Non-glycoside diphyllin derivative as well as preparation method and application thereof

Abstract

The invention discloses a non-glycoside diphyllin derivative as shown in a formula (I), and a pharmaceutically acceptable salt or solvate of the non-glycoside diphyllin derivative. The invention also discloses a preparation method and an intermediate of the compound, a pharmaceutical composition containing the compound and application of the compound. The non-glycoside diphyllin derivative disclosed by the invention has excellent anti-tumor cell growth activity and can be used as an anti-tumor drug. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry and pharmacology, and specifically relates to a non-glycoside schizofiarin derivative, a pharmaceutically acceptable salt or solvate thereof, and a preparation method and use thereof. Background Art

[0002] Diphyllin (DP) is a naphthyl lignan with a 4-hydroxyl group isolated from Diphyllin. It has received increasing attention due to its wide range of biological activities, including antiviral, antitumor, anti-inflammatory, antioxidant and antibacterial effects. In particular, its safety and significant anticancer properties have attracted the attention of researchers in recent years. Diphyllin exhibits a wide range of antiproliferative activities against various cancer cell lines, including lymphocytic leukemia, colorectal cancer, gastric adenocarcinoma, liver cancer, cervical cancer, ovarian cancer, head and neck cancer, etc. It is reported that naturally occurring or synthetic glycosylated diphyllin derivatives have significant antitumor properties. For example, the natural lignan D-xylose glycoside Cleistanthin A and D-quinoside Patentiflorin A both have strong antitumor activity, and the in vitro inhibition of tumor cell proliferation activity IC 50 The value is at the nanomolar level; for example, the recently reported glycoside derivative PHY34 was found to induce late autophagy inhibition by inhibiting the activity of V-ATPase and apoptosis susceptibility protein (CAS), thereby reducing the tumor burden of high-grade serous ovarian cancer. However, these glycoside derivatives are hampered as anti-tumor therapeutic agents due to their low water solubility and poor metabolic stability. The glycosidic bond has poor metabolic stability in the human body and is easily inactivated by endogenous glycosidase hydrolysis, and the chemical synthesis is relatively complex. Therefore, there is an urgent need to structurally modify this abundant natural product to obtain a sanguine derivative with excellent metabolic stability and strong tumor cell proliferation inhibition activity.

[0003] Summary of the invention

[0004] The object of the present invention is to provide a non-glycoside structure of schizofia schizofia derivatives, and pharmaceutically acceptable salts or solvates thereof. Such compounds do not contain glycosidic bonds that are easily hydrolyzed in the body, are metabolically stable and have excellent tumor cell proliferation inhibitory activity.

[0005] In the first aspect of the present invention, there is provided a non-glycoside sarmentin derivative as shown in formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0006]

[0007] When Z 2 When Z does not exist, 1, Z 3 Independently selected from CORb, Rb;

[0008] Each Rb is independently selected from hydrogen, halogen, -OH, -CN, -NH 2 、-(C=O)OH、-SO 3 H, -(C1-C3 alkylene)OH, -(C=O)O(C1-C6 alkyl), -O(C=O)(C1-C6 alkyl), -(C=O)NH 2 、-(C=O)NH(C1-C6 alkyl)、-(C=O)N(C1-C6 alkyl) 2 , C1-C6 alkyl, -O(C1-C6 alkyl), -O(C1-C3 alkylene)O(C1-C6 alkyl), -S(C1-C6 alkyl), -(C1-C3 alkylene)S(C1-C6 alkyl), -SO 2 O(C1-C6 alkyl), -SO 2 NH(C1-C6 alkyl), -SO 2 N(C1-C6 alkyl) 2 、-NH(C1-C6 alkyl)、-N(C1-C6 alkyl) 2 、-(C1-C3 alkylene)NH(C1-C6 alkyl)、-(C1-C3 alkylene)N(C1-C6 alkyl) 2 , -(C1-C6 alkyl)(C1-C3 alkylene)N(C1-C6 alkyl) 2 , a substituted or unsubstituted 3-12 membered alkyl ring group, a substituted or unsubstituted 3-12 membered heteroalkyl ring group, a substituted or unsubstituted 5-10 membered aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group;

[0009] "" indicates absence, single key or double key;

[0010] Unless otherwise specified, the term "substituted" means that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen, -OH, -CN, -NO 2 、-NH 2 , -NCO, -OCN, -SCN, -NCS, -N 3 , oxo (=O), -CF 3 、-(C1-C3 alkylene)OH、-O(C1-C3 alkyl)、-S(C1-C3 alkyl)、-C(O)X'R 4 or -X'C(O)R 5 、-SO 3 R 4 、-OSO 2 OR 4 、-NR 6 SO 2OR 5 、-NR 6 R 7 、-SO 2 NR 6 R 7 、-NH-SO 2 -R 6 、-N + R 6 R 7 R 8 、-C(O)N(R 9 ) 2 、-SO 2 R 10 、-NR 11 C(O)N(R 11 ) 2 、-B(OH) 2 、-B(O(C1-C6 alkyl or alkylene)) 2 、-P(O)(OH) 3 、-OP(O)(OC1-C3 alkyl) 2 , C1-C6 alkyl, C2-C6 unsaturated alkyl, 3-12-membered alkyl ring group, 3-12-membered heteroalkyl ring group, 5-10-membered aryl, 3-12-membered aromatic heterocyclic group, 3-12-membered heterocyclic group, -(C1-C3 alkylene)-3-12-membered heterocyclic ring;

[0011] X' is a chemical bond or oxygen or sulfur, R 4 R is independently selected from hydrogen, C1-C6 alkyl, C2-C8 alkenyl, 3-12 membered alkyl ring, 5-10 membered aryl, 3-12 membered heterocyclic group, 5 Independently selected from hydrogen, C1-C6 alkyl, C2-C8 alkenyl, 3-12 membered alkyl ring group, 5-10 membered aryl group, 3-12 membered heterocyclic group;

[0012] R 6 , R 7 and R 8 Each independently selected from hydrogen, C1-C6 alkyl, C2-C8 alkenyl, -C(O)X'R 4 or -X'C(O)R 5 , or R 6 and R 7 Together with the nitrogen atom to which they are attached, they form a 4-8 membered heterocyclic ring; wherein R 6 or R 7 Not all -C(O)X'R 4 or -X'C(O)R 5 ;

[0013] R 9 are independently selected from hydrogen or C1-C6 alkyl, or two R9 Together with the N atom to which they are attached, they form a 4-8 membered heterocyclic ring;

[0014] R 10 Independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered alkyl ring group, 3-12 membered heterocyclic group, 5-10 membered aryl group;

[0015] R 11 are independently selected from hydrogen, C1-C6 alkyl, or two R 11 Together with the N atom to which they are attached, they form a 4-8 membered heterocyclic ring;

[0016] Wherein, the heteroalkyl ring and the aromatic heterocyclic ring each independently have 1-3 (preferably 1, 2 or 3) heteroatoms selected from N, O and S.

