Substituted bridged ring inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a substituted bridged ring inhibitor as well as a preparation method and application thereof. Specifically, the compound has a structure as shown in a formula (A0), the invention also discloses a preparation method of the compound and application of the compound as a KRASG12D inhibitor, and the compound has a very good selective inhibition effect on KRASG12D and has better pharmacodynamic and pharmacokinetic performance and lower toxic and side effects. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of drugs, and particularly relates to a substituted bridged-ring inhibitor, a preparation method thereof and an application thereof. Background Art

[0002] Approximately one quarter of all human cancers are caused by RAS mutations, and nearly one million people lose their lives each year as a result. Among the RAS family, KRAS mutations account for 85% of all RAS mutations. KRAS mutations are found in nearly 90% of pancreatic cancers, 30 - 40% of colon cancers, and 15 - 20% of lung cancers (mainly non-small cell lung cancers). The most common mutations in KRAS are G12C and G12D mutations. The G12C mutation mainly occurs in HSCLC, while the G12D mutation mainly occurs in pancreatic cancer. So far, no drugs targeting KRAS G12D mutations have been approved for marketing.

[0003] Currently, the conventional treatment regimens for pancreatic cancer in clinical practice include gemcitabine monotherapy, gemcitabine combined with albumin-bound paclitaxel, and the FOLFIRINOX regimen (oxaliplatin + irinotecan + 5-FU / LV), etc. Among them, liposomal irinotecan is suitable for the treatment of advanced pancreatic cancer patients (second-line therapy) with poor chemotherapy effect by gemcitabine in combination with fluorouracil and leucovorin. However, generally speaking, the current effective treatment means for pancreatic cancer are limited, and the overall survival time of patients does not exceed 1 year. Although the exploration of drugs for advanced pancreatic cancer patients is continuously carried out, the research progress is still relatively slow so far.

[0004] Since the KRAS G12D target protein is pathologically related to various diseases, especially pancreatic cancer, there is currently a need for new KRAS G12D inhibitors for clinical treatment. Highly selective and highly active KRAS G12D inhibitors can be more effective in treating diseases such as cancers caused by KRAS G12D mutations, and have the potential to reduce off-target effects, thus having a more urgent clinical need. Summary of the Invention

[0005] The purpose of the present invention is to provide a class of novel compounds having selective inhibitory effects on KRAS G12D and / or better pharmacodynamic properties and their uses.

[0006] In the first aspect of the present invention, there is provided a compound of formula (A0), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs:

[0007]

[0008] Ring C is selected from the following groups:

[0009] Y is a bond or O;

[0010] is

[0011] Z is selected from a bond or a substituted or unsubstituted C1-C6 alkylene group; wherein, the substitution means being substituted by one or more Rs;

[0012] W is selected from a substituted or unsubstituted C3-C 14 cycloalkyl, or a substituted or unsubstituted 4- to 14-membered saturated or unsaturated heterocyclic group; wherein, the substitution means being substituted by one or more Rs;

[0013] R 1 is selected from hydrogen or deuterium; n is 0, 1, 2, 3, 4, 5 or 6;

[0014] R 11 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic group;

[0015] m is 0, 1, 2, 3, 4, 5 or 6;

[0016] R 10 is selected from the following groups:

[0017] V1, V2, V3, V5 are each independently selected from: N or CR v ; R v are the same or different and are each independently selected from the following substituted or unsubstituted groups: H, C1-C3 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclic group, C1-C3 alkoxy, C3-C6 cycloalkyloxy, 4- to 6-membered heterocyclic oxy, halo-C1-C3 alkyl, halo-C3-C6 cycloalkyl, halo-4- to 6-membered heterocyclic group, (HO)-C1-C3 alkyl, (HO)-C3-C6 cycloalkyl, (NH2)-C1-C3 alkyl, (NH2)-C3-C6 cycloalkyl, halogen, CN, -C≡CH, -C≡C-CH3, -C≡C-(C3-C6 cycloalkyl), -C≡C-(4- to 6-membered heterocyclic group), OH, NH2, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl), SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl), wherein, the substitution means being substituted by one or more Rs;

[0018] or V1 and V2 cyclize to form a substituted or unsubstituted group: phenyl or 5- to 6-membered heteroaryl; wherein, the substitution means being substituted by one or more Rs;

[0019] X is selected from: S, or O;

[0020] Each R is the same or different and is independently selected from: deuterium, C1-C 18 alkyl, deuterated C1-C 18 alkyl, halogenated C1-C 18 alkyl, (C3-C 18 cycloalkyl)C1-C 18 alkyl, (4-20 membered heterocyclic group)C1-C 18 alkyl, (C1-C 18 alkoxy)C1-C 18 alkyl, (C3-C 18 cycloalkyloxy)C1-C 18 alkyl, (4-20 membered heterocyclic group oxy)C1-C 18 alkyl, vinyl, ethynyl, (C1-C6 alkyl)vinyl, deuterated (C1-C6 alkyl)vinyl, halogenated (C1-C6 alkyl)vinyl, (C1-C6 alkyl)ethynyl, deuterated (C1-C6 alkyl)ethynyl, halogenated (C1-C6 alkyl)ethynyl, (C3-C 14 cycloalkyl)ethynyl, (4-14 membered heterocyclic group)ethynyl, C1-C 18 alkoxy, deuterated C1-C 18 alkoxy, halogenated C1-C 18 alkoxy, 4-20 membered heterocyclic group C(O), C3-C 20 cycloalkyl, 4-20 membered heterocyclic group, C6-C 14 aryl, 5-14 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amine, amide, sulfonamide, sulfone or urea.

[0021] In another preferred embodiment, the compound is a compound of (Formula I0),

[0022]

[0023] wherein, R x is selected from hydrogen, or CH3;

[0024] R p is selected from hydrogen, or C1-C3 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group;

[0025] R 10 、Z、W、R 1 、n and m are as defined above.

[0026] In another preferred embodiment, R 10 is Among them, V1, V2, V3, and V5 are each independently selected from: N, or CR v ; R v Same or different, each independently selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C1-C3 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclic oxy group, halo C1-C3 alkyl, halo C3-C6 cycloalkyl, halo 4-6 membered heterocyclic group, (HO)-C1-C3 alkyl, (HO)-C3-C6 cycloalkyl, (NH2)-C1-C3 alkyl, (NH2)-C3-C6 cycloalkyl, halogen, CN, -C≡CH, -C≡C-CH3, -C≡C-(C3-C6 cycloalkyl), -C≡C-(4-6 membered heterocyclic group), OH, NH2, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl), SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl).

[0027] In another preferred example, R 10 is Among them, R y2 is NH2, R y1 , R y3 , R y4 and R y5 are each independently selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C1-C3 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclic oxy group, halo C1-C3 alkyl, halo C3-C6 cycloalkyl, halo 4-6 membered heterocyclic group, (HO)-C1-C3 alkyl, (HO)-C3-C6 cycloalkyl, (NH2)-C1-C3 alkyl, (NH2)-C3-C6 cycloalkyl, halogen, CN, -C≡CH, -C≡C-CH3, -C≡C-(C3-C6 cycloalkyl), -C≡C-(4-6 membered heterocyclic group), OH, NH2, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl), SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl).

[0028] In another preferred example, Ry5 is selected from: halo C1-C3 alkyl (such as CF3, CF2CF3), C3-C6 cycloalkyl, or 4-6 membered heterocyclic group.

[0029] In another preferred example, Ry1 is selected from: H or halogen.

[0030] In another preferred example, R y3Selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, -C≡CH, -C≡C-CH3, -C≡C-(C3-C6 cycloalkyl), -C≡C-(4-6 membered heterocyclic group), or halogen.

[0031] In another preferred example, Ry4 is selected from: C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, -C≡CH, -C≡C-CH3, -C≡C-(C3-C6 cycloalkyl), -C≡C-(4-6 membered heterocyclic group), or halogen.

[0032] In another preferred example, R 10 is

[0033] U is selected from: N, CH, CD, CF;

[0034] R 4 is selected from the following groups which may be substituted or unsubstituted: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;

[0035] R 5 , R 6 , R 7 , R 9 are the same or different and are each independently selected from the following groups which may be substituted or unsubstituted: H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; wherein the substitution means being substituted by one or more R;

[0036] R 8 is NH2.

