the highest concentration being 1 μM, diluted 3 times.

[0162] 5. Sample addition procedure: Add the prepared test samples of different concentrations to the culture plate, with two replicates for each sample. Incubate the culture plate in an incubator for 6 days (37℃, 5% CO2).

[0163] 6. Color development procedure: Take out the 96-well cell culture plate, add 50 μL of CTG reagent to each well, and incubate at room temperature for 10 minutes.

[0164] 7. Plate reading procedure: Take out the 96-well cell culture plate, place it in the microplate reader, and use the microplate reader to measure the chemiluminescence.

[0165] Data analysis: The data was processed and analyzed using Microsoft Excel and Graphpad Prism 9.

[0166] Table 1. IC50 of the compounds in this application for inhibiting the in vitro cell proliferation of the aforementioned cells. 50 value

[0167] Conclusion: The results show that the compound in this application has strong inhibitory activity against the proliferation of OVCAR-3 and BT474 cells, and its activity is superior to that of the control compound trabectedin.

Claims

1. A jugillin-like compound, characterized in that, It is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: in, Q 1 For N or CR 12 ; Q 2 For N or CR 11 ; R 1 R 11 R 12 and R 2 Independently hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -N(R) 1-1 )-R 1 -2 -N(R) 1-1 )-S(O)2-R 1-2 -C 1-6 Alkylene-N(R) 1-1 )-C(O)R 1-2 -OC 3-12 Cycloalkyl, -O- (4 to 12-membered heterocyclic alkyl), -O- (4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -OC 3-12 Cycloalkyl-N(R) 1-1 )-C(O)R 1-2 -N(R) 1-1 )-C(O)R 1-2 -C(O)R 1-2 -OC(O)-N(R) 1-1 )R 1-2 -N(R) 1-1 )-C(O)-OR 1-2 -N(R) 1-1 )-C(O)-N(R 1-1 )R 1-2 -N(R) 1-1 )-(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -N(R) 1-1 )-C 3-12 Cycloalkyl-N(R) 1-3 )-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-C(O)R 1-2 -(4 to 12-membered heterocyclic alkylene)-N(R 1-1 )-C(O)R 1-2 or -N(R) 1-1 )C(O)-C 1-6 Alkylene-R 1-2 The C mentioned 1-6 Alkyl, C 1-6 Alkylene, C 3-12 cycloalkyl, C 3-12 Cycloalkylene, 4- to 12-membered heterocycloalkylene, and 4- to 12-membered heterocycloalkyl are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 alkylene -OH, -C 1-6 Alkylene -SH, -C 1-6 Alkylene-S(C 1-6 alkyl) and -C 1-6 Substitution of alkylene-NH2; Or, R 1 With R 11 Together with their respective attached atoms, they are conceived as 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl; each of the cycloalkyl or heterocycloalkyl is optionally bonded by one or more atoms selected from halogens, -C 1-6 Alkyl substituents; R 3 For hydrogen, deuterium, -C 1-6 Alkyl, -CH2-NR 3-1 R 3-2 -CH2-NR 3-1 C(O)R 3-2 -CH2-OC(O)-NR 3-1 R 3-2 -CH2-NR 3-1 C(O)-OR 3-2 -CH2-NR 3-1 C(O)NR 3-1 R 3-2 -CH2-N(R) 3-1 )C(O)R 3-2 -CH2-N(R) 3-1 )C(O)-C 1-6 Alkylene-R 3-2 or -C(O)-R 3-2 The C mentioned 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -O-NH-CH3, -NHC 1-6 Alkyl and -SC 1-6 Alkyl substituents; R 4 For hydrogen, deuterium, -C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 3-12 Cycloalkyl or -C(O) (4 to 12-membered heterocycloalkyl), wherein the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally separated by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents; Or R 3 With R 4 Together with the atoms attached thereto, they form 5-12 membered heterocyclic alkyl groups; each of the 5-12 membered heterocyclic alkyl groups is optionally bonded by one or more groups selected from halogen, oxo group, -OH, -CN, -NH2, -NHC. 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -C 1-6 Alkyl, -C 1-6 Alkylene -OH, -C(O)C 1-6 Alkylene -OH, -C(O)-C 3-12 Substituents of cyclohexene alkyl-OH and -C(O)-(4 to 12-membered heterocyclohexene alkyl)-OH; R 1-1 R 3-1 Each is independently hydrogen, deuterium, and C. 1-6 Alkyl or halogenated C 1-6 alkyl; R 1-2 R 3-2 Each independently is C 1-6 Alkyl, C 3-12 Cycloalkyl or 4- to 12-membered heterocyclic alkyl; the C 1-6 Alkyl, C 3-12 The cycloalkyl group and the 4- to 12-membered heterocycloalkyl group are each optionally selected independently from one or more halogens, -OH, -SH, -NH2, -O-NH-CH3, C 3-6 cycloalkyl, -NHC 1-6 Alkyl and -SC 1-6 Alkyl substituents; Y can be either -OH or -CN.