[0017] In another preferred embodiment, R 1 It is independently a substituted or unsubstituted 6-10 membered aryl group, a substituted or unsubstituted 5-6 membered heteroaryl group, or a substituted or unsubstituted 8-12 membered fused heterocyclic group, wherein the substitution means that one or more (e.g., 1, 2, 3) hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen, hydroxyl, cyano, or C1-C3 alkyl.

[0018] In another preferred embodiment, R 1 Independently selected from substituted or unsubstituted 6-membered aryl groups,

[0019]

[0020] In another preferred embodiment, R 1 and R is independently a substituted or unsubstituted 6-membered heteroaryl.

[0021] In another preferred embodiment, R 1 and independently a substituted or unsubstituted 6-membered nitrogen-containing heteroaryl group.

[0022] In another preferred embodiment, R 1 Independently selected from substituted or unsubstituted 6-membered heteroaryl groups:

[0023]

[0024] In another preferred embodiment, R 1 and independently a substituted or unsubstituted 8-12 membered fused heterocyclic group.

[0025] In another preferred embodiment, R 1 and independently a substituted or unsubstituted 9-10 membered fused heterocyclic group.

[0026] In another preferred embodiment, R 1and R is independently a substituted or unsubstituted 9-10 membered benzoaryl or a substituted or unsubstituted 9-10 membered benzoheterocyclyl.

[0027] In another preferred embodiment, R 1 Independently selected from substituted or unsubstituted 8-12 membered fused heterocyclic groups, the following group:

[0028]

[0029] In another preferred embodiment, R 2 Independently selected from H or C1-C6 alkyl.

[0030] In another preferred embodiment, R 2 Independently selected from C1-C6 alkyl, preferably -CH 3 .

[0031] In another preferred embodiment, R 3 Independently selected from or

[0032] In another preferred embodiment, Rc is independently selected from halogen, preferably F.

[0033] In another preferred embodiment, the compound has a structure of the following formula (Ia), formula (Ib) or formula (Ic):

[0034]

[0035] Among them, R 1 , R 2 , R 3 , Ra, Rb, Z 1 , Z 2 , Z 3 , nAs described above.

[0036] In another preferred embodiment, Cy is preferably a 6-membered aromatic ring substituted with (Ra)n.

[0037] In another preferred embodiment, each Ra is independently selected from halogen, -OH, -SH, -CN, -NH 2 -、-NO 2 , -(C1-C3 alkylene)OH, C1-C6 alkyl, -O(C1-C6 alkyl), -O(C1-C3 alkylene)O(C1-C6 alkyl), -S(C1-C6 alkyl), -S(C1-C3 alkylene)S(C1-C6 alkyl), -NH(C1-C6 alkyl), -NH(C1-C3 alkylene)NH(C1-C6 alkyl), -N(C1-C6 alkyl) 2 、-NH(C1-C3 alkylene)N(C1-C6 alkyl) 2, -N(C1-C6 alkyl)(C1-C3 alkylene)N(C1-C6 alkyl) 2 , or two Ra form a substituted or unsubstituted 3-12 membered alkane ring, or a substituted or unsubstituted 3-12 membered heterocyclic ring through two adjacent C atoms on Cy.

[0038] In another preferred embodiment, each Ra is preferably independently -O-(C1-C6 alkyl) or -O-(C1-C3 alkylene)-O-(C1-C6 alkyl).

[0039] In another preferred embodiment, each Ra is preferably independently -O-(C1-C3 alkyl).

[0040] In another preferred embodiment, n is preferably 2.

[0041] In another preferred embodiment, when n is 2, each Ra may be the same or different.

[0042] In another preferred embodiment, each Ra is preferably a methoxy group.

[0043] In another preferred embodiment, when Z 1 , Z 2 , Z 3 When both exist, Z 1 , Z 2 , Z 3 Each independently selected from CH 2 , NH, O, S, SO 2 、C=O、CHRb、C(Rb) 2 、NRb.

[0044] In another preferred embodiment, when Z 1 , Z 2 , Z 3 When both exist, Z 1 , Z 2 , Z 3 Each independently selected from CH 2 、O、C=O、CHRb、C(Rb) 2 .

[0045] In another preferred embodiment, when Z 2 When it does not exist, "------------" means it does not exist, no ring structure is formed, and the benzene ring is directly replaced by Z 1 , Z 3 Replace, that is, the following structure

[0046] In another preferred embodiment, when Z 2 When Z does not exist, 1 , Z 3Each is independently selected from CORb, Rb.

[0047] In another preferred embodiment, each Rb is independently selected from hydrogen atom, halogen, -OH, -CN, -NH 2 、-(C=O)OH、-SO 3 H, -(C1-C3 alkylene)OH, -(C=O)O(C1-C6 alkyl), -O(C=O)(C1-C6 alkyl), -(C=O)NH 2 、-(C=O)NH(C1-C6 alkyl)、-(C=O)N(C1-C6 alkyl) 2 , C1-C6 alkyl, -O(C1-C6 alkyl), -O(C1-C3 alkylene)O(C1-C6 alkyl), -S(C1-C6 alkyl), -(C1-C3 alkylene)S(C1-C6 alkyl), -SO 2 O(C1-C6 alkyl), -SO 2 NH(C1-C6 alkyl), -SO 2 N(C1-C6 alkyl) 2 、-NH(C1-C6 alkyl)、-N(C1-C6 alkyl) 2 、-(C1-C3 alkylene)NH(C1-C6 alkyl)、-(C1-C3 alkylene)N(C1-C6 alkyl) 2 , -(C1-C6 alkyl)(C1-C3 alkylene)N(C1-C6 alkyl) 2 .