[0037] In another preferred example, U, R 6 , R 7 , R 9 and R 8 are as defined above;

[0038] R 5 is selected from the following groups which may be substituted or unsubstituted: H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; wherein the substitution means being substituted by one or more R;

[0039] R 4Selected from the group consisting of substituted or unsubstituted groups: H, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C1-C3 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclic oxy group, halo C1-C3 alkyl, halo C3-C6 cycloalkyl, halo 4-6 membered heterocyclic group, (HO)-C1-C3 alkyl, (HO)-C3-C6 cycloalkyl, (NH2)-C1-C3 alkyl, (NH2)-C3-C6 cycloalkyl, halogen, CN, -C≡CH, OH, NH2, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl), SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl); wherein said substitution means being substituted by one or more R.

[0040] In another preferred embodiment, R 4 and R 5 As defined above, U is CH, R 6 、R 7 and R 9 are independently H or deuterium, and R8 is NH2.

[0041] In another preferred embodiment, R 10 is

[0042] U’ is selected from: O, or S;

[0043] U” is selected from: N, or C(CN);

[0044] R 7’ 、R 8’ 、R 9’ are the same or different and are each independently selected from the group consisting of substituted or unsubstituted groups: H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; wherein said substitution means being substituted by one or more R;

[0045] R 5’ is NH2.

[0046] In another preferred embodiment, the compound has the structure shown in formula (I-A), or formula (I-B):

[0047]

[0048] R 10 、Z、W、R 1 and n are as defined above.

[0049] In another preferred embodiment, the compound is selected from the group consisting of:

[0050]

[0051] Among them, V1, V2, V3, V5, R v , Z, W, R 1 and n are defined as described above.

[0052] In another preferred example, the compound has a structure represented by formula (II-A), or formula (II-B), or formula (II-C) or formula (II-D), or formula (II-E) or formula (II-F):

[0053]

[0054]

[0055] R 12 are the same or different and each independently selected from hydrogen or deuterium;

[0056] R 4 is selected from the following groups of substituted or unsubstituted groups: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; wherein, the substitution means being substituted by one or more R;

[0057] R 5 is selected from the following groups of substituted or unsubstituted groups: H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; wherein, the substitution means being substituted by one or more R;

[0058] o is 0, 1 or 2;

[0059] Among them, V1, V2, V3, V5, and R are defined as described above.

[0060] In another preferred example, is selected from the following groups of substituted or unsubstituted groups: aniline, naphthylamine, 5-6 membered monocyclic heteroaryl (such as pyridyl) amine, 9-10 membered bicyclic heteroaryl (such as indazolyl, benzothiazole, benzothiophene, benzofuran, quinoline, quinazoline) amine, wherein the substitution is by one or more groups selected from the following: halogen, hydroxyl, cyano, NH2, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C2-C6 alkenyl, C2-C6 alkynyl; preferably, is selected from:

[0061]

[0062] In another preferred example, Selected from the group consisting of substituted or unsubstituted groups: 9-10 membered bicyclic heteroaryl (such as indazolyl, benzothiazole, benzothiophene, benzofuran, pyridothiazole, pyridothiophene, pyridofuran) amines, wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, NH2, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C2-C6 alkenyl, C2-C6 alkynyl; preferably, Selected from:

[0063] In another preferred embodiment, W is selected from: substituted or unsubstituted 4-7 membered monocyclic heterocyclic group, substituted or unsubstituted C3-C7 monocyclic cycloalkyl, substituted or unsubstituted 6-10 membered bicyclic heterocyclic group, substituted or unsubstituted C6-C10 bicyclic cycloalkyl, substituted or unsubstituted 7-12 membered tricyclic heterocyclic group, substituted or unsubstituted C7-C 12 Tricyclic cycloalkyl, preferably, W is a substituted or unsubstituted 8-12 membered N-containing heterocyclic group, wherein said substitution means being substituted by one or more R, and the definition of R is as described in claim 1;

[0064] Preferably, ring W is selected from:

[0065] In another preferred embodiment, the compound is selected from the group consisting of:

[0066]

[0067]

[0068] Or selected from the group consisting of:

[0069] Or selected from the group consisting of:

[0070]

[0071]

[0072] Or selected from the group consisting of:

[0073]

[0074] Or selected from the group consisting of:

[0075]

[0076] In another preferred embodiment, rings C, Y, A, Z, W, R1 , R 10 , R 11 and m are independently selected from the corresponding groups in the above specific compounds.

[0077] In another preferred embodiment, the compound is preferably the compound prepared in the examples.

[0078] In the second aspect of the present invention, there is provided a method for preparing a compound of formula (A0), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, wherein, including steps (taking formula I0 as an example):

[0079]

[0080] (i) In an inert solvent, in the presence of a base, with or without a Pd catalyst, with or without a condensing agent, the compound of formula V-1 reacts with the compound of formula V-2 to obtain the compound of formula V-3;

[0081] (ii) In an inert solvent, in the presence of a base, with or without a Pd catalyst, the compound of formula V-3 reacts with the compound of formula V-4 to obtain the compound of formula V-5;

[0082] (iii) The compound of formula V-5 is deprotected by an acid (such as TFA, HCl, etc.) or under Pd-catalyzed hydrogenation conditions to remove protecting groups PG1, PG2 and / or PG3 to obtain the compound of formula (I0);

[0083] In the formula,

[0084] X1, X2 and X3 are each independently selected from: OH, halogen, OTf, OTs or OMs;

[0085] PG1 and PG2 are each independently selected from: Boc, Cbz, Bn or PMB;

[0086] PG3 is selected from: none, Boc, Cbz, Bn or PMB;

[0087] V1, V2, V3, V5, R 1 , R x , Z, W and n are as defined above.

[0088] In the third aspect of the present invention, there is provided a pharmaceutical composition, which comprises one or more compounds, their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs as described in the first aspect; and a pharmaceutically acceptable carrier.

[0089] In another preferred embodiment, the pharmaceutical composition further comprises a drug selected from the group consisting of: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomab tiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, okatinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.), EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Cabozantinib,Sunitinib, donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Milciclib, Trilaciclib, Lerociclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) or combinations thereof.

[0090] In a fourth aspect of the present invention, there is provided the use of a compound as described in the first aspect, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or the pharmaceutical composition as described in the third aspect, for the preparation of a drug for preventing and / or treating a disease related to the G12D activity or expression level of KRAS.

[0091] In another preferred example, the disease is a tumor or a disorder disease.

[0092] In another preferred example, the disease is selected from the group consisting of: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, gastric cancer, liver cancer, large intestine cancer, melanoma, lymphoma, blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.

[0093] In a fourth aspect of the present invention, there is provided a method for non-diagnostically and non-therapeutically inhibiting KRAS G12D which comprises the step of administering to a desired subject an effective amount of a compound as described in the first aspect, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or administering the pharmaceutical composition as described above.

[0094] In another preferred example, the subject is a mammal, preferably a human.

[0095] In a fifth aspect of the present invention, there is provided an in vitro method for inhibiting KRAS G12DA method for inhibiting the activity of KRAS, comprising the step of contacting a compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs as described in the first aspect, or a pharmaceutical composition as described above, with a protein or a cell, so as to inhibit the activity of KRAS G12D .

[0096] In another preferred embodiment, the cell is selected from the group consisting of macrophages, intestinal cells (including intestinal stem cells, intestinal epithelial cells), or a combination thereof.

[0097] In another preferred embodiment, the cell is from a rodent (such as a mouse, a rat), or a primate (such as a human).

[0098] 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 hereinafter (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be repeated one by one here. Detailed implementation manners

[0099] Through long-term and in-depth research, the inventors of the present invention unexpectedly prepared a novel class of compounds that have selective inhibitory effects on KRAS G12D and / or better pharmacodynamic properties. On this basis, the inventors completed the present invention.

[0100] Terms

[0101] In the present invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0102] The term "alkyl", by itself or as part of other groups, refers to a straight-chain or branched-chain alkyl group, which may contain 1-20 carbon atoms, such as 1-18 carbon atoms, especially 1-18 carbon atoms, preferably contains 1-10 carbon atoms (C1-C10), and more preferably contains 1-6 carbon atoms (C1-C6 or C1-C3). Typical "alkyl" includes methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. In the present invention, alkyl also includes substituted alkyl. "Substituted alkyl" means that one or more positions in the alkyl group are substituted, especially 1-4 substituents, which can be substituted at any position. Typical substitutions include but are not limited to one or more of the following groups: such as hydrogen, deuterium, halogen (for example, a single halogen substituent or a polyhalogen substituent, the latter such as trifluoromethyl or an alkyl group containing Cl3), cyano, nitro, oxygen (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR a , SRa , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , NR b R c , NR b S(=O)2R e , NR b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O)2NR b R c , NR d P(=O)2NR b R c , NR b C(=O)R a , or NR b P(=O)2R e , wherein R as used herein a may independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, a 5- to 14-membered heterocycle or a C6-C14 aryl ring, R b , R c and R d may independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, a 5- to 14-membered heterocycle or a C6-C14 aryl ring, or R b and R c together with the N atom may form a heterocycle; R eIt can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, 5-14 membered heterocycle or C6-C14 aryl ring. The above typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl ring, can be optionally substituted.

