Ring group substituted aromatic heterocyclic ring inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a substituted cyclo-substituted aromatic heterocycle inhibitor as well as a preparation method and application thereof. Specifically, the compound disclosed by the invention has a structure shown in a formula (I), and each substituent group is defined in the specification. The invention further discloses a preparation method of the compound and application of the compound as a KRAS mutation inhibitor. The compound has a very good inhibition effect on KRAS mutation and has better pharmacodynamic and pharmacokinetic performance and lower toxic and side effects.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a ring-substituted aromatic heterocyclic inhibitor, a preparation method and an application thereof. Background Art

[0002] RAS mutations cause approximately a quarter of all human tumors, resulting in nearly one million deaths each year. Within 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 (primarily non-small cell lung cancer).

[0003] KRAS protein, a small GTPase encoded by the KRAS gene, is an important regulator of cell growth. Once activated, KRAS activates multiple signaling pathways, promoting cell proliferation. The most common sites of KRAS protein mutation are codons 12, 13, and 61, with mutations at codon 12 being the most common. The most common KRAS G12 mutations are G12A, G12C, G12D, G12V, and G12S. Mutations such as G12C, G12D, and G12V occur primarily in NSCLC, CRC, and pancreatic cancer. To date, no drugs have been approved for simultaneous targeting of multiple KRAS mutations.

[0004] Because KRAS mutant target proteins are pathologically associated with a variety of diseases, particularly lung cancer, pancreatic cancer, and colorectal cancer, novel KRAS mutant inhibitors are currently needed for clinical treatment. Highly active KRAS mutant inhibitors could more effectively treat KRAS mutation-induced cancers and other diseases, while potentially reducing off-target effects, thus creating a more pressing clinical need. Summary of the Invention

[0005] The object of the present invention is to provide a novel class of compounds having an inhibitory effect on KRAS mutation and / or better pharmacodynamic properties and their use in preventing and treating KRAS mutation-related diseases.

[0006] In the first aspect of the present invention, there is provided a compound of formula I, or a stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof:

[0007]

[0008] Where,

[0009] Ring B is selected from the following group of substituted or unsubstituted groups: C3-C 20 Cycloalkyl, 4-20 membered saturated or partially saturated heterocyclic group;

[0010] L1 is selected from none, O or NR L , R L The following groups are substituted or unsubstituted: H, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 20 Cycloalkyl, 4-20 membered saturated or unsaturated heterocyclic group;

[0011] V 1 、V 2 、V 3 Each independently selected from the group consisting of CH, CR 1 or N; R 1 Selected from the group consisting of substituted or unsubstituted H, deuterium, cyano, halogen, nitro, amino (-NH2), hydroxyl, oxo (=O), C1-C 10 Alkyl, halogenated C1-C 10 Alkyl, C2-C 10 Alkenyl, halogenated C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C3-C 20 Cycloalkyl, phenyl, benzyl, 4-20 membered saturated or unsaturated heterocyclic group, C2-C6 ester group, amino group, amide group (-CONH2), sulfone group or urea group;

[0012] R 2 Selected from the following substituted or unsubstituted groups: C4-C 14 Cycloalkyl, 4-14 membered heterocyclic group, C6-C 14 Aryl, 5-14 membered heteroaryl, -OR a 、-NR a R b 、-CONR a R b 、-SO2NR a R b 、-NR a COR b 、-NR a SO2R b or -NR a CONR a R b ; Each R a 、R b The same or different, each independently selected from the following groups: substituted or unsubstituted: H, C1-C 10 Alkyl, C4-C 14 Cycloalkyl, 4-14 membered heterocyclyl, 4-14 membered heterocyclylalkyl, or R a and Rb and the atoms connected thereto form a substituted or unsubstituted 4-14 membered heterocyclic group; wherein the substitution refers to substitution by one or more R;

[0013] X is selected from the group consisting of: bond, O, NH, N(C1-C3 alkyl), -C≡C-;

[0014] Y is selected from: a bond, a substituted or unsubstituted C1-C6 alkylene; wherein the substitution refers to substitution by one or more R;

[0015] 1) Z is selected from:

[0016] Wherein, W1 is selected from the following groups: substituted or unsubstituted: C3-C 20 Cycloalkyl, 4-20 membered saturated or unsaturated heterocyclic group; R 4 Selected from the group consisting of substituted or unsubstituted H, deuterium, cyano, halogen, nitro, amino (-NH2), hydroxyl, oxo (=O), C1-C 10 Alkyl, halogenated C1-C 10 Alkyl, C2-C 10 Alkenyl, halogenated C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C3-C 20 Cycloalkyl, phenyl, benzyl, 4-20 membered saturated or unsaturated heterocyclic group, C2-C6 ester group, amino group (NR a R b ), amide (-CONH2), =CH2, halo =CH2, C1-C 10 Alkylene, halogenated C1-C 10 Alkylene, sulfone or urea; wherein n is 0, 1, 2, 3, 4, 5, 6, 7 or 8, and the substitution refers to substitution by one or more R;

[0017] or

[0018] 2) Z is selected from: -L4-Q2 or

[0019] Wherein, ring W2 is selected from the following groups: substituted or unsubstituted: none, C3-C6 cycloalkylene, 4-6 membered saturated or unsaturated heterocyclylene;

[0020] L4 is selected from the group consisting of a substituted or unsubstituted bond, a C1-C6 alkylene group, and a deuterated C1-C6 alkylene group;

[0021] Q2 is selected from the following substituted or unsubstituted groups: C1-C 10 Alkoxy, C3-C 10Cycloalkyl-O-, 4-10 membered heterocyclyl-O-, C3-C 10 Cycloalkyl (C1-C6 alkylene) -O-, 4-10 membered heterocyclic (C1-C6 alkylene) -O-, C3-C 10 Cycloalkyl C1-C6 alkyleneoxy, 4-10 membered heterocyclic C1-C6 alkyleneoxy, C3-C 10 Cycloalkyl, phenyl, benzyl, naphthyl, 4-12 membered heterocyclic group, NHR 9 or NR 9 R 10 ; R 9 and R 10 Each independently selected from the following groups: substituted or unsubstituted C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, (C3-C 10 cycloalkyl)C1-C6 alkylene, (4-10 membered heterocyclic)C1-C6 alkylene, or R 9 and R 10 The N atom to which it is connected together forms a substituted or unsubstituted 4-10 membered heterocyclic group; wherein the substitution refers to substitution by one or more R;

[0022] Unless otherwise specified, the substitution refers to substitution by one or more R, each R being the same or different and independently selected from the group consisting of: H, deuterium, halogen, nitro, hydroxyl, oxo (=O), cyano, amino, C1-C6 alkyl, =CH2, halogenated =CH2, ≡CH, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C2-C6 alkenyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, hydroxy-substituted C3-C6 cycloalkyl, hydroxy-substituted 4-7 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -N(C1-C6 alkyl)2, -N(C1-C6 alkyl)(C3-C6 cycloalkyl), C3-C6 cycloalkyl-O-, 4-7 membered heterocyclyl-O-, C3-C6 cycloalkyl(C1-C6 alkylene)-, 4-6 membered heterocyclyl(C1-C6 alkylene)-, C3-C6 cycloalkyl-O-(C1-C6 alkylene)-, 4-6 membered heterocyclyl-O-(C1-C6 alkylene)-, (C C-C6 alkyl)-C≡C-, (deuterated C1-C6 alkyl)-C≡C-, (halogenated C1-C6 alkyl)-C≡C-, (C3-C6 cycloalkyl)-C≡C-, (4-6 membered heterocyclyl)-C≡C-, C1-C6 ester group, amino group, amide group, sulfonamide group, sulfone group or urea group.