[0048] In another preferred embodiment, Rb is independently selected from 3-12 membered alkyl ring group, 3-12 membered heteroalkyl ring group, 5-10 membered aryl group, 5-10 membered heteroaryl group.

[0049] In another preferred embodiment, when Z 1 , Z 2 , Z 3 When both exist, Z 1 , Z 2 , Z 3 Each independently selected from CH 2 ,O,C=O.

[0050] In another preferred embodiment, the compound has the structure of the following formula (Id) or formula (Ie):

[0051]

[0052] Among them, R 1 , R 2 , Rc are as described above.

[0053] In another preferred embodiment, the term "substituted" refers to one or more hydrogen atoms on the group being replaced by a substituent selected from the group consisting of halogen, -OH, -CN, -NH 2 , C1-C3 alkyl, -O(C1-C6 alkyl).

[0054] In another preferred embodiment, R 1 , R 2 , R 3 、Ra、Rb、Rc、Z 1 , Z 2 , Z 3 , n are each independently the corresponding group in Compound 1-31.

[0055] In another preferred embodiment, the compound is selected from the following group:

[0056]

[0057]

[0058] In another preferred embodiment, the compound is the compound shown in the examples.

[0059] IC of the whole compound of the present invention at the HT-29 cell level 50 The range of the survival rate is small, and most of them are in the range of A<50nM, with excellent activity; at the same time, the compound has excellent anti-proliferative activity against three typical RAS mutation cell lines of colorectal cancer, which is much better than the positive reference and the activity can reach the nanomolar level, which shows that the compound of the present invention has a good effect on colorectal cancer cell lines with different mutations, and is expected to have great clinical application value; in terms of pharmacokinetic, some embodiments of the present invention have a higher peak concentration C max and oral exposure AUC, it has good drugability and potential for further development, and is very significant in optimizing the physicochemical properties of natural products.

[0060] In the second aspect of the present invention, a method for preparing a non-glycoside schizofiarin derivative as shown in formula (I) is provided, wherein the method comprises the steps of:

[0061]

[0062] a) Compound 1 reacts with trifluoromethanesulfonic anhydride to obtain Compound 2;

[0063] b) Compound 2 is subjected to Suzuki reaction, alkaline hydrolysis reaction and amine condensation reaction in sequence to obtain a compound of formula I.

[0064] Among them, R 1 , R 2 , Rc are defined as above.

[0065] In the third aspect of the present invention, a pharmaceutical composition is provided, comprising the compound described in the first aspect, a pharmaceutically acceptable salt, prodrug or solvate thereof; and a pharmaceutically acceptable carrier.

[0066] In the fourth aspect of the present invention, a method for preparing a pharmaceutical composition is provided, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of the first aspect of the present invention, its pharmaceutically acceptable salt, prodrug or solvate, thereby forming a pharmaceutical composition.

[0067] In the fifth aspect of the present invention, there is provided use of the compound as described in the first aspect of the present invention, or a pharmaceutically acceptable salt, prodrug or solvate thereof, for preparing a drug for treating and / or preventing tumor-related diseases.

[0068] In another preferred embodiment, the tumor includes but is not limited to breast cancer, cervical cancer, endometrial cancer, ovarian cancer, colon cancer, rectal cancer, pancreatic cancer, liver cancer, lung cancer, non-small cell lung cancer, brain metastasis of lung cancer, oral squamous cell carcinoma, head cancer, neck cancer, head and neck cancer, oral or nasal mucosal cancer, laryngeal cancer, kidney cancer, renal cell carcinoma, ovarian cancer, spleen cancer, small intestine cancer, large intestine cancer, gastric cancer, esophageal cancer, esophageal cancer, lung squamous cell carcinoma, bile duct cancer, gallbladder cancer, melanoma, urothelial carcinoma, urogenital tract cancer, genital cancer, prostate cancer, testicular cancer, bladder cancer, blood cancer, skin cancer, bone marrow cancer, brain cancer, central nervous system cancer, muscle tissue cancer, thyroid cancer, or a combination thereof.

[0069] In another preferred embodiment, the tumor disease is selected from colon cancer, rectal cancer, and colorectal cancer.

[0070] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0071] After long-term and in-depth research, the inventors screened and obtained a class of novel non-glycoside schizofiarin derivatives. The non-glycoside schizofiarin derivatives have excellent tumor cell proliferation inhibition activity and excellent oral pharmacodynamic properties, and can be used to prepare a pharmaceutical composition for preventing and / or treating cell proliferation diseases. Based on the above findings, the inventors completed the present invention.

[0072] the term

[0073] The term "halogen" is meant to include, for example but not limited to, radioactive and non-radioactive forms of fluorine, chlorine, bromine, iodine, etc. In a preferred embodiment, the halogen is selected from fluorine, chlorine and bromine.

[0074] The term "C1-C6 alkylene" refers to an alkyl group having a specified number of carbon atoms, such as 1 to 6 carbon atoms, which contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene include methylene-(CH 2 )-, ethylene-(CH 2 CH 2 )-、n-propylene-(CH 2 CH 2 CH 2 )-, isopropylidene-(CH 2 CH(CH 3 ))-, etc. The alkylene group may be a cyclic or acyclic, branched or unbranched carbon chain portion, and may be optionally substituted with one or more substituents.

[0075] The term "C1-C6 alkyl" refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety, and an alkyl group having 1 to 6 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, and those moieties which are positional isomers of these moieties. The alkyl group may be substituted or unsubstituted.

[0076] The term "C2-C6 unsaturated alkyl" refers to a straight or branched alkyl group containing double bonds or triple bonds having a certain number of carbon atoms. The unsaturated alkyl group may be an alkenyl group, an alkynyl group or a dienyl group, for example, a C2-C6 unsaturated alkyl group includes a C2-C6 alkenyl group, a C2-C6 alkynyl group or a C2-C6 dienyl group, and may be optionally substituted with one or more substituents.