[0103] The term "alkylene" refers to the group formed by removing one hydrogen atom from "alkyl or substituted alkyl", such as methylene, ethylene, propylene, isopropylidene (such as ), butylene (such as ), pentylene (such as ), hexylene (such as ), heptylene (such as ), etc. In addition, the term also includes the case where one methylene group of the alkylene (such as C1-C18 alkylene) is replaced by a cycloalkylene group (such as C3-C20 cycloalkylene), for example, "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkylene C1-C18 alkylene", and the alkylene is preferably C1-C3 alkylene.

[0104] The terms "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkylene C1-C18 alkylene" have the same meaning, which refers to the group formed by removing two hydrogen atoms from cycloalkylalkyl or alkylcycloalkyl, such as etc.

[0105] In the present invention, the term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon group containing one or more double bonds and usually having a length of 2 to 20 carbon atoms. The alkenyl is preferably C2-C6 alkenyl, more preferably C2-C4 alkenyl. The alkenyl includes but is not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc. In the present invention, the alkenyl includes substituted alkenyl.

[0106] The term "alkynyl" refers to a straight-chain or branched-chain hydrocarbon group containing one or more triple bonds and usually having a length of 2 to 20 carbon atoms. The alkynyl is preferably C2-C6 alkynyl, more preferably C2-C4 alkynyl. The alkynyl includes but is not limited to ethynyl, propynyl or similar groups. In the present invention, the alkynyl also includes substituted alkynyl, and the substituents can be halogenated, hydroxyl, cyano, nitro, etc.

[0107] In the present invention, the term "cycloalkyl" refers to a group of completely saturated cyclic hydrocarbon compounds, including 1-4 rings, and each ring contains 3-8 carbon atoms. The term "C3-C 20"refers to those containing a cycloalkyl group with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. The cycloalkyl group is preferably C3-C 14 cycloalkyl, more preferably C3-C 10 cycloalkyl, more preferably a C3-C6 monocyclic cycloalkyl, C7-C 10 bicyclic or tricyclic cycloalkyl. "Substituted cycloalkyl" means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which can be substituted at any position. In the present invention, "cycloalkyl" includes substituted cycloalkyl, and typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., a mono-halogen substituent or a poly-halogen substituent, the latter such as trifluoromethyl or an alkyl group containing Cl3), cyano, nitro, oxygen (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR a 、SR a 、S(=O)R e 、S(=O)2R e 、P(=O)2R e 、S(=O)2OR e 、P(=O)2OR e 、NR b R c 、NR b S(=O)2R e 、NR b P(=O)2R e 、S(=O)2NR b R c 、P(=O)2NR b R c 、C(=O)OR d 、C(=O)R a 、C(=O)NR b R c 、OC(=O)R a 、OC(=O)NR b R c 、NR b C(=O)OR e 、NR d C(=O)NR b R c 、NR d S(=O)2NR b R c 、NR d P(=O)2NR b R c 、NR b C(=O)R a 、or NRb P(=O)2R e , wherein R as used herein a can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, R b , R c and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R b and R c together with the N atom can form a heterocycle; R e can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above typical substituents can be optionally substituted. Typical substitutions also include spiro, bridged or fused ring substituents, especially spiroalkyl, spiroalkenyl, spiroheterocycle (excluding heteroaromatic ring), bridged alkyl, bridged alkenyl, bridged heterocycle (excluding heteroaromatic ring), fused ring alkyl, fused ring alkenyl, fused ring heterocyclic group or fused ring aromatic group, and the above cycloalkyl, cycloalkenyl, heterocyclic group and heteroaromatic group can be optionally substituted. Examples of cycloalkyl include but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, etc.

[0108] The term "C3-C20 subcycloalkyl" refers to the group formed by removing two hydrogen atoms from cycloalkyl, such as:

[0109] etc.

[0110] In the present invention, the term "heterocyclic group" refers to a cyclic group that is fully saturated or partially unsaturated (including but not limited to, for example, 3- to 7-membered monocyclic, 4- to 7-membered monocyclic, 6- to 11-membered bicyclic, or 8- to 16-membered tricyclic or polycyclic systems), in which at least one heteroatom is present in a ring containing at least one carbon atom. The term "4- to 20-membered heterocyclic group" refers to a heterocyclic group containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms. "Heterocyclic group" has the same meaning as "saturated or unsaturated heterocyclic group". "Heterocyclic group" is preferably a 4- to 14-membered heterocyclic group (including but not limited to, for example, 4- to 6-membered monocyclic, 7- to 10-membered bicyclic, or 8- to 14-membered tricyclic or polycyclic systems), more preferably a 4- to 12-membered heterocyclic group, more preferably a 4- to 10-membered heterocyclic group, such as a 4- to 6-membered monocyclic heterocyclic group, 7- to 10-membered bicyclic or tricyclic heterocyclic group, more preferably a 4- to 8-membered heterocyclic group, more preferably a 4- to 6-membered heterocyclic group. Each heterocyclic ring containing a heteroatom may carry 1, 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms, or sulfur atoms, where the nitrogen atom or sulfur atom may be oxidized, and the nitrogen atom may also be quaternized. The heterocyclic group may be attached to the residue of any heteroatom or carbon atom of the ring or ring system, preferably attached to an N or C atom of the ring or ring system. Typical monocyclic heterocycles include but are not limited to azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidinonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholine sulfoxide, thiomorpholine sulfone, 1,3-dioxolanyl, and tetrahydro-1,1-dioxothiophene, etc. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups; the spiro, fused, and bridged heterocyclic groups involved are optionally connected to other groups by a single bond, or further fused to other cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups through any two or more atoms on the ring; the heterocyclic group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclic group, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylate groups.

[0111] The term "C4-C20 heteroacyclic group" refers to a group formed by removing two hydrogen atoms from a heterocyclic group, such as:

[0112] etc.

[0113] In the present invention, the term "aryl" refers to an aromatic cyclic hydrocarbon group having 1 to 5 rings, especially monocyclic and bicyclic groups. Among them, "C6-C 14 aryl" refers to an aromatic cyclic hydrocarbon group containing 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring carbon atoms. Aryl includes phenyl, biphenyl or naphthyl. Wherever there are two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be linked by single bonds (such as biphenyl), or fused (such as naphthalene, anthracene, etc.). "Substituted aryl" means that one or more positions in the aryl are substituted, especially 1 to 3 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, a monohalogen substituent or a polyhalogen substituent, the latter such as trifluoromethyl or an alkyl group containing Cl3), cyano, nitro, oxo group (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR a 、SR a 、S(=O)R e 、S(=O)2R e 、P(=O)2R e 、S(=O)2OR e ,P(=O)2OR e 、NR b R c 、NR b S(=O)2R e 、NR b P(=O)2R e 、S(=O)2NR b R c 、P(=O)2NR b R c 、C(=O)OR d 、C(=O)R a 、C(=O)NR b R c 、OC(=O)R a 、OC(=O)NR b R c 、NR b C(=O)OR e ,NR d C(=O)NR b R c 、NR d S(=O)2NR b R c 、NR d P(=O)2NR b R c 、NR b C(=O)R a 、or NRb P(=O)2R e , wherein R as used herein a may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl ring, R b , R c and R d may independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aryl ring, or R b and R c together with the N atom may form a heterocycle; R e may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl ring. The above typical substituents may be optionally substituted. Typical substitutions also include fused ring substituents, especially fused cycloalkyl, fused alkenyl, fused heterocyclic or fused aryl ring groups, and the above cycloalkyl, cycloalkenyl, heterocyclic and heteroaryl groups may be optionally substituted.

[0114] The term "heteroaryl" refers to an aromatic cyclic hydrocarbon group containing 1 - 4 heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur. Among them, "5 - 14 membered heteroaryl" refers to a heteroaromatic system containing 1 - 4 heteroatoms and 5 - 14 ring atoms. The heteroaryl is preferably a 5 - to 10 - membered ring, more preferably a 5 - or 6 - membered ring, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl and tetrazolyl, etc. "Heteroaryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate groups.