[0023] In another preferred embodiment, the compound has a structure shown in formula (II):

[0024]

[0025] in,

[0026] R 5 Selected from the following substituted or unsubstituted groups: C 1-6 Alkyl, halogenated C 1-6 Alkyl or C1-C6 alkoxy;

[0027] R 6 Selected from the following substituted or unsubstituted groups: C 3-7 Cycloalkyl, or 4-7 membered saturated or unsaturated heterocyclic group;

[0028] Or, R 6 and R 5 The N atom connected thereto forms a ring B, wherein the ring B is selected from the following substituted or unsubstituted groups: C3-C 10 Cycloalkyl, 4-10 membered saturated or partially saturated heterocyclic group;

[0029] The substitution mentioned herein refers to one or more R substitutions;

[0030] Y, Z, R, R 2 、V 1 、V 2 and V 3 As described in the first aspect of the present invention.

[0031] In another preferred embodiment, R 5 Selected from substituted or unsubstituted C 1-6 alkyl;

[0032] R 6 Selected from the following substituted or unsubstituted groups: C 3-6 Cycloalkyl or 4-6 membered heterocyclic group;

[0033] Or, R 6 and R 5 The N atom commonly connected thereto forms ring B, wherein ring B is a substituted or unsubstituted group selected from the group consisting of a 5-7 membered heterocyclyl, a 7-9 membered heterospirocyclyl, a 6-10 membered heterobridged cyclyl, a 6-10 membered heterobridged cycloalkenyl, and a 7-10 membered heterocondensed cyclyl;

[0034] The substitution mentioned herein refers to one or more hydrogen being replaced by a group selected from the group consisting of halogen, amino, C 1-6 Alkyl, halogenated C 1-6 alkyl.

[0035] In another preferred embodiment, in Formula II, when R6 and R 5 The N atom connected thereto forms a ring B structure selected from the group consisting of: Substituted or unsubstituted Substituted or unsubstituted is selected from the following substituted or unsubstituted groups: The substitution refers to substitution by one or more groups selected from the group consisting of deuterium, or C1--C6 alkyl.

[0036] In another preferred embodiment, the compound has a structure shown in formula (III):

[0037]

[0038] Where,

[0039] R 4 Selected from the group consisting of: H, deuterium, cyano, halogen, nitro, amino (-NH2), hydroxyl, oxo (=O), C1-C 10 Alkyl, halogenated C1-C 10 Alkyl, C2-C 10 Alkenyl, halogenated C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C3-C 20 Cycloalkyl, phenyl, benzyl, 4-20 membered saturated or unsaturated heterocyclic group, C2-C6 ester group, amino group (NR a R b ), amide (-CONH2), =CH2, halo =CH2, C1-C 10 Alkylene, halogenated C1-C 10 an alkylene group, a sulfone group, or a urea group;

[0040] or two R adjacent to or on the same carbon atom 4 Forming a substituted or unsubstituted group selected from the following group: C3-C6 cycloalkyl, 4-7 membered heterocyclyl; the substitution refers to substitution by one or more groups selected from the following group: halogen, C1-C6 alkyl, halo C1-C6 alkyl, C2-C6 alkenyl, halo C2-C6 alkenyl, =CH2, halo =CH2;

[0041] n' is 0, 1, 2, 3, 4, 5, or 6;

[0042] Ring B, R, n, R 2 , V 1 , V 2 and V 3 As described in the first aspect of the present invention.

[0043] In another preferred embodiment, The ring W1 is selected from the following groups: substituted or unsubstituted 4-7 membered monocyclic heterocyclic group, substituted or unsubstituted C 3-6 substituted or unsubstituted 6-10 membered bicyclic spirocyclic heterocyclic group, substituted or unsubstituted 6-9 membered bicyclic cyclic heterocyclic group, substituted or unsubstituted 9-12 membered tricyclic heterocyclic group, substituted or unsubstituted 9-12 membered bridged heterocyclic group, substituted or unsubstituted 11-14 membered tetracyclic heterocyclic group, substituted or unsubstituted C7-C 10 Bridged cycloalkyl; wherein the substitution refers to substitution by one or more R; wherein the tricyclic heterocyclic group and the tetracyclic heterocyclic group are spirocyclic and / or cyclic;

[0044] Preferably, The middle ring W1 is selected from a substituted or unsubstituted 4-7 membered monocyclic nitrogen-containing heterocyclic group, a substituted or unsubstituted 8-9 membered bicyclic N-containing fused heterocyclic group, a substituted or unsubstituted 8-9 membered bicyclic N-containing spirocyclic heterocyclic group, or a substituted or unsubstituted 10 membered tricyclic nitrogen-containing heterocyclic group, or a substituted or unsubstituted 11 membered tetracyclic heterocyclic group, wherein the substitution refers to substitution with one or more R, and R is defined as described in the first aspect of the present invention;

[0045] The monocyclic nitrogen-containing heterocyclic group, bicyclic N-containing fused heterocyclic group, bicyclic N-containing spirocyclic heterocyclic group, tricyclic nitrogen-containing heterocyclic group and tetracyclic heterocyclic group optionally contain 0-3 heteroatoms independently selected from the following group: N, S or O; the tricyclic nitrogen-containing heterocyclic group and tetracyclic heterocyclic group are spirocyclic and annular;

[0046] More preferably, Select from the following groups:

[0047]

[0048] wherein n' is 0, 1, 2, 3, 4, 5 or 6; R, R 4 and n are as defined in claim 1, R, R 4 Located on any ring or alkylene chain of a polycyclic ring (such as a bridged ring or a spiro ring);

[0049] More preferably, Selected from:

[0050]

[0051] wherein n' is an integer of 0, 1, 2, 3, 4, 5 or 6; R, R 4 and n are as defined in claim 1, and R is located on any ring of a polycyclic ring (such as a bridged ring or a spiro ring) or an alkylene chain.

[0052] In another preferred embodiment, when for hour,

[0053] Y is selected from a bond, a substituted or unsubstituted C1-C6 alkylene group;

[0054] Ring W2 is selected from the following groups: substituted or unsubstituted C3-C6 cycloalkylene, 4-7 membered saturated or unsaturated heterocyclylene;

[0055] L4 is selected from the group consisting of a substituted or unsubstituted bond, a C1-C6 alkylene group, and a deuterated C1-C6 alkylene group;

[0056] Q2 is selected from the following groups substituted or unsubstituted: 5-7 membered heterocyclyl, C1-C6 alkoxy, C3-C6 cycloalkyl-O-, 4-7 membered heterocyclyl-O-, deuterated C1-C6 alkoxy, C3-C6 cycloalkyl (C1-C6 alkylene) -O-, 4-7 membered heterocyclyl (C1-C6 alkylene) -O-, C3-C6 cycloalkyl C1-C6 alkyleneoxy, 4-7 membered heterocyclyl C1-C6 alkyleneoxy, C3-C7 cycloalkyl, phenyl, benzyl, NHR 9 NR 9 R 10 ;

[0057] R 9 and R 10 Each is independently selected from the following groups: substituted or unsubstituted: C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, (C3-C6 cycloalkyl) C1-C6 alkylene, (4-7 membered heterocyclyl) C1-C6 alkylene, or R 9 and R 10 The N atom to which it is connected forms together a substituted or unsubstituted 4-8 membered heterocyclic group; wherein the substitution refers to substitution by one or more R;

[0058] Preferably, Q2 is selected from the following substituted or unsubstituted groups: 5-7 membered heterocyclyl, C1-C6 alkoxy, C3-C6 cycloalkyl-O-, 4-7 membered heterocyclyl-O-, deuterated C1-C6 alkoxy, C3-C6 cycloalkyl (C1-C6 alkylene) -O-, 4-7 membered heterocyclyl (C1-C6 alkylene) -O-, C3-C7 cycloalkyl, NHR 9 NR 9 R 10 ;

[0059] R 9 and R 10 Each is independently selected from the following groups: substituted or unsubstituted: C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, (C3-C6 cycloalkyl) C1-C6 alkylene, (4-7 membered heterocyclyl) C1-C6 alkylene, or R 9 and R 10The N atom to which it is connected forms together a substituted or unsubstituted 4-8 membered heterocyclic group; wherein the substitution refers to substitution by one or more R;