2. The succarpine-like compound as described in claim 1, characterized in that, It satisfies at least one of the following conditions: (1) R 1 -NH2, -C 1-6 Alkylene-N(R) 1-1 )-C(O)R 1-2 -N(R) 1-1 )-R 1-2 -O-(4 to 6-membered heterocyclic alkylene)-C(O)R 1-2 -OC 3-6 Cycloalkyl-N(R) 1-1 )-C(O)R 1-2 -N(R) 1-1 )-(4 to 6-membered heterocyclic alkylene)-C(O)R 1-2 -(4 to 6-membered heterocyclic alkylene)-C(O)R 1-2 -(4 to 6-membered heterocyclic alkylene)-N(R 1-1 )-C(O)R 1-2 or -N(R) 1-1 )-C(O)R 1-2 The C mentioned 1-6 Alkylene, C 3-6 The cycloalkyl group or 4- to 6-membered heteroalkyl group is optionally surrounded by one or more elements selected from halogen, -OH, -SH, -NH2, -NHC. 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 alkylene -OH, -C 1-6 Alkylene -SH, -C 1-6 Alkylene-S(C 1-6 alkyl) and -C 1-6 Substitution of alkylene-NH2; (2) R 1-1 It is hydrogen, deuterium or C 1-6 alkyl; (3) R 1-2 C 1-6 Alkyl, C 3-6 Cycloalkyl or 4- to 6-membered heterocyclic alkyl; the C 1-6 Alkyl, C 3-6 The cycloalkyl group or 4- to 6-membered heterocycloalkyl group is optionally surrounded by one or more elements selected from halogen, -OH, -O-NHCH3, -SH, -NH2, cyclopropyl, -NHC 1-6 Alkyl and -SC 1-6 Alkyl substituents; (4) R 2 Hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, the C 1-6 Each alkyl group is optionally surrounded by one or more elements selected from halogens, -OH, -SH, -NH2, and -NHC. 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 alkylene -OH, -C 1-6 Alkylene -SH, -C 1-6 Alkylene-S(C 1-6 alkyl) and -C 1-6 Substitution of alkylene-NH2; (5) R 3-1 It is hydrogen, deuterium or C 1-6 alkyl; (6) R 3-2 C 1-6 Alkyl, C 3-6 Cycloalkyl or 4- to 6-membered heterocyclic alkyl; the C 1-6 Alkyl, C 3-6 The cycloalkyl group or 4- to 6-membered heterocycloalkyl group is optionally surrounded by one or more elements selected from halogen, -OH, -O-NHCH3, -SH, -NH2, cyclopropyl, -NHC 1-6 Alkyl and -SC 1-6 Alkyl substituents; (7) R 3 For hydrogen, deuterium, -C 1-6 Alkyl, -CH2-NH2, -CH2-NH-C 1-6 Alkyl group, -CH2-N(C) 1-6 alkyl)-C 1-6 Alkyl group, -CH2-NHC(O)-C 1-6 Alkyl or -CH2-N(C) 1-6 Alkyl)C(O)-C 1-6 Alkyl, the C 1-6 Each alkyl group is optionally surrounded by one or more elements selected from halogens, -OH, -SH, -NH2, and -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents; (11) R 11 Hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl or -NHC 1-6 alkyl; (12) R 12 Hydrogen, deuterium, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl or -NHC 1-6 alkyl; (13) R 4 For hydrogen, deuterium, C 1-6 Alkyl or -C(O)C 1-6 Alkyl, the C 1-6 The alkyl group is optionally surrounded by one or more elements selected from halogens, -OH, -SH, -NH2, and -NHC. 1-6 Alkyl and -SC 1-6 Alkyl substituents.