[0077] The term "3-12 membered cycloalkyl" refers to a non-aromatic group (including saturated, partially saturated or unsaturated groups) having 3 to 12 carbon atoms, having a monocyclic ring or a condensed ring (including a bridged ring system and a spirocyclic system). Therefore, the alkane ring or alkane ring group can be a saturated alkane ring or an unsaturated alkane ring. In the condensed ring system of a saturated alkane ring, one or more rings are saturated alkane rings. In the condensed ring system of an unsaturated alkane ring, one or more rings can be a saturated alkane ring or an unsaturated alkane ring.

[0078] The term "3-12 membered heteroalkyl ring group" refers to a 3-12 membered non-aromatic group (including saturated, partially saturated or unsaturated groups) containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, including a monocyclic or polycyclic system, wherein the polycyclic system can be a fused ring, a bridged ring system and a spirocyclic system. In the fused ring system, one or more rings can be an alkyl ring group, an aryl group or a heteroaryl group.

[0079] The term "5-10 membered aromatic ring group" includes 5 to 10 membered substituted or unsubstituted monocyclic aromatic groups, wherein each atom of the ring is carbon (i.e., carbocyclic aromatic group). Preferably, the aromatic group includes 5- to 10-membered rings, more preferably 6- to 10-membered rings, such as phenyl and naphthyl.

[0080] The term "3-12 yuan aromatic heterocyclic group" refers to a 3 to 12 yuan ring structure, more preferably a 5 to 12 yuan ring, more preferably a 5 to 10 yuan ring, and its ring structure includes 1 to 4 heteroatoms (e.g., N, O, S). The heterocycle can be a monocyclic, bicyclic, spirocyclic or polycyclic ring. The heterocyclic group includes, for example, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinoline, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenazine, phenothiazine, furan, phenoxazine, pyrrolidine, oxolane, thiopentane, oxazole, piperidine, piperazine, morpholine, lactone, lactams such as azetidinone and pyrrolidone, Sudan, sultone etc. The heterocycle can be substituted at one or more positions with substituents as described above, for example, halogen, trifluoromethyl, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, imino, amido, cyano, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, and the like.

[0081] The term "heterocyclic group" includes heteroalkylcyclic groups and aromatic heterocyclic groups.

[0082] The term "8-12 membered fused heterocyclic group" refers to a fused ring composed of 8-12 ring atoms formed by the fusion of two or more rings, wherein at least one or more of the rings may be a benzene ring, an aromatic heterocyclic ring or a heteroalkyl ring, and the ring structure contains one or more heteroatoms selected from nitrogen, oxygen and sulfur. The fused heterocyclic group may be 8-12 members, such as 8-10 members, 9-10 members. The fused heterocyclic group includes, but is not limited to, benzofuran, benzothiophene, indole, benzimidazole, benzothiazole, quinoline, isoquinoline, and the like.

[0083] As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of..."

[0084] In the present invention, the term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is a substituent described above, or a substituent appearing in the embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. It will be appreciated by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.

[0085] Unless otherwise specified as "substituted or unsubstituted", the groups described in the present invention may be substituted by substituents selected from the following groups: deuterium, halogen, cyano, nitro, hydroxyl, amino, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-12 membered heteroaryl, and 5-10 membered aryl.

[0086] Unless otherwise specified, the compounds of the present invention and their pharmaceutically acceptable salts may also exist in the form of variants including stereoisomers, enantiomers, diastereomers, atropisomers, optical isomers, racemates, polymorphs, solvates or isotope-labeled compounds, and these variants are also included in the scope of the present invention.

[0087] The "pharmaceutically acceptable salt" is a conventional non-toxic salt formed by the reaction of the compound of formula (I) with an inorganic acid or an organic acid. For example, conventional non-toxic salts can be prepared by the reaction of the compound of formula (I) with an inorganic acid or an organic acid, wherein the inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid and phosphoric acid, and the organic acid includes citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid and isethionic acid, etc. or the compound of the general formula (I) forms an ester with propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, aspartic acid or glutamic acid, and then forms a sodium salt, potassium salt, calcium salt, aluminum salt or ammonium salt with an inorganic base; or the compound of the general formula (I) forms a methylamine salt, ethylamine salt or ethanolamine salt with an organic base; or the compound of the general formula (I) forms an ester with lysine, arginine or ornithine, and then forms a corresponding inorganic acid salt with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid, or a corresponding organic acid salt with formic acid, acetic acid, picric acid, methanesulfonic acid or ethanesulfonic acid.

[0088] Preparation method of compound

[0089] The following schemes and examples describe methods for preparing compounds of formula (I). Raw materials and intermediates are purchased from commercial sources, prepared by known procedures, or otherwise described. In some cases, the order of the steps in executing the reaction scheme may be changed to promote the reaction or to avoid unwanted side reaction products.

[0090] Preferably, the compounds of the present invention can be prepared by the following steps:

[0091]

[0092] a) Compound 1 reacts with trifluoromethanesulfonic anhydride to obtain Compound 2;

[0093] b) Compound 2 is subjected to Suzuki reaction, alkaline hydrolysis reaction and amine condensation reaction in sequence to obtain a compound of formula I.

[0094] Among them, R 1 , R 2 , Rc are as described above.

[0095] Pharmaceutical compositions and methods of administration

[0096] The compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compound of the present invention as the main active ingredient can be used to treat, prevent and alleviate cancer.

[0097] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 0.1-1000 mg of the compound of the present invention per dose, and more preferably, contains 0.5-500 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0098] One or more pharmaceutically acceptable carriers may also be added to the drug of the present invention, including conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field.

[0099] The compounds and pharmaceutical compositions provided by the present invention may be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and may be present in suitable solid or liquid carriers or diluents and in suitable sterile devices for injection or instillation.

[0100] The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The unit dosage of the preparation formula generally contains 0.05-400 mg of the compound of formula (I), preferably, the unit dosage of the preparation formula contains 1 mg-500 mg of the compound of general formula (I).

[0101] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention, and representative administrations include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. A particularly preferred administration is oral.

[0102] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0103] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 0.2 to 1000 mg, preferably 0.5 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0104] The main advantages of the present invention include:

[0105] 1. The present invention provides a novel non-glycoside schizofiarin derivative and a preparation method thereof.