[0060] More preferably, Select from the following groups:

[0061]

[0062]

[0063] In another preferred embodiment, R 2 is selected from substituted or unsubstituted 11-13 membered tricyclic heterocyclyl, or substituted or unsubstituted 7-9 membered bicyclic heterocyclyl, wherein the substitution is substituted by one or more groups selected from the group consisting of deuterium, halogen, hydroxyl, cyano, oxo (=O), -NH2, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl ... -C6 ester group, amino group, amide group, sulfone group, urea group, sulfonamide group, C3-C6 cycloalkyl-O-, 4-7 membered heterocyclyl-O-, -NH-(C1-C6 alkyl), -NH-(C3-C6 cycloalkyl), hydroxyl-substituted C3-C6 cycloalkyl, hydroxyl-substituted 4-6 membered heterocyclyl; the heterocyclyl contains 1, 2, 3, 4 or 5 heteroatoms independently selected from the following group: S, N or O; and the heterocyclyl is a spirocyclic and / or cyclic structure:

[0064] Preferably, R 2 Select from the following groups:

[0065]

[0066] More preferably, R 2 Select from the following groups:

[0067]

[0068] In another preferred embodiment, ring B is selected from the following substituted or unsubstituted groups: C 3-7 cycloalkyl, 4-7 membered monocyclic heterocyclic group, 7-9 membered bridged heterocyclic group, 7-9 membered bridged heterocyclic alkenyl group, 7-10 membered spirocyclic heterocyclic group, 6-10 membered bicyclic fused heterocyclic group,

[0069] wherein the substitution is substituted by one or more groups selected from the group consisting of halogen, hydroxy, cyano, -NH2, oxo (=O), thio (=S), C1-C6 alkyl, cyano-substituted C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 ester, amino, acyl, Amine, sulfone, urea, sulfonamide, C3-C6 cycloalkyl-O-, 4-6 membered heterocyclyl-O-, -C(O)-NRcRd, hydroxy-substituted C3-C6 cycloalkyl, hydroxy-substituted 4-6 membered heterocyclyl; Rc and Rd are each independently selected from the following group: H, C1-C6 alkyl, C3-C6 cycloalkyl, or Rc and Rd and the nitrogen atom to which they are commonly attached together form a substituted or unsubstituted 4-7 membered heterocyclyl;

[0070] Preferably, ring B is selected from the following group:

[0071]

[0072] More preferably, Ring B is selected from the following group:

[0073] In another preferred embodiment, the compound has a structure shown in formula (IV):

[0074]

[0075] Where,

[0076] Ring B, V 1 、V 2 、V 3 、R 2 、R 4 and n are as defined in the first aspect of the present invention.

[0077] In another preferred embodiment, V1 is selected from the following group: N.

[0078] In another preferred embodiment, V2 is selected from the following group: N.

[0079] In another preferred embodiment, V3 is selected from the following group: N, CH or CR 1 ; R 1 Selected from the group consisting of cyano, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl; preferably selected from: chloro, cyano, methyl, isopropyl, cyclopropyl, trifluoromethyl,.

[0080] In another preferred embodiment, L1 is selected from none or NR L , R LThe following groups are substituted or unsubstituted: H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 11 Cycloalkyl, 4-11 membered saturated or unsaturated heterocyclic group, the substitution means substitution by one or more R.

[0081] In another preferred embodiment, L1 is selected from the following group: None or NR L , R L Selected from C 1-6 Alkyl; preferably methyl.

[0082] In another preferred embodiment, ring B is selected from the following substituted or unsubstituted groups: C3-C 10 Cycloalkyl, 4-11 membered saturated or partially saturated heterocyclic group, wherein the substitution refers to substitution by one or more R, wherein R is as described in the first aspect of the present invention.

[0083] In another preferred embodiment, ring B is selected from the following substituted or unsubstituted groups: C 3-6 Cycloalkyl, monocyclic 5-7 membered heterocyclic group, bicyclic 7-9 membered heterospirocyclic group, 6-10 membered heterobridged cyclic group, 6-10 membered heterobridged cycloalkenyl group, bicyclic 7-10 membered heterocondensed cyclic group; wherein the substitution means that one or more hydrogens are replaced by a group selected from the group consisting of halogen, amino, C 1-6 Alkyl, halogenated C 1-6 alkyl.

[0084] In another preferred embodiment, R 2 Selected from the following groups: 8-13 membered heterocyclic group, -NR a R b 、-CONNR a R b 、-NR a COR b ;

[0085] R a Select from the following group: C 1-6 alkyl;

[0086] R b is selected from substituted or unsubstituted bicyclic or tricyclic 8-12 membered heterocyclic groups, substituted or unsubstituted 8-10 membered heterocyclic groups (C 1-6 alkylene);

[0087] The substitution refers to substitution by one or more groups selected from the group consisting of cyano, amino;

[0088] Wherein, the heterocyclic group is cyclic, spirocyclic, bridged, or a combination thereof.

[0089] In another preferred embodiment, Y is selected from a bond, a substituted or unsubstituted C1-C6 alkylene group; wherein the substitution refers to substitution by one or more of the following groups: deuterium, halogen, C1-C6 alkyl.

[0090] In another preferred embodiment, the compound is selected from the following group:

[0091]

[0092] Or choose from:

[0093]

[0094]

[0095] Or choose from:

[0096] Or choose from:

[0097]

[0098]

[0099] Or choose from:

[0100]

[0101] Or choose from:

[0102]

[0103] Or choose from:

[0104]

[0105] Or choose from:

[0106]

[0107]

[0108] Or choose from:

[0109]

[0110] In another preferred embodiment, the compound is the compound prepared in the examples.

[0111] In another preferred embodiment, each substituent is the corresponding group in the compound prepared in the example.

[0112] In the second aspect of the present invention, a pharmaceutical composition is provided, comprising one or more compounds as described in the first aspect of the present invention, or their stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs; and a pharmaceutically acceptable carrier.

[0113] 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 thereof), 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, Oclatinib), PI3K inhibitors (such as Idelalisib, D uvelisib, 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, Rocieletinib, 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 Visusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.), SOS1 inhibitors (such as BI1701963), or a combination thereof.

[0114] In the third aspect of the present invention, there is provided a use of the compound as described in the first aspect of the present invention, or its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or the pharmaceutical composition as described in the second aspect of the present invention, for preparing a drug for preventing and / or treating a disease associated with the activity or expression of KRAS mutations, preferably, the disease is a tumor or a disorder.

[0115] In another preferred embodiment, 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, colon cancer, melanoma, lymphoma, blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer, or a combination thereof.

[0116] In the fourth aspect of the present invention, a method for inhibiting KRAS mutation is provided, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of the first aspect of the present invention, or its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or the pharmaceutical composition of the second aspect of the present invention.

[0117] In another preferred embodiment, the method is non-diagnostic and non-therapeutic.

[0118] In another preferred embodiment, the method is in vitro.

[0119] In another preferred embodiment, the subject is a mammal, preferably a human.

[0120] In another preferred embodiment, the object is a cell.

[0121] In the fifth aspect of the invention, an in vitro method for inhibiting the activity of a KRAS mutant is provided, comprising the steps of contacting the compound as described in the first aspect, its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or the pharmaceutical composition as described in the third aspect with a protein or cell, thereby inhibiting the activity of the KRAS mutant.

[0122] In another preferred embodiment, the cells are selected from the group consisting of macrophages, intestinal cells (including intestinal stem cells, intestinal epithelial cells), or a combination thereof.

[0123] In another preferred embodiment, the cells are from rodents (such as mice and rats) or primates (such as humans).