[0115] In the present invention, the term "alkoxy" refers to a straight - chain or branched - chain alkoxy, including alkyl - O -, alkyl - O - alkyl, wherein, "C1 - C 18 alkoxy" refers to a straight - chain or branched - chain alkoxy having 1 to 18 carbon atoms, including C1 - C 18 alkyl - O -, - C1 - C6 alkyl - O - C1 - C6 alkyl, including, without limitation, methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. It is preferably C1 - C8 alkoxy, more preferably C1 - C6 alkoxy.

[0116] In the present invention, the term "cycloalkyloxy" is cycloalkyl - O -, wherein, "C3 - C 20 cycloalkyloxy" refers to C3 - C 20 cycloalkyl - O -, wherein the definition of C3 - C 20 cycloalkyl is as described above.

[0117] In the present invention, the term "heterocyclic group oxy" refers to heterocyclic group -O-, wherein, "4-20 membered heterocyclic group oxy" refers to 4-20 membered heterocyclic group -O-, and the definition of the 4-20 membered heterocyclic group is as described above.

[0118] In the present invention, the term "C1-C 18 alkylene oxy" refers to the group obtained by removing one hydrogen atom from "C1-C 18 alkoxy".

[0119] In the present invention, the term "halogen" or "halo" refers to chlorine, bromine, fluorine, iodine.

[0120] In the present invention, the term "halogenated" means substituted by halogen.

[0121] In the present invention, the term "deuterated" means substituted by deuterium.

[0122] In the present invention, the term "hydroxyl" refers to the group with the structure OH.

[0123] In the present invention, the term "nitro" refers to the group with the structure NO2.

[0124] In the present invention, the term "cyano" refers to the group with the structure CN.

[0125] In the present invention, the term "ester group" refers to the group with the structure -COOR, wherein R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle. The ester group is preferably -COO C1-C6 alkyl.

[0126] The term "amino group" refers to the group with the structure -NRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety. The amino group is preferably NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2.

[0127] The term "amide group" refers to the group with the structure -CONRR' or -NRCOR', wherein R and R' can each independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. The amide group is preferably CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl).

[0128] The term "sulfonamido" refers to a group having the structure -S2ONRR' or -NRSO2R', where R and R' can each independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. The sulfonamido group is preferably SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl).

[0129] The term "sulfonyl" refers to a group having the structure -SO2R, where R can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above.

[0130] The term "ureido" refers to a group having the structure -NRCONR'R", where R, R' and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R" can be the same or different in the dialkylamine moiety.

[0131] The term "alkylaminoalkyl" refers to a group having the structure -RNHR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different.

[0132] The term "dialkylaminoalkyl" refers to a group having the structure -RNHR'R", where R, R' and R" can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R" can be the same or different in the dialkylamine moiety.

[0133] The term "heterocyclylalkyl" refers to a group having the structure -RR', where R can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl; R' represents a heterocycle or substituted heterocycle.

[0134] In the present invention, the term "substituted" means that one or more hydrogen atoms on a specific group are replaced by specific substituents. The specific substituents are the substituents described correspondingly in the foregoing, or the substituents appearing in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituents may be the same or different at each position. Those skilled in the art should understand that the combinations of substituents contemplated by the present invention are those that are stable or chemically achievable combinations. The substituents include, for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic group, aryl, heteroaryl, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, C1-C6 alkoxy group, C1-C10 sulfonyl group, and C1-C6 ureido group, etc.

[0135] Unless otherwise stated, it is assumed that any heteroatom with an unsatisfied valence has sufficient hydrogen atoms to supplement its valence.

[0136] When the substituent is a non-terminal substituent, it is a subunit of the corresponding group. For example, an alkyl group corresponds to an alkylene group, a cycloalkyl group corresponds to a cycloalkylene group, a heterocyclic group corresponds to a heterocycloalkylene group, an alkoxy group corresponds to an alkyleneoxy group, etc.

[0137] In the present invention, "plurality" means 2, 3, 4, 5.

[0138] Active ingredient

[0139] As used herein, "the compounds of the present invention" refers to the compounds represented by Formula I, and also includes the stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates of the compounds of Formula I.

[0140] The salts that may be formed by the compounds in the present invention also fall within the scope of the present invention. Unless otherwise specified, the compounds in the present invention are understood to include their salts. The term "salt" used herein refers to acid salts or basic salts formed with inorganic or organic acids and bases. In addition, when the compound in the present invention contains a basic moiety, it includes, but is not limited to, pyridine or imidazole, and when it contains an acidic moiety, it includes, but is not limited to, carboxylic acid. The zwitterions ("inner salts") that may be formed are included within the scope of the term "salt". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in the separation or purification steps during the preparation process. The compounds of the present invention may form salts. For example, Compound I reacts with a certain amount, such as an equivalent amount, of an acid or a base, and the salt precipitates out in a medium or is obtained by lyophilization in an aqueous solution.

[0141] The basic fragments contained in the compounds of the present invention, including but not limited to amines, pyridine or imidazole rings, may form salts with organic or inorganic acids. Typical acids that can form salts include acetate (such as with acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate (e.g., 2-hydroxyethanesulfonate), lactate, maleate, mesylate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectinate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (such as formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate such as p-toluenesulfonate, laurate, and so on.

[0142] Certain compounds of the present invention may contain acidic fragments, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical salts formed with bases include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed with organic bases (such as organic amines), such as benzathine, dicyclohexylamine, haibamine (the salt formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, and so on. The basic nitrogen-containing groups can form quaternary ammonium salts with halides, such as small molecule alkyl halides (such as chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl), dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate), long-chain halides (such as chlorides, bromides, and iodides of decyl, dodecyl, tetradecyl, and hexadecyl), aralkyl halides (such as benzyl and phenyl bromides), and so on.

[0143] Prodrugs and solvates of the compounds of the present invention are also within the scope. Here, the term "prodrug" refers to a compound that, when treating related diseases, undergoes chemical transformation through metabolic or chemical processes to produce the compounds, salts, or solvates of the present invention. The compounds of the present invention include solvates, such as hydrates.

[0144] The compounds, salts, or solvates of the present invention may exist in tautomeric forms (such as amides and iminoethers). All these tautomers are part of the present invention.

[0145] Stereoisomers of all compounds (e.g., those due to asymmetric carbon atoms that may exist for various substitutions), including their enantiomeric forms and diastereomeric forms, are within the scope contemplated by the present invention. The individual stereoisomers of the compounds in the present invention may not coexist with other isomers (e.g., having special activities as a pure or substantially pure optical isomer), or may also be a mixture, such as a racemate, or a mixture formed with all other stereoisomers or a part thereof. The chiral centers of the present invention have two configurations, S or R, as defined by the recommendations of the International Union of Pure and Applied Chemistry (IUPAC) in 1974. The racemic form can be resolved by physical methods, such as fractional crystallization, or by separation and crystallization after derivation into diastereoisomers, or by chiral column chromatography. The individual optical isomers can be obtained from the racemate by suitable methods, including but not limited to traditional methods, such as recrystallization after salting with an optically active acid.

[0146] The compounds in the present invention, obtained by preparation, separation and purification in sequence, have a weight content equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compounds), and are listed in the description in the text. Such "very pure" compounds of the present invention are also part of the present invention here.

[0147] All configurational isomers of the compounds of the present invention are within the covered scope, whether in the form of a mixture, pure or very pure. The definition of the compounds in the present invention includes both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of carbocycles and heterocycles.

[0148] Throughout the specification, groups and substituents can be selected to provide stable moieties and compounds.

[0149] The definitions of specific functional groups and chemical terms are introduced in detail below. For the present invention, chemical elements are consistent with those defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. The definitions of specific functional groups are also described therein. In addition, the basic principles of organic chemistry and specific functional groups and reactivity are also described in "Organic Chemistry", Thomas Sorrell, University ScienceBooks, Sausalito: 1999, the entire content of which is incorporated by reference.

[0150] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all such compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures, and other mixtures. Additionally, asymmetric carbon atoms may represent substituents such as alkyl groups. All isomers and their mixtures are included within the scope of the present invention.

[0151] According to the present invention, the ratios of isomers in a mixture of isomers can be diverse. For example, in a mixture with only two isomers, the following combinations are possible: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present invention. Similar ratios that are readily understood by those of ordinary skill in the art, as well as ratios for more complex mixtures of isomers, are also within the scope of the present invention.