[0106] 2. The non-glycoside schizofiarin derivatives of the present invention have excellent anti-tumor cell proliferation effects, especially on different colorectal cancer cell lines.

[0107] 3. The non-glycoside schizofiarin derivatives of the present invention have excellent pharmacokinetic properties.

[0108] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0109] Preparation of Intermediate A: (E)-1-(Benzo[d][1,3]dioxazol-5-yl)-4-(2-carboxyvinyl)-3-(hydroxymethyl)-6,7-dimethoxy-2-naphthoic acid

[0110]

[0111] Step 1: Dissolve feroxamine (380 mg, 1 mmol) in anhydrous DCM (10 ml), stir at -10 °C for 5 min, and then slowly add Tf 2 O (36 mg, 1.3 mmol) and TEA (1 ml, 7 mmol), the reaction solution was stirred at -10 ° C for 0.5 h. The reaction solution was quenched with water, extracted with DCM (30 ml × 3), and the organic phase was washed with saturated brine. 2 SO 4 After drying, filtration and vacuum concentration, the crude product was purified by flash column chromatography (PE / DCM=10 / 1) to obtain 400 mg of a light yellow solid (A-1). LC-MS: ESI m / z: 513.05 [M+H] + ; 1 HNMR (400MHz, CDCl 3 )δ:7.43(s,1H),7.15(s,1H),6.99(d,J=7.9Hz,1H),6.85(d,J=1.3Hz,1H),6.82(dd ,J=7.9,1.6Hz,1H),6.10(d,J=17.7Hz,1H),5.48(s,2H),4.09(s,3H),3.84(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ:168.2,153.4,151.0,148.1,147.8,140.4,135.7,131.3,131.1,127.0,1 26.3,123.5,119.5,110.4,108.4,106.5,101.5,99.4,65.7,56.2,56.0.19F NMR(376MHz,CDCl 3 )δ-73.4.

[0112] Step 2: Dissolve intermediate A-1 (1 g, 2 mmol) in toluene (10 ml), and add 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-ethyl acrylate (904 mg, 4 mmol), Cs 2 CO 3 (1.3 g, 4 mmol) and Pd(dtbpf)Cl 2 (146 mg, 0.2 mmol), the reaction solution was stirred at 85 °C for 12 h under nitrogen atmosphere. The reaction solution was quenched by adding water (40 ml), extracted with EA (50 ml × 3), and the organic phase was washed with Na 2 SO 4After drying, filtration and vacuum concentration, the crude product was purified by flash column chromatography (EA / PE=4 / 1) to obtain 0.8 g of a yellow solid (A-2). LC-MS: ESI m / z: 463 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ8.31(d,J=16.2Hz,1H),7.40(s,1H),7.15(s,1H),6.98(d,J=7.9Hz,1H),6.84(d,J=1.3Hz,1H),6.82(dd,J=7.9,1.6Hz,1H),6.2 9(d,J=16.2Hz,1H),6.11(d,J=1.3Hz,1H),6.06(d,J=1.3Hz,1H),5.46(s,2 H), 4.35 (q, J = 7.1Hz, 2H), 4.09 (s, 3H), 3.82 (s, 3H), 1.40 (t, J = 7.1Hz, 3H).

[0113] Step 3: Dissolve intermediate A-2 (0.8 g, 1.7 mmol) in THF / H 2 O (10 / 1, 11 ml) solution, add LiOH·H 2 O (357 mg, 8.5 mmol), the reaction solution was stirred at room temperature for 1 h. HCl (2 M) was added to the reaction solution to adjust the pH to 5, and EA (30 ml × 3) was used for extraction. The organic phase was purified by Na 2 SO 4 After drying, filtration and vacuum concentration, 0.8 g of a light yellow solid (A) was obtained. LC-MS: ESI m / z: 453.1 [M+H] + .

[0114] Preparation of Intermediate B: (E)-4-(2-carboxyvinyl)-1-(7-fluorobenzo[d][1,3]dioxazol-5-yl)-3-(hydroxymethyl)-6,7-dimethoxy-2-naphthoic acid

[0115]

[0116] Step 1: Dissolve 2-(2-bromo-4,5-dimethoxyphenyl)-1,3-dioxolane (2.5 g, 8.70 mmol) in anhydrous THF (15 ml), slowly add n-butyl lithium (3 ml, 2.5 M) solution to the solution at -65 to -78 °C in a nitrogen atmosphere, and heat the mixture to room temperature and stir for 2 h. The reaction solution was quenched by adding water (30 ml) at 0 °C, extracted with ether (30 mL × 3), and the organic phase was purified by Na 2 SO 4After drying, filtration and vacuum concentration, 2.3 g of yellow solid (B-1) was obtained. LC-MS: ESI m / z: 379 [M+H] + .

[0117] Step 2: Dissolve intermediate B-1 (2.3 g, 6.1 mmol) in HOAc (20 mL), add DEADC (1.20 mL, 6.1 mmol) to the solution, and stir the mixture at 140 °C for 1 h. Add saturated NaHCO 3 The solution was adjusted to pH 7, extracted with EA (30 mL × 3), and the organic phase was purified by Na 2 SO 4 Dry, filter and concentrate in vacuo, and purify the crude product by silica gel column chromatography to obtain 1.5 g of yellow solid (B-2). LC-MS: ESI m / z: 487 [M+H] + .

[0118] Step 3: Dissolve B-2 (1.5 g, 3.1 mmol) in methanol (20 mL), add sodium borohydride (1.2 g, 32.8 mmol) to the solution in batches at 0°C, and stir the mixture at room temperature for 2 h. Add 6 M hydrochloric acid to the reaction solution at 0°C to adjust pH = 2, extract with EA (30 mL x 3), and the organic phase is purified by Na 2 SO 4 Dry, filter and concentrate in vacuo, and purify the crude product by silica gel column chromatography (EA / PE=4 / 1) to obtain 1 g of yellow solid (B-3). LC-MS: ESI m / z: 399 [M+H] + .