[0124] 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 described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS DETAILED DESCRIPTION

[0125] After long and in-depth research, the inventors unexpectedly prepared a new class of compounds that have inhibitory effects on KRAS mutations and / or better pharmacodynamic properties. Based on this, the inventors completed the present invention.

[0126] the term

[0127] In the present invention, unless otherwise specified, the terms used have the general meanings commonly known to those skilled in the art.

[0128] The term "alkyl" refers to a straight or branched chain alkane group or a cyclic hydrocarbon group (including hydrocarbon groups connected to other parts through carbon atoms on the ring or non-ring), preferably a straight or branched chain alkane group, containing 1-20 carbon atoms, such as 1-18 carbon atoms, especially 1-18 carbon atoms, preferably 1-10 carbon atoms (C1-C10), more preferably 1-6 carbon atoms (C1-C6). 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 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 monohalogen substituent or a polyhalogen substituent, the latter such as a trifluoromethyl group or an alkyl group containing Cl3), nitrile, 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 NR b P(=O)2R e , where R appears here aR may independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, 5-14 membered heterocyclic ring or C6-C14 aromatic ring, b 、R c and R d can independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, 5-14 membered heterocyclic ring or C6-C14 aromatic ring, or R b and R c Together with the N atom, it can form a heterocyclic ring; R e and C-C alkyl, C-C cycloalkyl, C-C alkenyl, C-C cycloalkenyl, C-C alkynyl, 5-14 membered heterocyclic ring or C-C aromatic ring. The above typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic ring or aromatic ring, may be optionally substituted.

[0129] The term "alkylene" refers to a group formed by removing a hydrogen atom from an alkyl or substituted alkyl group, such as methylene (e.g. or -CH2-), ethylene (such as ), propylene (such as ), isopropylidene (such as ), butylene (such as ), pentylene (such as ), hexamethylene (such as ), heptylene (such as ), In addition, the term also includes a methylene group of an alkylene group (such as C1-C18 alkylene) 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". In the present invention, alkylene also includes substituted alkylene, and the substituent can be a halogenated group (such as -CHF- or -CF2-), hydroxyl, cyano, nitro, etc.

[0130] The term "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkylene C1-C18 alkylene" has the same meaning and refers to a group formed by removing two hydrogen atoms from a cycloalkylalkyl or alkylcycloalkyl group, such as

[0131] etc. Preferably, C1-C6 alkylene is C3-C6 cycloalkylene. In the present invention, "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkylene C1-C18 alkylene" also includes substituted "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkylene C1-C18 alkylene", and the substituent may be halo, hydroxyl, cyano, nitro, etc.

[0132] In the present invention, the term "alkenyl" refers to a straight or branched hydrocarbon group containing one or more double bonds and generally having a length of 2 to 20 carbon atoms. Alkenyl is preferably C2-C6 alkenyl, more preferably C2-C4 alkenyl. Alkenyl includes, but is not limited to, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc. In the present invention, alkenyl includes substituted alkenyl. In the present invention, alkenyl also includes substituted alkenyl, and the substituents may be halo, hydroxyl, cyano, nitro, etc.

[0133] The term "alkynyl" refers to a straight or branched hydrocarbon group containing one or more triple bonds and typically having a length of 2 to 20 carbon atoms. Alkynyl groups are preferably C2-C6 alkynyl groups, more preferably C2-C4 alkynyl groups. Alkynyl groups include, but are not limited to, ethynyl, propynyl, and similar groups. In the present invention, alkynyl groups also include substituted alkynyl groups, and the substituents may be halo, hydroxyl, cyano, nitro, and the like.

[0134] In the present invention, the term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon compound group, including 1-4 rings, each containing 3-8 carbon atoms. 20 " refers to a cycloalkyl group containing 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 C3-C6 monocyclic cycloalkyl, C7-C 10 Bicyclic or tricyclic cycloalkyl. "Substituted cycloalkyl" means that one or more positions in the cycloalkyl 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 (for example, a monohalogen substituent or a polyhalogen substituent, the latter such as trifluoromethyl or an alkyl containing Cl3), nitrile, 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 NR b P(=O)2R e , where R appears here a R may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclyl, aryl or heteroaryl. b 、R c and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R b and R c Together with the N atom, it can form a heterocyclic ring; R e Can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic radical, aryl or heteroaryl.Above-mentioned typical substituents can be optionally substituted.Typical substitution also includes spirocycle, pyrimidocyclic or fused ring substituents, especially spirocyclic alkyl, spirocyclic alkenyl, spirocyclic heterocycle (excluding heteroaromatic ring), pyrimidocyclic alkyl, pyrimidocyclic alkenyl, pyrimidocyclic heterocycle (excluding heteroaromatic ring), fused cycloalkyl, fused cycloalkenyl, fused ring heterocyclic radical or fused ring aromatic ring radical, above-mentioned cycloalkyl, cycloalkenyl, heterocyclic radical and heteroaryl can be optionally substituted.The example of cycloalkyl includes but is not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl etc.

[0135] The term "C3-C20 cycloalkylene" refers to a group formed by removing two hydrogen atoms from a cycloalkyl group, such as:

[0136]

[0137] In the present invention, the term "heterocyclyl" refers to a fully saturated or partially unsaturated cyclic group (including but not limited to a 3-7 membered monocyclic ring, a 4-7 membered monocyclic ring, a 6-11 membered bicyclic ring, or an 8-16 membered tricyclic or polycyclic ring system), wherein at least one heteroatom is present in the ring having at least one carbon atom. The term "4-20 membered heterocyclyl" refers to a heterocyclyl containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms. "Heterocyclyl" has the same meaning as "saturated or unsaturated heterocyclyl" and includes, for example, benzo 4-7 membered heterocyclyl. "Heterocyclyl" is preferably a 4-14 membered heterocyclyl (including but not limited to a 4-6 membered monocyclic, 7-10 membered bicyclic or 8-14 membered tricyclic or polycyclic ring system), more preferably a 4-12 membered heterocyclyl, more preferably a 4-10 membered heterocyclyl, such as a 4-6 membered monocyclic heterocyclyl, a 7-11 membered bicyclic or tricyclic heterocyclyl, more preferably a 4-8 membered heterocyclyl, more preferably a 4-6 membered heterocyclyl. Each heterocyclic ring containing a heteroatom may have 1, 2, 3 or 4 heteroatoms, each of which is independently selected from a nitrogen atom, an oxygen atom or a sulfur atom, wherein the nitrogen atom or sulfur atom may be oxidized and the nitrogen atom may be quaternized. The heterocyclic group may be attached to the residue of any heteroatom or carbon atom of the ring or ring system, preferably 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, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxanyl, and tetrahydro-1,1-dioxythiophene, and the like. The polycyclic heterocyclic group refers to a heterocyclic group including spirocyclic, fused and bridged rings; wherein the spirocyclic, fused and bridged heterocyclic groups are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring; the heterocyclic group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, thiol, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate.

[0138] The term "4-20 membered heterocyclylene" refers to a group formed by removing two hydrogen atoms from a heterocyclyl group, such as:

[0139]

[0140] In the present invention, the term "aryl" refers to an aromatic cyclic hydrocarbon group having 1-5 rings, especially a monocyclic and bicyclic group. 14 "Aryl" refers to an aromatic cyclic hydrocarbon compound group containing 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring carbon atoms. Aryl is preferably C6-C 10 Aryl. Aryl includes phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be connected by a single bond (such as biphenyl) or fused (such as naphthalene, anthracene, etc.). "Substituted aryl" means that one or more positions in the aryl group are substituted, especially 1-3 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 (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclyl, aryl, heteroaryl, 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 NRd 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 , where R appears here a R may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aryl. b 、R c and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R b and R c Together with the N atom, it can form a heterocyclic ring; R e The alkyl radicals may independently represent hydrogen, deuterium, an alkyl radical, a cycloalkyl radical, an alkenyl radical, a cycloalkenyl radical, an alkynyl radical, a heterocyclic radical, or an aryl radical. The aforementioned typical substituents may optionally be substituted. Typical substitutions also include fused ring substituents, particularly fused ring alkyl radicals, fused ring alkenyl radicals, fused ring heterocyclic radicals, or fused ring aromatic radicals, wherein the aforementioned cycloalkyl radicals, cycloalkenyl radicals, heterocyclic radicals, and heterocyclic aromatic radicals may optionally be substituted.