[0152] The present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic weight or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl. Compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, that contain one or more of the aforementioned isotopes or other isotopic atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as 3 H and 14 C radioactive isotopes, are also included and are useful in tissue distribution studies of drugs and substrates. Tritium, which is 3 H, and carbon-14, which is 14 C, are relatively easy to prepare and detect and are preferred isotopes. Additionally, heavier isotope substitutions such as deuterium, which is 2H has advantages in certain therapies due to its good metabolic stability, such as increasing the half-life in vivo or reducing the dosage. Therefore, it can be preferentially considered in certain cases. Isotopically labeled compounds can be prepared by general methods, by replacing non-isotopic reagents with readily available isotopic labeling reagents, using the procedures disclosed in the examples.

[0153] If the synthesis of a specific enantiomer of a compound of the present invention is to be designed, it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, the resulting diastereomeric mixture is separated, and then the chiral auxiliary is removed to obtain the pure enantiomer. Additionally, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed into diastereomeric salts with a suitable optically active acid or base, and then separated by conventional means such as fractional crystallization or chromatography, and then the pure enantiomer is obtained.

[0154] As described herein, the compounds of the present invention can be taken with any number of substituents or functional groups to expand their scope of inclusion. Generally, the term "substituted", whether it appears before or after the term "optional", in the formulations of the present invention includes the general formula of substituents, which means replacing a hydrogen radical with a specified structural substituent. When multiple positions in a specific structure are substituted with multiple specific substituents, each position of the substituent can be the same or different. The term "substituted" as used herein includes all allowable substitutions of organic compounds. Broadly speaking, allowable substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, a heteroatom such as nitrogen can have a hydrogen substituent or any allowable organic compound as described above to supplement its valence. Additionally, the present invention is not intended to limit the allowable substituted organic compounds in any way. The present invention believes that combinations of substituents and variable groups are good for the treatment of diseases in the form of stable compounds, such as infectious diseases or proliferative diseases. The term "stable" here refers to a compound that is stable enough to maintain the integrity of the compound structure for a sufficient period of time for detection, preferably effective for a sufficient period of time, and is used herein for the above purposes.

[0155] Metabolites of the compounds and their pharmaceutically acceptable salts involved in this application, as well as prodrugs that can be converted in vivo into the structures of the compounds and their pharmaceutically acceptable salts involved in this application, are also included in the claims of this application. In the present invention, the term "prodrug" refers to a compound that is obtained by chemically modifying a drug to introduce a labile group, which is inactive or has less activity in vitro, but releases the active drug through the participation of enzymes (such as hydrolases, oxidases, etc.) or non-enzymatic participation (such as pH, light, radiation, etc.) in vivo to exert its pharmacological effect. Examples of the prodrugs include (but are not limited to): carboxylic acid esters, phosphate esters, carbamates, carbonates, etc. Examples of the labile group structures include (but are not limited to):

[0156]

[0157] Preparation method

[0158] The preparation method of the compound of formula (A0) of the present invention will be described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention pertains.

[0159] Typically, the preparation process flow of the compounds of the present invention is as follows. Unless otherwise specified, the raw materials and reagents used can be purchased through commercial channels.

[0160] Preferably, the compounds of the present invention are prepared by the following method (taking formula (I0) as an example)

[0161]

[0162] (i) In an inert solvent, in the presence of a base, with or without a Pd catalyst, with or without a condensing agent, the compound of formula V-1 reacts with the compound of formula V-2 to obtain the compound of formula V-3;

[0163] (ii) In an inert solvent, in the presence of a base, with or without a Pd catalyst, the compound of formula V-3 reacts with the compound of formula V-4 to obtain the compound of formula V-5;

[0164] (iii) The protecting groups PG1, PG2 and / or PG3 of the compound of formula V-5 are removed under the action of an acid (such as TFA, HCl, etc.) or under Pd-catalyzed hydrogenation conditions to obtain the compound of formula (I0);

[0165] In the formula,

[0166] X1, X2 and X3 are each independently selected from: OH, halogen, OTf, OTs or OMs;

[0167] PG1 and PG2 are each independently selected from: Boc, Cbz, Bn or PMB;

[0168] PG3 is selected from: none, Boc, Cbz, Bn or PMB;

[0169] V1, V2, V3, V5, R 1 、R x 、Z, W and n are as defined above.

[0170] Pharmaceutical compositions and methods of administration

[0171] The pharmaceutical composition according to the present invention is used for preventing and / or treating the following diseases: inflammation, cancer, cardiovascular diseases, infections, immune diseases, metabolic diseases.

[0172] The compound of general formula (I0) can be used in combination with other drugs known for treating or ameliorating similar conditions. When administered in combination, the mode of administration and dosage of the original drug can remain unchanged, while the compound of formula I is taken simultaneously or subsequently. When the compound of formula (I0) is taken simultaneously with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of formula I simultaneously can be preferably used. The combination of drugs also includes taking the compound of formula (I0) and one or more other known drugs over an overlapping time period. When the compound of formula (I0) is used in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage when they are used alone.

[0173] Drugs or active ingredients that can be used in combination with the compounds of general formula (I0) include, but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomabtiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, ocaritinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.), EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Cabozantinib, Sunitinib, donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Milciclib, Trilaciclib, Lerociclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) or combinations thereof. The dosage forms of the pharmaceutical composition of the present invention include (but are not limited to): injections, tablets, capsules, aerosols, suppositories, films, dripping pills, external rubbing agents, controlled-release or sustained-release or nano preparations.

[0174] The pharmaceutical composition of the present invention comprises a compound of the present invention or a pharmaceutically acceptable salt thereof within a safe and effective amount range, and a pharmaceutically acceptable excipient or carrier. The "safe and effective amount" herein refers to: an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 - 2000 mg of the compound of the present invention per dose, and more preferably, contains 10 - 1000 mg of the compound of the present invention per dose. Preferably, the "per dose" is a capsule or a tablet.

[0175] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gelling substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" herein means that the components in the composition can be admixed with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Some examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0176] There is no particular limitation on the administration mode of the compound or pharmaceutical composition of the present invention. Representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0177] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or calcium phosphate, or is mixed with the following components: (a) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxypropylmethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizing agents, such as paraffin wax; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0178] Solid dosage forms, such as tablets, dragees, capsules, pills, and granules, can be prepared with coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed and released in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and wax-like substances. If necessary, the active compound can also be in the form of microcapsules with one or more of the above excipients.

[0179] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifying agents, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances, etc.

[0180] In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and fragrances.

[0181] In addition to the active compound, the suspension may contain suspending agents, for example, ethoxylated isooctadecanol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum monostearate, and agar, or mixtures of these substances, etc.

[0182] Compositions for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstituting into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0183] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required under sterile conditions.

[0184] The treatment method of the present invention can be administered alone or in combination with other treatment means or therapeutic drugs.

[0185] 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. For a person weighing 60 kg, the daily dosage is usually 1 - 2000 mg, preferably 50 - 1000 mg. Of course, the specific dosage should also consider factors such as the administration route and the health status of the patient, which are within the scope of the skills of a skilled physician.

[0186] The present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I0) according to the present invention or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, thereby forming a pharmaceutical composition.

[0187] The present invention also provides a treatment method, which comprises the steps of: administering to a subject in need of treatment the compound of general formula (A0) according to the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, or administering the pharmaceutical composition according to the present invention, for selectively inhibiting KRAS G12D .

[0188] Compared with the prior art, the present invention has the following main advantages:

[0189] (1) The compound has a good selective inhibitory effect on KRAS G12D ;

[0190] (2) The compound has better pharmacodynamic and pharmacokinetic properties and lower toxicity and side effects.

[0191] The following further elaborates the present invention in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are usually carried out under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0192] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the method of the present invention. The preferred methods and materials described herein are for illustrative purposes only.

[0193] The compound structure of the present invention is determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).

[0194] NMR is detected using a Bruker AVANCE-400 nuclear magnetic resonance instrument. The solvents for determination include deuterated dimethyl sulfoxide (DMSO-d6), deuterated acetone (CD3COCD3), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), etc. Tetramethylsilane (TMS) is used as the internal standard, and the chemical shift is measured in parts per million (ppm).

[0195] Liquid chromatography-mass spectrometry (LC-MS) was detected using a Waters SQD2 mass spectrometer. The determination of HPLC was performed using an Agilent 1100 high-pressure chromatograph (Microsorb 5 micron C18 100x 3.0 mm chromatographic column).