[0119] The method for preparing intermediate B from intermediate B-3 refers to the synthesis of intermediate A. 760 mg of light yellow solid (B) was obtained. LC-MS: ESI m / z: 471.1 [M+H] + .

[0120] General method for preparing Examples 1 to 31:

[0121] Intermediate A or B (50 mg, 0.1 mmol) was dissolved in DCM (2 ml), and N, N, N', N'-tetramethylchloroformamidine hexafluorophosphate (TCFH, 62 mg, 0.2 mmol) and N-methylimidazole (NMI, 27.1 mg, 0.3 mmol) were added in sequence at room temperature. After the reaction solution was stirred at room temperature for 0.5 or 1 h, the corresponding amino compound (0.2 mmol) was added to the mixture, and then the reaction solution was stirred at room temperature for 1 h or overnight. The reaction solution was quenched by adding water (5 ml), extracted with DCM (10 ml × 3), and the organic phase was purified by Na 2 SO 4Dry, filter and concentrate in vacuo, and purify the crude product by flash column chromatography or reverse phase column chromatography to obtain the product.

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130] Effect Example 1: Anti-HT-29 Cell Proliferation Activity Test of Example Compounds HT29 cells in good condition were taken out and plated in a 96-well plate, 100 μL per well, about 3000 cells / well. 37°C, 5% CO 2 , 95% relative humidity incubator overnight. Weigh an appropriate amount of the test compound and dissolve it in McCoy's 5A medium containing 10% FBS. Slowly aspirate the old medium in the 96-well plate and add the medium solution containing different concentrations of the test compound. The test compound was tested at 100, 25, 6.25, 1.56, 0.39, 0.098, 0.024, 0.006, and 0.0015 μM concentrations for calculating the half inhibition concentration; 500, 125, and 31.25 nM concentrations were tested for comparing cell survival rates. Subsequently, incubate at 37°C, 5% CO 2 After incubation for 72 h in an incubator at 95% relative humidity, 50 μL of CTG (CellTiter Glo) staining solution was added to each well, and the absorbance at 562 nm was measured using an ELISA reader. The average value was taken for duplicate well tests. Cell survival rate and half inhibitory concentration (IC 50 ), and cell viability at concentrations of 500, 125, and 31.25 nM. The test results are shown in Table 1.

[0131] Results: The compounds of the present invention have excellent anti-proliferative effects on human colon adenocarcinoma cell line (HT29). The IC 50 All are less than 50 nM, and the IC 50 In the range of 50-100 nM, the IC 50 The value is less than 20 nM, such as Examples 5, 18-19, and 21, wherein the IC of Example 1950 <10nM. (IC 50 The range of values ​​is as follows: A < 50 nM, 50 nM ≤ B < 100 nM, C ≥ 100 nM; the range of cell viability % is as follows: a < 50%; b ≥ 50%)

[0132] Table 1: Data results of the anti-HT-29 cell proliferation activity and cell survival rate of the compounds of the present invention

[0133]

[0134]

[0135] Effect Example 2: Anti-SW480, HCT116, LS-174T Cell Proliferation Activity Test of Example Compounds

[0136] The colorectal cancer tumor cell proliferation assay was based on human cell lines SW480 (human primary colon adenocarcinoma cells with KRAS G12V mutation), HCT-116 (human colon cancer cells with KRAS G13D mutation), and LS-174T (human colorectal adenocarcinoma cells with KRAS G12D mutation).

[0137] SW480 cells, HCT-116 cells, and LS-174T cells (cell bank of the Chinese Academy of Sciences) in good condition were inoculated into 96-well plates (Corning). The subsequent cell culture method and detection were the same as those in Example 1. SW480, HCT-116, and LS-174T cells were treated with different concentrations of the example compounds for 72 h. A total of 10 concentrations of 100, 25, 6.25, 1.56, 0.39, 0.098, 0.024, 0.006, 0.0015, and 0 μM were detected to calculate the half inhibitory concentration (IC 50 ), and set up control wells with DMSO solvent added and blank wells without cells (pure culture medium).

[0138] Calculate cell survival rate (%) = [A (DMSO) -A (加药) ] / [A (DMSO) -A (空白) ]×100%. (A (加药) : absorbance of wells with cells and drug solution; A (空白) : absorbance of wells with culture medium but no cells; A (DMSO) : Absorbance of wells with cells and DMSO added). Cell viability and half inhibitory concentration (IC 50 ) Statistical analysis was performed using Microsoft Office Excel and Graphpad software.

[0139] Results: The compounds of the present invention have potent proliferation inhibitory activity against SW480, HCT-116, and LS-174T cells with KRAS mutations, with an in vitro half inhibitory concentration (IC 50 ) nanomolar level. Among them, the IC of Examples 5 and 21 on HCT-116 and LS-174T cells 50 The IC values ​​of the samples in SW480 cells were less than 0.05 μM and 0.1 μM, respectively. 50 They are less than 0.113 μM and 0.3 μM respectively, which are much better than the positive compound 5-fluorouracil (both greater than 5 μM). This indicates that the compound has a good inhibitory effect on colorectal cancer cells with KRAS mutations and may be developed into a new drug against KRAS mutant colorectal cancer. The test results are shown in Table 2.

[0140] Table 2: Anti-proliferation activity results of the compounds of the present invention against SW480, HCT116, and LS-174T cells

[0141]

[0142] Effect Example 3: Pharmacokinetic parameter test of the example compound in mice

[0143] Six male ICR mice (Shanghai Xipu-Bikai Laboratory Animals) were divided into two groups. The test compounds were prepared into appropriate solutions or suspensions; one group was intravenously injected (1 mg / kg), and the other group was orally administered (10 mg / kg). The blood collection time points were as follows: 5, 15 and 30 minutes, 1, 2, 4, 8, 12 and 24 hours after administration; blood samples were collected and stored in EDTA-2K anticoagulation tubes, and plasma was separated by centrifugation (centrifugation conditions: 5500rpm, 10min), and plasma samples were analyzed by LC-MS / MS.