[0141] 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 group 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. "Heteroaryl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate.

[0142] In the present invention, the term "alkoxy" refers to a linear or branched alkoxy group, including alkyl-O-, alkyl-O-alkyl, wherein "C1-C 18 "Alkoxy" refers to a straight or branched chain alkoxy group having 1 to 18 carbon atoms, including C1-C 18Alkyl-O-, -C1-C6 alkyl-O-C1-C6 alkyl, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably it is C1-C8 alkoxy, more preferably C1-C6 alkoxy.

[0143] In the present invention, the term "cycloalkyloxy" refers to cycloalkyl-O-, wherein "C3-C 20 "Cycloalkyloxy" refers to C3-C 20 Cycloalkyl-O-, wherein C3-C 20 Cycloalkyl is as defined above.

[0144] In the present invention, the term "heterocyclyloxy" refers to heterocyclyl-O-, wherein "4-20 membered heterocyclyloxy" refers to 4-20 membered heterocyclyl-O-, wherein the definition of 4-20 membered heterocyclyl is as described above.

[0145] In the present invention, the term "C1-C 18 "Alkyleneoxy" refers to "C1-C 18 Alkoxy is a group formed by removing a hydrogen atom.

[0146] In the present invention, the term "halogen" or "halo" refers to chlorine, bromine, fluorine, and iodine.

[0147] In the present invention, the term "halogenated" means substituted with halogen.

[0148] In the present invention, the term "deuterated" means substituted with deuterium.

[0149] In the present invention, the term "hydroxyl" refers to a group having the structure OH.

[0150] In the present invention, the term "nitro" refers to a group having the structure NO2.

[0151] In the present invention, the term "cyano" refers to a group having the structure CN.

[0152] In the present invention, the term "ester group" refers to a group having 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.

[0153] The term "amine group" refers to a group with the structure -NR'R", wherein R' and R" can independently represent hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, as defined above. In one embodiment, R' or R" are each independently selected from the following group: H, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl. R' and R" can be the same or different in the dialkylamine fragment. The amine group is preferably NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2.

[0154] The term "amido" refers to a group having the structure -CONR'R", wherein R' and R" can independently represent hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, as defined above. R' and R" can be the same or different in the dialkylamine moiety. The amide group is preferably -CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl).

[0155] The term "sulfone group" refers to a group having the structure -SO2R', wherein R' can independently represent hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, as defined above. The sulfone group is preferably -SO2C1-C6 alkyl.

[0156] The term "sulfonamido" refers to a group having the structure -SO2NR'R", wherein R' and R" can independently represent hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, as defined above. Sulfonamido is preferably -SO2NH2, -SO2NH(C1-C6 alkyl), -SO2NH(C3-C6 cycloalkyl).

[0157] The term "urea group" refers to a group having the structure -NR'CONR"R"', wherein R', R" and R"' can independently represent hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, as defined above. R', R" and R"' can be the same or different in the dialkylamine fragment. The urea group is preferably -NHCONH2, -NHCONH(C1-C6 alkyl).

[0158] The term "alkylaminoalkyl" refers to a group having the structure -R'NHR", wherein R' and R" can independently represent hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, as defined above. R' and R" can be the same or different. Alkylaminoalkyl is preferably -C1-C6 alkyleneNHC1-C6 alkyl.

[0159] The term "dialkylaminoalkyl" refers to a group having the structure -R'NR"R"', wherein R', R" and R"' can independently represent substituted or unsubstituted (alkylene) groups, substituted or unsubstituted (cycloalkylene) groups, substituted or unsubstituted (cycloalkenylene) groups, substituted or unsubstituted (arylene) groups, substituted or unsubstituted (heterocyclylene) groups, as defined above. R', R" and R"' can be the same or different in the dialkylamine moiety. Dialkylaminoalkyl is preferably -C1-C6 alkylene N(C1-C6 alkyl)2.

[0160] The term "heterocyclylalkyl" refers to a group with the structure -RR', wherein R can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl; and R' represents heterocyclyl or substituted heterocyclyl.

[0161] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is the substituent described above or the substituent appearing in the examples. Unless otherwise specified, a substituted group may have a substituent selected from the specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. The substituents include, but are not limited to, halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, and C1-C6 urea.

[0162] Unless otherwise stated, any heteroatom with insufficient valence is assumed to have sufficient hydrogen atoms to complete the valence.

[0163] When a substituent is non-terminal, it is a substituent of the corresponding group, for example, alkyl for alkylene, cycloalkyl for cycloalkylene, heterocyclyl for heterocyclylene, alkoxy for alkyleneoxy, and the like.

[0164] In the present invention, a plurality refers to 2, 3, 4, or 5.

[0165] Active ingredient

[0166] As used herein, "compounds of the present invention" refers to compounds represented by Formula I, and also includes stereoisomers or optical isomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the compounds of Formula I.

[0167] The salts that may be formed by the compounds of the present invention also fall within the scope of the present invention. Unless otherwise indicated, the compounds of the present invention are understood to include their salts. The term "salt" as used herein refers to acidic or basic salts formed with inorganic or organic acids and bases. In addition, when the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and contains an acidic fragment, including but 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 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 base, salts out in a medium, or is obtained by freeze-drying in an aqueous solution.

[0168] The compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (e.g., acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphor, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide,

[0014] Examples of the present invention include, for example, hydroxyethylsulfonates, lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoates, and the like.

[0169] Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-forming salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (e.g., organic amines), such as benzathine, dicyclohexylamine, hepamine (salt formed with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can react with halide quaternary ammonium salts, such as small molecular 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 tetradecyl), aralkyl halides (such as benzyl and phenyl bromide), etc.

[0170] Prodrugs and solvates of the compounds of the present invention are also encompassed. The term "prodrug" herein refers to a compound that undergoes chemical transformation via metabolic or chemical processes to produce a compound, salt, or solvate of the present invention when used to treat a relevant disease. The compounds of the present invention include solvates, such as hydrates.

[0171] The compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imino ethers). All such tautomers are part of the present invention.

[0172] All stereoisomers of the compounds (e.g., those that may exist due to asymmetric carbon atoms for various substitutions), including enantiomeric and diastereomeric forms, are contemplated by the present invention. Individual stereoisomers of the compounds of the present invention may not exist with other isomers (e.g., as a pure or substantially pure optical isomer having a particular activity), or may be mixtures, such as racemates, or mixtures with all other stereoisomers or portions thereof. The chiral centers of the present invention have either S or R configurations, as defined by the 1974 recommendations of the International Union of Pure and Applied Chemistry (IUPAC). Racemic forms can be resolved by physical methods, such as fractional crystallization, or by crystallization of diastereomers derived from them, or by separation by chiral column chromatography. Individual optical isomers can be obtained from the racemate by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by recrystallization.

[0173] The compounds of the present invention, obtained by sequential preparation, isolation, and purification, are described in the text to a concentration of 90% or greater by weight, for example, 95% or greater, or 99% or greater ("very pure" compounds). Such "very pure" compounds of the present invention are also considered part of the present invention.

[0174] All configurational isomers of the compounds of the present invention are encompassed, whether in mixture, pure or very pure form. The definition of the compounds of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.

[0175] Throughout the specification, groups and substituents may be chosen to provide stable fragments and compounds.

[0176] Specific functional groups and chemical term definitions are detailed below. For the purposes of this invention, chemical elements are referred to as Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. 1999. Specific functional group definitions are also provided therein. In addition, the basic principles of organic chemistry and specific functional groups and reactivity are also described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, which is incorporated by reference in its entirety.