[0196] The thin-layer chromatography silica gel plate used was Qingdao GF254 silica gel plate. For TLC, it was 0.15 - 0.20 mm, and for preparative thin-layer chromatography, it was 0.4 mm - 0.5 mm. For column chromatography, Qingdao silica gel 200 - 300 mesh silica gel was generally used as the carrier.

[0197] The starting materials in the examples of the present invention are all known and commercially available, or can be synthesized by adopting or according to the literature reported in the art.

[0198] Unless otherwise specified, all reactions of the present invention were carried out under the protection of dry inert gas (such as nitrogen or argon) by continuous magnetic stirring, and the reaction temperature was in degrees Celsius.

[0199] Example CA-1: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

[0200]

[0201] First step: Preparation of tert-butyl (1R,5S)-3-(7-(3-(bis(4-methoxybenzyl)amino)-5-chloro-2-fluoro-6-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0202] Dissolve ((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H))methanol (78 mg, 0.81 mmol) in tetrahydrofuran (2 mL), and then add sodium tert-butoxide (78 mg, 0.81 mmol). After stirring the mixture at room temperature for 1 min, add a solution of tert-butyl (1R,5S)-3-(7-(3-(bis(4-methoxybenzyl)amino)-5-chloro-2-fluoro-6-(trifluoromethyl)phenyl)-2-(methylsulfinyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 0.27 mmol) in tetrahydrofuran (1 mL). Stir the resulting mixture at room temperature for 1 h, then quench with water and extract with ethyl acetate (30 mL x 3). Wash the combined organic phases with saturated sodium chloride solution, dry over anhydrous sodium sulfate and filter. Concentrate the filtrate under reduced pressure, and separate the residue by silica gel column chromatography to obtain the target product (150 mg).

[0203] Step 2: Preparation of tert-butyl (1R,5S)-3-(7-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-5-(prop-1-yn-1-yl)-6-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H))methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0204] Under argon protection, tert-butyl (1R,5S)-3-(7-(3-(bis(4-methoxybenzyl)amino)-5-chloro-2-fluoro-6-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.15 mmol) was dissolved in toluene (3 mL). Subsequently, tributyl(prop-1-yn-1-yl)tin (198 mg, 0.60 mmol) and dichlorobis(tert-butyl)-(4-dimethylaminophenyl)phosphine palladium(II) (32 mg, 0.045 mmol) were added. The resulting mixture was stirred at 110 °C for 2 h under an argon atmosphere, then quenched with water and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (110 mg).

[0205] Step 3: Preparation of 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

[0206] tert-Butyl (1R,5S)-3-(7-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-5-(prop-1-yn-1-yl)-6-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 0.11 mmol) was dissolved in trifluoroacetic acid (4 mL). The resulting mixture was stirred at 40 °C for 2 h and then concentrated under reduced pressure. The residue was separated by preparative liquid chromatography to obtain the target product (40 mg).

[0207] LC-MS: m / z 663 (M + H) + 。 1 1H NMR (400 MHz, DMSO-d6): δ 7.93 (s, 1H), 6.90 (d, J = 8.4 Hz, 1H),

[0208] 6.07(s, 2H), 5.10–5.00(m, 1H), 4.84–4.72(m, 1H), 4.65–4.56(m, 1H), 4.09–3.93(m, 3H), 3.90–3.80(m, 2H), 3.59–3.42(m, 3H), 3.14–2.95(m, 4H), 2.86–2.78(m, 1H), 2.77–2.66(m, 1H), 2.12–1.40(m, 16H).

[0209] Example CA-1 was subjected to chiral resolution to obtain two isomers, Example CA-1A and Example CA-1B: 3-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline and 3-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

[0210]

[0211] Example C1A

[0212] LC-MS: m / z 663 (M + H) + 。

[0213] Example C1B

[0214] LC-MS: m / z 663 (M + H) + 。

[0215] The following compounds were synthesized from different starting materials in the same manner as in Example C1:

[0216] Example CA-2 3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-4-(1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

[0217]

[0218] LC-MS: m / z 677 (M+H) + 。

[0219] Example CA-2 was subjected to chiral resolution to obtain four isomers, namely Example CA-2A, Example CA-2B, Example CA-2C, and Example CA-2D: 3-((S)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-4-((1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline, 3-((R)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-4-((1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline, 3-((S)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-4-((1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline, and 3-((R)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-4-((1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-(prop-1-yn-1-yl)-4-(trifluoromethyl)aniline

[0220]

[0221] Example CA-2A

[0222] LC-MS: m / z 677 (M+H) + 。

[0223] Example CA-2B

[0224] LC-MS: m / z 677 (M+H) + 。

[0225] Example CA-2C

[0226] LC-MS: m / z 677 (M+H) + 。

[0227] Example CA-2D

[0228] LC-MS: m / z 677 (M+H) + 。

[0229] Example CA-3 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-ethynyl-4-(trifluoromethyl)aniline

[0230]

[0231] LC-MS: m / z 649 (M+H) + 。

[0232] Example CA-3 was resolved into two isomers, Example CA-3A and Example CA-3B: 3-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-ethynyl-4-(trifluoromethyl)aniline and 3-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-ethynyl-4-(trifluoromethyl)aniline

[0233]

[0234] Example CA-3A

[0235] LC-MS: m / z 649 (M+H) + 。

[0236] Example CA-3B

[0237] LC-MS: m / z 649 (M+H)+ 。

[0238] Example CB-1 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-5-chloro-2-fluoro-4-(trifluoromethyl)aniline

[0239]

[0240] Step 1: Dissolve tert-butyl (1R,5S)-3-(7-(3-(bis(4-methoxybenzyl)amino)-5-chloro-2-fluoro-6-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.05 mmol) in trifluoroacetic acid (2 mL). The resulting mixture was stirred at 40 °C for 2 h and then concentrated under reduced pressure. The residue was separated by preparative liquid chromatography to obtain the target product (15 mg, 45.6%).

[0241] LC-MS: m / z 659 (M+H) + 。

[0242] Example CB-1 was subjected to chiral resolution to obtain two isomers, Example CB-1A and Example CB-1B: 3-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-5-chloro-2-fluoro-4-(trifluoromethyl)aniline and 3-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-5-chloro-2-fluoro-4-(trifluoromethyl)aniline

[0243]

[0244] Example CB-1A

[0245] LC-MS: m / z 659 (M+H) + 。

[0246] Example CB-1B

[0247] LC-MS: m / z 659 (M+H) + 。

[0248] The following compounds were synthesized from different starting materials by the same method as in Example CB-1:

[0249] Example CB-2 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-methyl-4-(trifluoromethyl)aniline

[0250]

[0251] LC-MS: m / z 639 (M+H) + 。

[0252] Example CB-2 was subjected to chiral resolution to obtain two isomers, Example CB-2A and Example CB-2B: 3-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-methyl-4-(trifluoromethyl)aniline and 3-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-5-methyl-4-(trifluoromethyl)aniline

[0253]

[0254] Example CB-2A

[0255] LC-MS: m / z 639 (M+H) + 。

[0256] Example CB-2B

[0257] LC-MS: m / z 639 (M+H) + .

[0258] Example CB-3 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-3-methyl-4-(trifluoromethyl)aniline

[0259]

[0260] LC-MS: m / z 639 (M+H) + .

[0261] Example CB-3 was subjected to chiral resolution to obtain two isomers, Example CB-3A and Example CB-3B: 5-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-3-methyl-4-(trifluoromethyl)aniline and 5-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-2-fluoro-3-methyl-4-(trifluoromethyl)aniline

[0262]

[0263] Example CB-3A

[0264] LC-MS: m / z 639 (M+H) + .

[0265] Example CB-3B

[0266] LC-MS: m / z 639 (M+H) + .

[0267] Example CB-4 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)aniline

[0268]

[0269] LC-MS: m / z 641(M+H) + 。

[0270] Example CB-4 was subjected to chiral resolution to obtain two isomers, Example CB-4A and Example CB-4B: 3-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)aniline and 3-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)aniline

[0271] Example CB-4A

[0272] LC-MS: m / z 641(M+H) + 。

[0273] Example CB-4B

[0274] LC-MS: m / z 641(M+H) + 。

[0275] Examples CC-1A and CC-1B 4-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-amine and 4-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-amine

[0276]

[0277] Example CC-1A

[0278] LC-MS: m / z 631 (M+H)+.

[0279] Example CC-1B

[0280] LC-MS: m / z 631 (M+H)+.