[0144] The chromatography used a Waters X Bridge C18 column (50mm×2.1mm, 5μm), with an injection volume of 5μL, a flow rate of 1mL / min, and a running time of 1.5min. The mobile phase was 0.1% formic acid acetonitrile (B)-0.1% formic acid water (A), with gradient elution (0-0.01min, A / B=98 / 2-10 / 90; 0.01-0.3min, A / B=10 / 90; 0.3-0.31min, A / B=10 / 90-98 / 2; 0.31-1.5min, A / B=98 / 2). The mass spectrometry conditions were electrospray ionization (ESI), and the eluted compounds were detected in multiple reaction monitoring (MRM) mode. The ion source temperature was 450°C, the spray gas and auxiliary heating gas pressures were both 50psi, the curtain gas pressure was 20psi, and the collision chamber outlet voltage was 13.0V. The declustering potentials of the tested compounds were 79, 110, and 90 eV, and the collision energies were 19, 30, and 35 eV, respectively.

[0145] The blood concentration data of the compound in animals were fitted with a non-compartmental model using Phoenix WinNonlin software (version 8.3.5, Certara) to calculate the pharmacokinetic parameters. The time points where the blood concentration was below the detection limit were excluded during the PK parameter calculation process, and the bioavailability (F) was calculated using the following formula:

[0146] F = (AUC INF-PO ×Dose IV ) / (AUC INF-IV ×Dose PO )×100%, the test results are shown in Table 3.

[0147] Table 3: Oral pharmacokinetic parameters of the compounds of the present invention in mice

[0148]

[0149] The experimental results show that the compounds of the present invention have higher peak concentration Cmax and oral administration curve area AUC INF , showing good drugability and potential for further drug development.

[0150] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A non-glycoside sarmentin derivative as represented by formula (I), or a pharmaceutically acceptable salt or solvate thereof, in, R 1 Independently selected from substituted or unsubstituted 5-10 membered aromatic ring group, substituted or unsubstituted 8-12 membered fused heterocyclic group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group; R 2 independently selected from hydrogen atom, C1-C6 alkyl, -(C1-C6 alkylene)OH, -(C1-C6 alkylene)SH, -(C1-C6 alkylene)NH 2 , -(C1-C6 alkylene)COOH, -(C1-C6 alkylene)SO 3 H, -(C1-C6 alkylene)-CONH 2 、-(C1-C6 alkylene)SO 2 NH 2 、-(C1-C6 alkylene)O(C1-C6 alkyl), -(C1-C6 alkylene)S(C1-C6 alkyl), -(C1-C6 alkylene)NH(C1-C6 alkyl), -(C1-C6 alkylene)N(C1-C6 alkyl) 2 , -(C1-C6 alkylene)(C=O)O(C1-C6 alkyl), -(C1-C6 alkylene)-O(C=O)(C1-C6 alkyl), -(C1-C6 alkylene)-OSO 2 (C1-C6 alkyl), -(C1-C6 alkylene)-SO 2 O(C1-C6 alkyl), -(C1-C6 alkylene)-CONH(C1-C6 alkyl), -(C1-C6 alkylene)-CON(C1-C6 alkyl) 2 、-(C1-C6 alkylene)SO 2 NH(C1-C3 alkyl), -(C1-C6 alkylene)SO 2 N(C1-C3 alkyl) 2 , substituted or unsubstituted 3-12-membered cycloalkyl, -(C1-C6 alkylene)-substituted or unsubstituted 3-12-membered cycloalkane, substituted or unsubstituted 3-12-membered heteroalkyl ring group, -(C1-C6 alkylene)-substituted or unsubstituted 3-12-membered heterocycloalkane, substituted or unsubstituted 5-10-membered aryl, -(C1-C6 alkylene)-substituted or unsubstituted 5-10-membered aromatic ring, substituted or unsubstituted 3-12-membered aromatic heterocyclic group, -(C1-C6 alkylene)-substituted or unsubstituted 3-12-membered aromatic heterocycle; R 3 Independently selected from substituted or unsubstituted 3-12 membered alkane ring, substituted or unsubstituted 3-12 membered heteroalkane ring, substituted or unsubstituted 5-10 membered aromatic ring, substituted or unsubstituted 8-12 membered fused heterocyclic ring, substituted or unsubstituted 3-12 membered aromatic heterocyclic ring; Cy is a 5-10 membered aromatic ring substituted with (Ra)n, or a 5-10 membered aromatic heterocyclic ring substituted with (Ra)n; Each Ra is independently selected from halogen, -OH, -SH, -CN, -NH 2 -、-NO 2 , -(C1-C3 alkylene)OH, C1-C6 alkyl, -O(C1-C6 alkyl), -O(C1-C3 alkylene)O(C1-C6 alkyl), -S(C1-C6 alkyl), -S(C1-C3 alkylene)S(C1-C6 alkyl), -NH(C1-C6 alkyl), -NH(C1-C3 alkylene)NH(C1-C6 alkyl), -N(C1-C6 alkyl) 2 、-NH(C1-C3 alkylene)N(C1-C6 alkyl) 2 , -N(C1-C6 alkyl)(C1-C3 alkylene)N(C1-C6 alkyl) 2 , or two Ra form a substituted or unsubstituted 3-12 membered alkane ring, or a substituted or unsubstituted 3-12 membered heterocyclic ring through two adjacent C atoms on Cy; n is selected from 1, 2, 3, 4; When Z 1 , Z 2 , Z 3 When both exist, Z 1 , Z 2 , Z 3 Each independently selected from CH 2 , CO, NH, O, S, SO 2 , CHRb, C(Rb) 2 ,NRb; When Z 2 When Z does not exist, 1 , Z 3 Each independently selected from CORb, Rb; Each Rb is independently selected from hydrogen, halogen, -OH, -CN, -NH 2 、-(C=O)OH、-SO 3 H, -(C1-C3 alkylene)OH, -(C=O)O(C1-C6 alkyl), -O(C=O)(C1-C6 alkyl), -(C=O)NH 2 、-(C=O)NH(C1-C6 alkyl)、-(C=O)N(C1-C6 alkyl) 2 , C1-C6 alkyl, -O(C1-C6 alkyl), -O(C1-C3 alkylene)O(C1-C6 alkyl), -S(C1-C6 alkyl), -(C1-C3 alkylene)S(C1-C6 alkyl), -SO 2 O(C1-C6 alkyl), -SO 2 NH(C1-C6 alkyl), -SO 2 N(C1-C6 alkyl) 2 、-NH(C1-C6 alkyl)、-N(C1-C6 alkyl) 2 、-(C1-C3 alkylene)NH(C1-C6 alkyl)、-(C1-C3 alkylene)N(C1-C6 alkyl) 2 , -(C1-C6 alkyl)(C1-C3 alkylene)N(C1-C6 alkyl) 2 , a substituted or unsubstituted 3-12 membered alkyl ring group, a substituted or unsubstituted 3-12 membered heteroalkyl ring group, a substituted or unsubstituted 5-10 membered aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group; Indicates absence, single key, or double key; Unless otherwise specified, the term "substituted" means that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen, -OH, -CN, -NO 2 、-NH 2 , -NCO, -OCN, -SCN, -NCS, -N 3 , oxo (=O), -CF 3 、-(C1-C3 alkylene)OH、-O(C1-C3 alkyl)、-S(C1-C3 alkyl)、-C(O)X'R 4 or -X'C(O)R 5 、-SO 3 R 4 、-OSO 2 OR 4 、-NR 6 SO 2 OR 5 、-NR 6 R 7 、-SO 2 NR 6 R 7 、-NH-SO 2 -R 6 、-N + R 6 R 7 R 8 、-C(O)N(R 9 ) 2 、-SO 2 R 10 、-NR 11 C(O)N(R 11 ) 2 、-B(OH) 2 、-B(O(C1-C6 alkyl or alkylene)) 2 、-P(O)(OH) 3 、-OP(O)(OC1-C3 alkyl) 2 , C1-C6 alkyl, C2-C6 unsaturated alkyl, 3-12-membered alkyl ring group, 3-12-membered heteroalkyl ring group, 5-10-membered aryl, 3-12-membered aromatic heterocyclic group, 3-12-membered heterocyclic group, -(C1-C3 alkylene)-3-12-membered heterocyclic ring; X' is a chemical bond or oxygen or sulfur, R 4 R is independently selected from hydrogen, C1-C6 alkyl, C2-C8 alkenyl, 3-12 membered alkyl ring, 5-10 membered aryl, 3-12 membered heterocyclic group, 5 Independently selected from hydrogen, C1-C6 alkyl, C2-C8 alkenyl, 3-12 membered alkyl ring group, 5-10 membered aryl group, 3-12 membered heterocyclic group; R 6 , R 7 and R 8 Each independently selected from hydrogen, C1-C6 alkyl, C2-C8 alkenyl, -C(O)X'R 4 or -X'C(O)R 5 , or R 6 and R 7 Together with the N atom to which they are attached, they form a heterocyclic ring having 4 to 8 members in the ring structure; Among them, R 6 or R 7 Not all -C(O)X'R 4 or -X'C(O)R 5 ; R 9 are independently selected from hydrogen or C1-C6 alkyl, or two R 9 Together with the N atom to which they are attached, they form a 4-8 membered heterocyclic ring; R 10 Independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered alkyl ring group, 3-12 membered heterocyclic group, 5-10 membered aryl group; R 11 are independently selected from hydrogen, C1-C6 alkyl, or two R 11 Together with the N atom to which they are attached, they form a 4-8 membered heterocyclic ring; Wherein, the heteroalkyl ring and the aromatic heterocyclic ring each independently have 1-3 (preferably 1, 2 or 3) heteroatoms selected from N, O and S.