[0177] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all 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 mixtures thereof are encompassed by the present invention.

[0178] According to the present invention, mixtures of isomers can contain various ratios of isomers. For example, mixtures containing only two isomers can have the following ratios: 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, as well as ratios for more complex mixtures of isomers, are readily understood by those skilled in the art and are also within the scope of the present invention.

[0179] The present invention also includes isotopically labeled compounds that 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 mass or mass number. Examples of isotopes of 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 The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as 3 H and 14 Radioisotopes of C are also included and are useful in tissue distribution experiments of drugs and substrates. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. It is the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e. 2 H, due to its excellent metabolic stability, has advantages in certain therapeutics, such as increasing half-life in vivo or reducing dosage, and therefore, may be preferred in some cases. Isotopically labeled compounds can be prepared using conventional methods by replacing readily available isotopically labeled reagents with non-isotopic reagents using the protocols disclosed in the examples.

[0180] If a synthesis of a specific enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, followed by separation of the resulting diastereomeric mixture and removal of the chiral auxiliary to obtain the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with a suitable optically active acid or base, followed by separation by conventional means such as fractional crystallization or chromatography to obtain the pure enantiomer.

[0181] As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to broaden their scope. Generally, the term "substituted," whether preceded or followed by the term "optionally," in formulas of the present invention including substituents, refers to the replacement of a hydrogen radical with a substituent of the specified structure. When multiple positions in a particular structure are substituted with multiple substituents of the specified structure, the substituents may be the same or different at each position. As used herein, the term "substituted" includes all permissible substitutions in organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. For example, heteroatoms such as nitrogen may be substituted with hydrogen or any of the permissible organic compounds described above to supplement their valences. Furthermore, the present invention is not intended to limit the permissible substitutions in any way to organic compounds. The present invention recognizes that combinations of substituents and variables are advantageous for providing stable compounds for the treatment of diseases, such as infectious or proliferative diseases. As used herein, the term "stable" refers to compounds that are stable and maintain the structural integrity of the compound over a period of time sufficient to be detected, preferably over a period of time sufficient to be effective, as used herein for the purposes described above.

[0182] The metabolites of the compounds and pharmaceutically acceptable salts thereof involved in the present application, as well as prodrugs that can be converted into the structures of the compounds and pharmaceutically acceptable salts involved in the present application and in vivo, are also included in the claims of the present application.

[0183] Preparation method

[0184] The preparation method of the compound of formula (I) of the present invention is 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 optionally combined with various synthetic methods described in this specification or known in the art and easily prepared, and such combination can be easily carried out by those skilled in the art.

[0185] Typically, the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.

[0186] Preferably, the compounds of the present invention are prepared by the following method

[0187]

[0188] (i) reacting a compound of formula XI with a compound of formula X-II in an inert solvent in the presence of a base, with or without a Pd catalyst, and with or without a condensing agent to obtain a compound of formula X-III;

[0189] (ii) reacting a compound of formula X-III with a compound of formula X-IV in an inert solvent in the presence of a base with or without a Pd catalyst to obtain a compound of formula XV;

[0190] (ii) reacting a compound of formula XV with a compound of formula X-VI in an inert solvent in the presence of a base and Pd or other metal catalyst to obtain a compound of formula (I);

[0191] LG1, LG2, LG3, LG4, LG5 and LG6 are leaving groups, each independently selected from: H, OH, halogen, OTf, OTs, OMs, -B(OH)2, -B(KBF3), -Sn( n Bu)3,

[0192] The Pd catalyst is selected from: Pd(OAc)2, Pd(dba)2, Pd2(dba)3, XPhos PdG2, RuPhos PdG2, XantPhos-Pd-G2, cataCXium A-Pd-G2, XPhos PdG3, RuPhos PdG3, PdG3, SPhos PdG3, tBuXPhos-Pd-G3, XantPhos-Pd-G4, BrettPhos PG4, SPhos Pd G4, cataCXium A-Pd-G4, Rockphos PdG4, etc.;

[0193] R 2 , L1, Ring B, X, Y, Z, V 1 、V 2 and V 3 The definition of is as above.

[0194] Pharmaceutical compositions and methods of administration

[0195] The pharmaceutical composition of the present invention is used to prevent and / or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.

[0196] The compounds of general formula (I) can be used in combination with other drugs known to treat or improve similar conditions. When administered in combination, the original drug's mode of administration and dosage can remain unchanged, while the compound of formula (I) is taken simultaneously or subsequently. When the compound of formula I is taken simultaneously with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of formula I can be preferably used. Drug combination also includes taking the compound of formula I and one or more other known drugs during overlapping time periods. When the compound of formula I 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 of the compound of formula (I) or the known drug when taken alone.

[0197] The drugs or active ingredients that can be used in combination with the compound of formula (I) 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, Ocatinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omip alisib, 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 Visusertib, 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): injection, tablet, capsule, aerosol, suppository, film, pill, external use ointment, controlled release or sustained release, or nanoformulation.

[0198] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0199] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, 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.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0200] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0201] 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 dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0202] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0203] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0204] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0205] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0206] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0207] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0208] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0209] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0210] The present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound represented by general formula (I)-(IV) of the present invention or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, thereby forming a pharmaceutical composition.

[0211] The present invention also provides a treatment method, which comprises the steps of administering to a subject in need of treatment the compound of formula (I) of the present invention, or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or administering the pharmaceutical composition of the present invention, for inhibiting KRAS mutation.

[0212] Compared with the prior art, the main advantages of the present invention include:

[0213] (1) The compound has a good inhibitory effect on KRAS mutation;

[0214] (2) The compound has better pharmacodynamics and pharmacokinetic properties and lower toxic side effects.

[0215] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, for which specific conditions are not specified, were generally performed 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.

[0216] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0217] The structures of the compounds of the present invention are confirmed by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).

[0218] NMR was measured using a Bruker AVANCE-400 nuclear magnetic spectrometer. The measurement solvents included deuterated dimethyl sulfoxide (DMSO-d6), deuterated acetone (CD3COCD3), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). Tetramethylsilane (TMS) was used as the internal standard, and chemical shifts were measured in parts per million (ppm).

[0219] Liquid chromatography-mass spectrometry (LC-MS) was performed using a Waters SQD2 mass spectrometer, and HPLC was performed using an Agilent 1100 high pressure chromatograph (Microsorb 5micron C18 100 x 3.0 mm column).

[0220] TLC silica gel plates used were Qingdao GF254 silica gel plates, with a diameter of 0.15-0.20 mm for TLC and 0.4-0.5 mm for preparative thin layer chromatography. Column chromatography generally used Qingdao 200-300 mesh silica gel as a carrier.

[0221] The starting materials in the examples of the present invention are all known and commercially available, or can be synthesized using or according to literature data reported in the art.

[0222] Unless otherwise specified, all reactions of the present invention are carried out under the protection of dry inert gas (such as nitrogen or argon) with continuous magnetic stirring, and the reaction temperatures are all degrees Celsius.

[0223] Example A1: 2'-amino-1-(5-cyano-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6-(1,5-dimethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-4-yl)-5',6'-dihydrospiro[azetidine-3,4'-cyclopenta[b]thiophene]-3'-carbonitrile

[0224]

[0225] Step 1: Preparation of tert-butyl (1R,5S)-3-(6-chloro-5-cyano-2-(methylthio)pyrimidin-4-yl)-1,5-dimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0226] A mixture of 4,6-dichloro-2-(methylthio)pyrimidine-5-carbonitrile (250 mg, 1.14 mmol), tert-butyl (1R,5S)-1,5-dimethyl-3,8-azabicyclo[3.2.1]octane-8-carboxylate (329 mg, 1.37 mmol), and DIPEA (295 mg, 2.28 mmol) in dichloromethane (5 mL) was stirred at room temperature for 2 hours. The mixture was then diluted with dichloromethane and washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography to obtain the desired product (178 mg, 36.9% yield).