[0281] Examples CC-2A and CC-2B 4-((S)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-amine and 4-((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bipyrrolidine]-7a'(5'H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-amine

[0282]

[0283] Example CC-2A

[0284] LC-MS: m / z 635 (M+H)+.

[0285] Example CC-2B

[0286] LC-MS: m / z 635 (M+H)+.

[0287] Biological test examples

[0288] The following biological test examples further describe and explain the present invention, but these examples are not intended to limit the scope of the present invention.

[0289] KRAS Gl2D Binding inhibition experiment

[0290] Experimental procedure

[0291] The binding ability of the compound to KRAS was detected by TR-FRET technology. The biotin-labeled GDP-loaded KRAS G12D recombinant human protein was co-incubated with a Cy5-labeled tracer, europium-labeled streptavidin, and the compound (final concentration of 2% DMSO) in a buffer (HEPES (pH 7.5), MgCl2, Tween-20, and DTT). After incubation at 22 °C for 60 min, the reaction activity was detected by the dual-wavelength technique of an EnVision multimode microplate reader, and the protein-bound amount (POC) was calculated using the ratiometric emission factor. G12D 100 POC indicates the absence of the compound; 0 POC indicates that the control compound completely inhibits the binding of the tracer to KRAS

[0292] at this concentration. The POC values were curve-fitted using a four-parameter logistic model, and the IC G12D represents the 50 POC concentration value. 50

[0293] The results showed that the compounds of the examples of the present invention exhibited good inhibitory activity against KRAS G12D

[0294] ERK phosphorylation inhibition experiment

[0295] Experimental procedure

[0296] KRAS G12D mutant cells (such as GP2D, AGS, etc.) were seeded in a 384-well plate and cultured overnight in a 37 °C, 5% CO2 incubator.

[0297] 200 nL of the diluted compound was added using an Echo 500, with a final DMSO concentration of 0.5%, and cultured in a 37 °C, 5% CO2 incubator for 1 hour. hEGF was added and allowed to act for 10 minutes.

[0298] The culture medium was removed, and a cell fixative was added to fix the cells ​​

[0299] Wash once with PBS and incubate with cold 100% methanol.

[0300] Remove the methanol and add PBS to wash once.

[0301] Remove the PBS, add Li-Cor blocking buffer to each well, and block at room temperature for 1 hr.

[0302] Remove the blocking solution, add the primary antibody mixture to each well, and incubate overnight at 4°C or at room temperature.

[0303] Remove the primary antibody mixture and add PBST to wash 3 times.

[0304] Add the secondary antibody mixture and incubate in the dark at room temperature for 45 min.

[0305] Remove the secondary antibody mixture, add PBST to wash 3 times, finally aspirate the PBST, invert and centrifuge at 1000 rpm for 1 min.

[0306] Read with Odyssey CLx.

[0307] The results show that the compound in the embodiment of the present invention shows good inhibitory activity against the phosphorylation of ERK in KRAS G12D mutant cells.

[0308] Inhibitory experiment of the compound on the proliferation of KRAS G12D mutant cells

[0309] Experimental procedure: 1. Cell culture

[0310] (a) Resuscitate the cells in a T75 cell culture flask:

[0311] (b) Passage the cells when the cell confluence reaches 80 - 90%.

[0312] 2. Cell proliferation detection

[0313]

[0314] Experimental procedure

[0315] Use a nanoliter pipetting system to add the diluted test compound to a 384-well cell culture plate, and set up replicate wells. Add an equal volume of medium to the positive control group; add an equal volume of DMSO to the negative control group, and centrifuge at 1000 rpm at room temperature for 1 min.

[0316] Inoculate the cells into a) a 384-well culture plate. Add an equal amount and volume of cells to the negative control group, and only add an equal volume of medium to the positive control group. Centrifuge at 1000 rpm at room temperature for 1 min. The final DMSO concentration of the compound is 0.5%. Place it in a 37°C, 5% CO2 constant temperature incubator and incubate for 7 days.

[0317] Add 20 μL / well of 3D into a 384-well cell culture plate, shake at 320 rpm for 20 min in the dark, and incubate at room temperature in the dark for 2 hrs.

[0318] Read the luminescence value using an Envision multimode microplate reader.

[0319] 3. Data analysis

[0320] Use the following formula to calculate the inhibition rate (IR) of the test compound: IR (%) = (1 - ((RLU compound - RLU blank control) / (RLU vehicle control - RLU blank control))) * 100%. Calculate the inhibition rates of compounds at different concentrations in Excel, and then use GraphPad Prism software to plot the inhibition curve and calculate related parameters, including the minimum inhibition rate, maximum inhibition rate, and IC 50 .

[0321] The reference compound MRTX1133 has the following structure:

[0322]

[0323] Table 1 Cell proliferation inhibition activities of the compounds in the examples of the present invention

[0324] GP2D AsPC-1 <![CDATA[IC 50 (nM)]]> <![CDATA[IC 50 (nM)]]> MRTX1133 1.28 6.77 Example C1 2.72 9.29 Example C1A 1.24 6.75 Example C1B >100 264.30

[0325] The results show that the compounds in the examples of the present invention exhibit good inhibitory activities against the proliferation of KRAS G12D mutant cells.

[0326] Pharmacokinetic test evaluation

[0327] Male ICR mice, weighing 22 - 24 g, after fasting overnight, were orally administered a solution of 30 mg / kg of the compound of the present invention or the control compound [10% DMSO + 60% PEG400 + 30% aqueous solution]. Blood samples were collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, and 24 h after administration of the compound of the present invention, and the concentrations of the compound of the present invention or the control compound in plasma were determined by LC / MS / MS.

[0328] It can be seen from the test results that the compound of the present invention has good oral pharmacokinetic properties.

[0329] Pharmacokinetic test evaluation

[0330] Male SD rats, weighing about 220 g, were fasted overnight and then orally administered a solution of 30 mg / kg of the compound of the present invention or a control compound [10% DMSO + 60% PEG400 + 30% aqueous solution]. Blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, and 24 h after administration of the compound of the present invention, and the concentration of the compound of the present invention or the control compound in plasma was determined by LC / MS / MS.

[0331] It can be seen from the test results that the compound of the present invention has good pharmacokinetic properties.

[0332] Antitumor activity pharmacodynamic test and evaluation (AsPC-1 CDX tumor model)

[0333] 100 μL of AsPC-1 tumor cell suspension containing 5x10 6 was subcutaneously inoculated into the right posterior abdomen of nude mice. The health status of the mice was monitored daily, and measurement began when the tumor grew to be palpable. The tumor volume calculation formula was used: 0.5 x L x W 2 , where L and W represent the length and width of the tumor, respectively. When the tumor grew to ~200 mm 3 , the mice were randomly grouped. The mice were intraperitoneally injected or orally administered the corresponding dose of the compound daily, and their general status was monitored simultaneously. The tumor was measured 3 times a week, and the body weight was measured 2 times a week.

[0334] It can be seen from the test results that the compound of the present invention has good antitumor effects.

[0335] All documents mentioned in the present invention are cited in this application as references, as if each document was cited separately as a reference. 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 appended claims of this application.