2. The non-glycoside sarmentin derivative as shown in formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt or solvate thereof, It is characterized in that R 1 It is independently a substituted or unsubstituted 6-10 membered aryl group, a substituted or unsubstituted 5-6 membered heteroaryl group, or a substituted or unsubstituted 8-12 membered fused heterocyclic group, wherein the substitution means that one or more (e.g., 1, 2, 3) hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen, hydroxyl, cyano, or C1-C3 alkyl.

3. The non-glycoside sarmentin derivative as shown in formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt or solvate thereof, It is characterized in that R 1 Independently selected from substituted or unsubstituted 6-membered aryl, substituted or unsubstituted 6-membered heteroaryl, and substituted or unsubstituted 9-10-membered fused heterocyclic group.

4. The non-glycoside sarmentin derivative as shown in formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt or solvate thereof, It is characterized in that R 2 R is independently selected from H or C1-C6 alkyl; 3 Independently selected from wherein Rc is independently selected from halogen.

5. The non-glycoside sarmentin derivative as shown in formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt or solvate thereof, It is characterized in that The compound has the structure of the following formula (Ia), formula (Ib) or formula (Ic), Among them, R 1 , R 2 , R 3 , Ra, Rb, Z 1 , Z 2 , Z 3 , nAs described above.

6. The non-glycoside sarmentin derivative of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt or solvate thereof, It is characterized in that The compound has the following structure: Among them, R 1 , R 2 , Rc are as described above.

7. The non-glycoside sarcosyl derivative of formula (I) as claimed in any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, having a structure as shown in any one of compounds 1 to 31:

8. A pharmaceutical composition, It is characterized in that The pharmaceutical composition comprises: (a) a therapeutically effective amount of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof; and (b) a pharmaceutically acceptable carrier.

9. Use of the non-glycoside sarmentin derivative represented by formula (I) as described in any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, It is characterized in that Used for preparing drugs for treating and / or preventing tumors.

10. The use according to claim 9, It is characterized in that The tumors include, but are not limited to, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, colon cancer, rectal cancer, pancreatic cancer, liver cancer, lung cancer, non-small cell lung cancer, brain metastasis of lung cancer, oral squamous cell carcinoma, head cancer, neck cancer, head and neck cancer, oral or nasal mucosal cancer, laryngeal cancer, kidney cancer, renal cell carcinoma, ovarian cancer, spleen cancer, small intestine cancer, large intestine cancer, stomach cancer, esophageal cancer, esophageal cancer, lung squamous cell carcinoma, bile duct cancer, gallbladder cancer, melanoma, urothelial carcinoma, urogenital tract cancer, genital cancer, prostate cancer, testicular cancer, bladder cancer, blood cancer, skin cancer, bone marrow cancer, brain cancer, central nervous system cancer, muscle tissue cancer, thyroid cancer, or a combination thereof.

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