[0227] LCMS: m / z 424 (M+H) + .

[0228] Step 2: Preparation of tert-butyl (1R,5S)-3-(6-chloro-5-cyano-2-(methylsulfonyl)pyrimidin-4-yl)-1,5-dimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0229] To a mixture of tert-butyl (1R,5S)-3-(6-chloro-5-cyano-2-(methylthio)pyrimidin-4-yl)-1,5-dimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (178 mg, 0.42 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was added oxone (516 mg, 0.84 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour, then quenched with water and extracted with dichloromethane. The combined organic phases were washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography to obtain the desired product (146 mg, yield: 76.4%).

[0230] LCMS: m / z 456 (M+H) + .

[0231] Step 3: Preparation of tert-butyl (1R,5S)-3-(6-chloro-5-cyano-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyrimidine-4-1,5-dimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0232] A solution of tert-butyl (1R,5S)-3-(6-chloro-5-cyano-2-(methylsulfonyl)pyrimidin-4-yl)-1,5-dimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and ((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol (130 mg, 0.62 mmol) in dichloromethane (5 mL) was stirred at room temperature for 16 hours, then quenched with water and extracted with dichloromethane. The combined organic phases were washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography to obtain the desired product (125 mg, 34.8% yield).

[0233] LCMS: m / z 579 (M+H) + .

[0234] Step 4: Preparation of tert-butyl (1R,5S)-3-(6-(2'-amino-3'-cyano-5',6'-dihydrospiro[azetidine-3,4'-cyclopenta[b]thiophene]-1-yl)-5-cyano-2-((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)methoxy)-1,5-dimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0235] Tert-butyl (1R,5S)-3-(6-chloro-5-cyano-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyrimidine-4-1,5-dimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (125 mg, 0.22 mmol) ), 2'-amino-5',6'-dihydrospiro[azetidine-3,4'-cyclopentane[b]thiophene]-3'-carbonitrile (60 mg, 0.29 mmol) and DIPEA (98 mg, 0.76 mmol) in 1,4-dioxane (3 mL) was stirred at 90 ° C for 2 hr, and then directly separated by silica gel column chromatography to obtain the target product (85 mg, yield: 51.7%).

[0236] LCMS: m / z 748 (M+H) + .

[0237] Step 5: 2'-amino-1-(5-cyano-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6-(1,5-dimethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-4-yl)-5',6'-dihydrospiro[azetidine-3,4'-cyclopenta[b]thiophene]-3'-carbonitrile

[0238] A solution of tert-butyl (1R,5S)-3-(6-(2'-amino-3'-cyano-5',6'-dihydrospiro[azetidine-3,4'-cyclopenta[b]thiophene]-1-yl)-5-cyano-2-((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)methoxy)-1,5-dimethyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (85 mg, 0.11 mmol) in trifluoroacetic acid (2 mL) was stirred at room temperature for 10 min and then concentrated under reduced pressure. The residue was separated by preparative liquid chromatography to give the target product (20 mg, yield: 28.1%).

[0239] LCMS: m / z 648 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ7.26(s,2H),4.65–3.86(m,8H),3.51(m,2H),3.11–2.91(m,4H),2.79–2.5 6(m,5H),2.06–1.98(m,1H),1.98–1.89(m,1H),1.87–1.65(m,5H),1.62–1.38(m,5H),1.24(s,6H).

[0240] The following compounds were synthesized using the same method as in Example A1 with different starting materials:

[0241] Example A2: 2'-amino-1-(5-cyano-6-(1,5-dimethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyrimidin-4-yl)-5',6'-dihydrospiro[azetidine-3,4'-cyclopenta[b]thiophene]-3'-carbonitrile

[0242]

[0243] LCMS: m / z 604 (M+H) + .

[0244] Example A3: 2'-amino-1-(5-cyano-6-(1,5-dimethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(3-(dimethylamino)-3-methylazetidin-1-yl)pyrimidin-4-yl)-5',6'-dihydrospiro[azetidine-3,4'-cyclopenta[b]thiophene]-3'-carbonitrile

[0245]

[0246] LCMS: m / z 559 (M+H) + .

[0247] Example A4: 2'-amino-1-(5-cyano-6-(1,5-dimethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((1-(morpholinomethyl)cyclopropyl)methoxy)pyrimidin-4-yl)-5',6'-dihydrospiro[azetidine-3,4'-cyclopenta[b]thiophene]-3'-carbonitrile

[0248]

[0249] LCMS: m / z 616 (M+H) + .

[0250] Example A5: 2'-amino-1-(5-cyano-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)-6-(1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-4-yl)-5',6'-dihydrospiro[azetidine-3,4'-cyclopenta[b]thiophene]-3'-carbonitrile

[0251]

[0252] LCMS: m / z 590 (M+H) + .

[0253] Example A6: 2'-amino-1-(5-cyano-2-(((2R,7aS)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)-6-(2-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-4-yl)-5',6'-dihydrospiro[azetidine-3,4'-cyclopenta[b]thiophene]-3'-carbonitrile

[0254]

[0255] LCMS: m / z 590 (M+H) + .

[0256] Example A7: 1-(6-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-cyano-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyrimidin-4-yl)-2'-amino-5',6'-dihydrospiro[azetidine-3,4'-cyclopenta[b]thiophene]-3'-carbonitrile

[0257]

[0258] LCMS: m / z 620 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ7.25(s,2H),4.51–4.15(m,6H),4.02(s,2H),3.57(s,2H),3.33–3.30(m,1H) ), 3.23–3.15(m,2H),3.08–2.94(m,2H),2.75–2.58(m,5H),2.06–1.97(m,1H),1.95–1.41(m,12H).

[0259] Example A8: 1-(6-((cis)-2-oxo-6-azabicyclo[5.1.0]octan-6-yl)-5-cyano-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyrimidin-4-yl)-2'-amino-5',6'-dihydrospiro[azetidine-3,4'-cyclopenta[b]thiophene]-3'-carbonitrile

[0260]

[0261] LCMS: m / z 621 (M+H) + .

[0262] Example A9: 2'-amino-1-(5-cyano-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6-(1-oxo-6-azaspiro[3.5]non-6-yl)pyrimidin-4-yl)-5',6'-dihydrospiro[azetidine-3,4'-cyclopenta[b]thiophene]-3'-carbonitrile

[0263]

[0264] LCMS: m / z 635 (M+H) + .

[0265] Example A10: 2'-amino-1-(5-cyano-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6-(6-methyl-5,6-dihydroimidazo[1,5-a]piperazin-7(8H)-yl)pyrimidin-4-yl)-5',6'-dihydrospiro[azetidine-3,4'-cyclopenta[b]thiophene]-3'-carbonitrile

[0266]

[0267] LCMS: m / z 645 (M+H)+ .

[0268] Example A11: 2'-amino-1-(5-cyano-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6-(1-fluoro-6-methyl-5,6-dihydroimidazo[1,5-a]piperazin-7(8H)-yl)pyrimidin-4-yl)-5',6'-dihydrospiro[azetidine-3,4'-cyclopenta[b]thiophene]-3'-carbonitrile

[0269]

[0270] LCMS: m / z 663 (M+H) + .

[0271] Example A12: 2'-amino-1-(5-cyano-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-6-(((trans)-2-fluorocyclopropyl)(methyl)amino)pyrimidin-4-yl)-5',6'-dihydrospiro[azetidine-3,4'-cyclopenta[b]thiophene]-3'-carbonitrile

[0272]

[0273] LCMS: m / z 597 (M+H) + .