Claims

1. A compound of formula (A0), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs: The ring C is selected from the following group of groups: Y is a bond or O; For Z is selected from a bond or a substituted or unsubstituted group of the following group: C1-C6 alkylene; wherein, The substitution means being substituted by one or more Rs; W is selected from substituted or unsubstituted C3-C 14 cycloalkyl, or substituted or unsubstituted 4- to 14-membered saturated or unsaturated heterocyclic group; wherein the substitution means being substituted by one or more R; R 1 is selected from hydrogen or deuterium; n is 0, 1, 2, 3, 4, 5 or 6; R 11 selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic group; m is 0, 1, 2, 3, 4, 5 or 6; R 10 selected from the group consisting of: V1, V2, V3, V5 are each independently selected from: N or CR v ; R v same or different, each independently selected from the following groups of substituted or unsubstituted groups: H, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C1-C3 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclic oxy group, halogenated C1-C3 alkyl, halogenated C3-C6 cycloalkyl, halogenated 4-6 membered heterocyclic group, (HO)-C1-C3 alkyl, (HO)-C3-C6 cycloalkyl, (NH2)-C1-C3 alkyl, (NH2)-C3-C6 cycloalkyl, halogen, CN, -C≡CH, -C≡C-CH3, -C≡C-(C3-C6 cycloalkyl), -C≡C-(4-6 membered heterocyclic group), OH, NH2, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl), SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl), wherein the substitution means being substituted by one or more R; Or V1 and V2 cyclize to form a substituted or unsubstituted group selected from the group consisting of phenyl or 5-6 membered heteroaryl; wherein, the substitution means being substituted by one or more Rs; X is selected from: S, or O; Each R is the same or different and is independently selected from: deuterium, C1-C 18 alkyl, deuterated C1-C 18 alkyl, halogenated C1-C 18 alkyl, (C3-C 18 cycloalkyl)C1-C 18 alkyl, (4-20 membered heterocyclic group)C1-C 18 alkyl, (C1-C 18 alkoxy)C1-C 18 alkyl, (C3-C 18 cycloalkoxy)C1-C 18 alkyl, (4-20 membered heterocyclic group oxy)C1-C 18 alkyl, vinyl, ethynyl, (C1-C6 alkyl)vinyl, deuterated (C1-C6 alkyl)vinyl, halogenated (C1-C6 alkyl)vinyl, (C1-C6 alkyl)ethynyl, deuterated (C1-C6 alkyl)ethynyl, halogenated (C1-C6 alkyl)ethynyl, (C3-C 14 cycloalkyl)ethynyl, (4-14 membered heterocyclic group)ethynyl, C1-C 18 alkoxy, deuterated C1-C 18 alkoxy, halogenated C1-C 18 alkoxy, 4-20 membered heterocyclic group C(O), C3-C 20 cycloalkyl, 4-20 membered heterocyclic group, C6-C 14 aryl, 5-14 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amine, amide, sulfonamide, sulfone or urea group.

2. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to claim 1, characterized in that, The compound is a compound of formula (I0), Among them, R x is selected from hydrogen, or CH3; R p selected from hydrogen, or a C1-C3 alkyl group, a C3-C6 cycloalkyl group, or a 4-6 membered heterocyclic group; R 10 , Z, W, R 1 , n and m are as defined in claim 1.

3. The compound according to claim 1, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, characterized in that, R 10 wherein V1, V2, V3 and V5 are each independently selected from: N, or CR v ; R v identical or different, are each independently selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C1-C3 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclic oxy group, halo C1-C3 alkyl, halo C3-C6 cycloalkyl, halo 4-6 membered heterocyclic group, (HO)-C1-C3 alkyl, (HO)-C3-C6 cycloalkyl, (NH2)-C1-C3 alkyl, (NH2)-C3-C6 cycloalkyl, halogen, CN, -C≡CH, -C≡C-CH3, -C≡C-(C3-C6 cycloalkyl), -C≡C-(4-6 membered heterocyclic group), OH, NH2, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl), SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl).

4. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to claim 1, characterized in that, R 10 wherein R y2 is NH2, and R y1 , R y3 , R y4 and R y5 are each independently selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C1-C3 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclic oxy group, halogenated C1-C3 alkyl, halogenated C3-C6 cycloalkyl, halogenated 4-6 membered heterocyclic group, (HO)-C1-C3 alkyl, (HO)-C3-C6 cycloalkyl, (NH2)-C1-C3 alkyl, (NH2)-C3-C6 cycloalkyl, halogen, CN, -C≡CH, -C≡C-CH3, -C≡C-(C3-C6 cycloalkyl), -C≡C-(4-6 membered heterocyclic group), OH, NH2, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl), SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl). In another preferred example, Ry5 is selected from: halo C1-C3 alkyl (such as CF3, CF2CF3), C3-C6 cycloalkyl, or 4-6 membered heterocyclic group. In another preferred example, Ry1 is selected from: H or halogen. In another preferred example, R y3 is selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, -C≡CH, -C≡C-CH3, -C≡C-(C3-C6 cycloalkyl), -C≡C-(4-6 membered heterocyclic group), or halogen. In another preferred example, Ry4 is selected from: C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, -C≡CH, -C≡C-CH3, -C≡C-(C3-C6 cycloalkyl), -C≡C-(4-6 membered heterocyclic group), or halogen.

5. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to claim 1, characterized in that, R 10 For U is selected from: N, CH, CD, CF; R 4 selected from the group consisting of substituted or unsubstituted: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; R 5 、R 6 、R 7 、R 9 are the same or different and each independently selected from the group consisting of substituted or unsubstituted groups: H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; wherein said substitution means being substituted by one or more R; R 8 is NH2. In another preferred example, U, R 6 , R 7 , R 9 and R 8 are as defined above; R 5 selected from the group consisting of substituted or unsubstituted: H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; wherein said substitution means being substituted by one or more R; R 4 Selected from the group consisting of substituted or unsubstituted groups: H, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C1-C3 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclic oxy group, halo C1-C3 alkyl, halo C3-C6 cycloalkyl, halo 4-6 membered heterocyclic group, (HO)-C1-C3 alkyl, (HO)-C3-C6 cycloalkyl, (NH2)-C1-C3 alkyl, (NH2)-C3-C6 cycloalkyl, halogen, CN, -C≡CH, OH, NH2, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl), SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl); wherein said substitution means being substituted by one or more R. In another preferred example, R 4 and R 5 are as defined above, U is CH, R 6 , R 7 and R 9 are independently H or deuterium, and R8 is NH2.

6. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to claim 1, characterized in that, R 10 For U’ is selected from: O, or S; U” is selected from: N, or C(CN); R 7’ 、R 8’ 、R 9’ are the same or different and each independently selected from the group consisting of substituted or unsubstituted groups: H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; wherein said substitution means being substituted by one or more R; R 5’ is NH2.

7. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to claim 1, wherein, It has the structure shown in formula (I-A), or formula (I-B): R 10 、Z, W, R 1 and n are defined as described in claim 1.

8. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to claim 1, characterized in that, The compound is selected from the group consisting of: Among them, V1, V2, V3, V5, R v , Z, W, R 1 and n are defined as described in claim 1.

9. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to claim 1, characterized in that, It has the structure shown in formula (II-A), or formula (II-B), or formula (II-C) or formula (II-D), or formula (II-E) or formula (II-F): R 12 identical or different, each independently selected from hydrogen or deuterium; R 4 selected from the group consisting of substituted or unsubstituted groups: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; wherein said substitution means being substituted by one or more R; R 5 selected from the group consisting of substituted or unsubstituted: H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; wherein said substitution means being substituted by one or more R; o is 0, 1 or 2; Wherein, the definitions of V1, V2, V3, V5, and R are as described in claim 1.

10. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to claim 1, characterized in that, Selected from the group consisting of substituted or unsubstituted groups: aniline, naphthylamine, 5- to 6-membered monocyclic heteroaryl (such as pyridyl) amine, 9- to 10-membered bicyclic heteroaryl (such as indazolyl, benzothiazole, benzothiophene, benzofuran, quinoline, quinazoline) amine, wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, NH2, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclic group, C2-C6 alkenyl, C2-C6 alkynyl; preferably, Selected from:

11. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to claim 1, characterized in that, Selected from the group consisting of substituted or unsubstituted 9- to 10-membered bicyclic heteroaryl (such as indazolyl, benzothiazole, benzothiophene, benzofuran, pyridothiazole, pyridothiophene, pyridofuran) amines, wherein the substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, NH2, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclic group, C2-C6 alkenyl, C2-C6 alkynyl; preferably, Selected from:

12. A compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to any one of claims 1-8, characterized in that W is selected from: a substituted or unsubstituted 4- to 7-membered monocyclic heterocyclic group, a substituted or unsubstituted C3-C7 monocyclic cycloalkyl group, a substituted or unsubstituted 6- to 10-membered bicyclic heterocyclic group, a substituted or unsubstituted C6-C10 bicyclic cycloalkyl group, a substituted or unsubstituted 7- to 12-membered tricyclic heterocyclic group, a substituted or unsubstituted C7-C 12 tricyclic cycloalkyl group, preferably, W is a substituted or unsubstituted 8- to 12-membered N-containing heterocyclic group, wherein the substitution means being substituted by one or more Rs, and the definition of R is as described in claim 1; Preferably, ring W is selected from:

13. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to any one of claims 1 to 12, characterized in that, The compound is selected from the group consisting of: Or selected from the group consisting of: Or selected from the group consisting of: Or selected from the group consisting of: Or selected from the group consisting of:

14. A pharmaceutical composition, characterized in that, Comprising one or more compounds, their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs as described in any one of claims 1-13; And a pharmaceutically acceptable carrier.

15. Use of a compound according to any one of claims 1-13, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or the pharmaceutical composition according to claim 14, characterized in that For the preparation of a medicament for preventing and / or treating a disease related to the activity or expression level of KRAS G12D ​

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