3. The succulentinoid compound as described in claim 1, characterized in that, It satisfies at least one of the following conditions: (1) R 1 -NH2, -N(R) 1-1 )-R 1-2 or -N(R) 1-1 )-C(O)R 1-2 ; (2) R 1-1 It is hydrogen, deuterium, or -CH3; preferably, R 1-1 It is hydrogen or -CH3; (3) R 1-2 C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from -OH, cyclopropyl, or -O-NHCH3; preferably, R 1-2 C 1-6 Alkyl-OH, C 1-6 Alkyl-O-NHCH3 or C 1-6 Alkyl (C) 3-6 cycloalkyl)-OH; (4) R 2 It is hydrogen, deuterium, halogen, -OH, -CN, -NH2, -CH3, -OCH3 or -NHCH3; preferably, R 2 It can be hydrogen, deuterium, or -OCH3; (5) R 3-1 It is hydrogen, deuterium, or -CH3; preferably, R 1-1 It is hydrogen or -CH3; (6) R 3-2 -C 1-6 alkylene-OH; preferably, R 3-2 -C 1-3 alkylene-OH; (7) R 3 It can be hydrogen, deuterium, -CH3, or -CH2-NHCH3; (8) R 11 It is hydrogen, deuterium, -F, -Cl, -OH, -CH3, -OCH3, -NH2 or -NHCH3; preferably, R 11 It can be hydrogen, deuterium, or -OCH3; (9) R 12 It is hydrogen, deuterium, -F, -Cl, -OH, -CH3, -OCH3, -NH2 or -NHCH3; preferably, R 12 It is hydrogen; (10) R 4 It can be hydrogen, deuterium, or -CH3.

4. The succulentinoid compound as described in claim 1, characterized in that, It satisfies at least one of the following conditions: (1) R 1 -NH2, , , or ; (2) R 2 It is hydrogen; (3) R 3 It is hydrogen; (4) R 4 It is hydrogen or -CH3; (5) Y is CN.

5. The succulentinoid compound as described in claim 2, characterized in that, The compounds with the structure shown in formula (I) are compounds as shown in formulas (II) and (III): Among them, R 1 R 11 R 2 R 3 R 4 Y is as defined in any one of claims 1-4.

6. The succarpine-like compound as described in claim 5, characterized in that, The compounds shown in formulas (I), (II), and (III) are compounds with the structures shown in formulas (II-1) and (III-1). Among them, R 1 -NH2, -N(R) 1-1 )-R 1-2 or -N(R) 1-1 )-C(O)R 1-2 ; R 1-1 It can be hydrogen, deuterium, or -CH3; R 1-2 C 1-6 Alkyl; the C 1-6 Each alkyl group may optionally be substituted by one or more substituents selected from -OH, cyclopropyl, or -O-NHCH3; R 4 It can be hydrogen, deuterium, or -CH3; Y can be either -OH or -CN.

7. The succarpine-like compound as described in claim 1, characterized in that, The compound has any of the following structures: 、 、 、 、 、 、 。 8. A compound with the structure shown below: 。 9. A pharmaceutical composition, characterized in that, It comprises a sucrose compound as described in any one of claims 1-7, and one or more pharmaceutically acceptable carriers.

10. Use of a substance in the preparation of a medicament for the prevention or treatment of tumors or cancer, characterized in that, The substance is a sucrose compound as described in any one of claims 1-7 or a pharmaceutical composition as described in claim 9; The tumor or cancer mentioned is preferably breast cancer or ovarian cancer.

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