[0274] Formulation Example: Pharmaceutical Composition

[0275] Oral tablets:

[0276] The compound prepared in Example A1 was added with the auxiliary fillers microcrystalline cellulose (101) and lactose monohydrate, the internal disintegrant croscarmellose sodium, the binder hypromellose (E15), the external disintegrant croscarmellose sodium, and the lubricant magnesium stearate to prepare a 50 mg oral tablet.

[0277] Injection:

[0278] The compound prepared in Example A1 was added with sodium sulfobutyl beta-cyclodextrin, sodium chloride, water for injection, etc. to prepare an injection preparation.

[0279] Biological test examples

[0280] Biological test evaluation

[0281] 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.

[0282] 1. Cell Proliferation Assay

[0283]

[0284] Positive reference: MRTX1133

[0285]

[0286] 2. Experimental Procedure

[0287] Using a nanoliter pipette system, add the diluted test compound to a 384-well cell culture plate, setting up replicates. Add an equal volume of culture medium to the positive control group and an equal volume of DMSO to the negative control group. Centrifuge at 1000 rpm for 1 minute at room temperature.

[0288] A) Seed the cells into a 384 culture plate. For the negative control group, add an equal volume of cells, while for the positive control group, add an equal volume of culture medium alone. Centrifuge at 1000 rpm for 1 minute at room temperature. Add the final compound to a DMSO concentration of 0.5%. Incubate in a 37°C, 5% CO2 incubator for 7 days.

[0289] Add 20 μL / well of CellTiter- 3D to b) Place in a 384-well cell culture plate, shake at 320 rpm for 20 min in the dark, and incubate at room temperature for 2 hrs in the dark.

[0290] The luminescence value was read using Envision multi-function microplate reader.

[0291] 3. Data Analysis

[0292] The inhibition rate (IR) of the test compound was calculated using the following formula: IR (%) = (1 – (RLU 化合物 –RLU 空白对照 ) / (RLU 溶媒对照 –RLU 空白对照 ))*100%. The inhibition rates of compounds at different concentrations were calculated in Excel, and then inhibition curves were plotted and related parameters, including minimum inhibition rate, maximum inhibition rate, and IC, were calculated using GraphPad Prism software. 50 .

[0293] The results showed that the compounds of the present invention showed good inhibitory activity against KRAS mutations.

[0294] I. Pharmacokinetic Test Evaluation

[0295] Male ICR mice weighing approximately 18-25 g were fasted overnight and orally administered with a 100 mg / kg solution of the compound of the invention or a control compound (10% DMSO / 60% polyethylene glycol 400 / 30% aqueous solution as the vehicle). Blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10.0, and 24 hours after administration of the compound of the invention, and plasma concentrations of the compound of the invention or the control compound were determined by LC / MS / MS.

[0296] The test results show that the compound of the present invention has good pharmacokinetic properties.

[0297] II. Pharmacokinetic Test Evaluation

[0298] Male SD rats weighing approximately 220 g were fasted overnight and orally administered with a 100 mg / kg solution of the compound of the present invention or a control compound (10% DMSO / 60% polyethylene glycol 400 / 30% aqueous solution as the vehicle). Blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10.0, and 24 hours after administration of the compound of the present invention, and the plasma concentration of the compound of the present invention or the control compound was determined by LC / MS / MS.

[0299] The test results show that the compound of the present invention has good pharmacokinetic properties.

[0300] III. Pharmacodynamic Evaluation of Antitumor Activity (AsPC-1CDX Tumor Model)

[0301] 100uL containing 5x10 6 AsPC-1 tumor cell suspension was subcutaneously inoculated into the right posterior abdomen of nude mice. The health of the mice was monitored daily, and measurements were taken when the tumor grew to a palpable size. Tumor volume was calculated using the formula: 0.5 x L x W 2 , where L and W represent the length and width of the tumor, respectively. The tumor grows to 200 mm 3 Mice were randomly divided into groups. The corresponding dose of compound was administered orally daily, and their general condition was monitored. Tumors were measured three times a week, and body weights were measured twice a week.

[0302] The test results show that the compound of the present invention has a good anti-tumor effect.

[0303] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound of formula I, or a stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof: Where, Ring B is selected from the following group of substituted or unsubstituted groups: C3-C 20 Cycloalkyl, 4-20 membered saturated or partially saturated heterocyclic group; L1 is selected from none, O or NR L , R L The following groups are substituted or unsubstituted: H, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 20 Cycloalkyl, 4-20 membered saturated or unsaturated heterocyclic group; V 1 、V 2 、V 3 Each independently selected from the group consisting of CH, CR 1 or N; R 1 Selected from the group consisting of substituted or unsubstituted H, deuterium, cyano, halogen, nitro, amino (-NH2), hydroxyl, oxo (=O), C1-C 10 Alkyl, halogenated C1-C 10 Alkyl, C2-C 10 Alkenyl, halogenated C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C3-C 20 Cycloalkyl, phenyl, benzyl, 4-20 membered saturated or unsaturated heterocyclic group, C2-C6 ester group, amino group, amide group (-CONH2), sulfone group or urea group; R 2 Selected from the following substituted or unsubstituted groups: C4-C 14 Cycloalkyl, 4-14 membered heterocyclic group, C6-C 14 Aryl, 5-14 membered heteroaryl, -OR a 、-NR a R b 、-CONR a R b 、-SO2NR a R b 、-NR a COR b 、-NR a SO2R b or -NR a CONR a R b ; Each R a 、R b The same or different, each independently selected from the following groups: substituted or unsubstituted: H, C1-C 10 Alkyl, C4-C 14 Cycloalkyl, 4-14 membered heterocyclyl, 4-14 membered heterocyclylalkyl, or R a and R b and the atoms connected thereto form a substituted or unsubstituted 4-14 membered heterocyclic group; wherein, The substitution refers to substitution by one or more R; X is selected from the group consisting of: bond, O, NH, N(C1-C3 alkyl), -C≡C-; Y is selected from: a bond, a substituted or unsubstituted C1-C6 alkylene; wherein the substitution refers to substitution by one or more R; 1) Z is selected from: Wherein, W1 is selected from the following groups: substituted or unsubstituted: C3-C 20 Cycloalkyl, 4-20 membered saturated or unsaturated heterocyclic group; R 4 Selected from the group consisting of substituted or unsubstituted H, deuterium, cyano, halogen, nitro, amino (-NH2), hydroxyl, oxo (=O), C1-C 10 Alkyl, halogenated C1-C 10 Alkyl, C2-C 10 Alkenyl, halogenated C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C3-C 20 Cycloalkyl, phenyl, benzyl, 4-20 membered saturated or unsaturated heterocyclic group, C2-C6 ester group, amino group (NR a R b ), amide (-CONH2), =CH2, halo =CH2, C1-C 10 Alkylene, halogenated C1-C 10 Alkylene, sulfone or urea; wherein n is 0, 1, 2, 3, 4, 5, 6, 7 or 8, and the substitution refers to substitution by one or more R; or 2) Z is selected from: -L4-Q2 or Wherein, ring W2 is selected from the following groups: substituted or unsubstituted: none, C3-C6 cycloalkylene, 4-6 membered saturated or unsaturated heterocyclylene; L4 is selected from the group consisting of a substituted or unsubstituted bond, a C1-C6 alkylene group, and a deuterated C1-C6 alkylene group; Q2 is selected from the following substituted or unsubstituted groups: C1-C 10 Alkoxy, C3-C 10 Cycloalkyl-O-, 4-10 membered heterocyclyl-O-, C3-C 10 Cycloalkyl (C1-C6 alkylene) -O-, 4-10 membered heterocyclic (C1-C6 alkylene) -O-, C3-C 10 Cycloalkyl C1-C6 alkyleneoxy, 4-10 membered heterocyclic C1-C6 alkyleneoxy, C3-C 10 Cycloalkyl, phenyl, benzyl, naphthyl, 4-12 membered heterocyclic group, NHR 9 or NR 9 R 10 ; R 9 and R 10 Each independently selected from the following groups: substituted or unsubstituted C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, (C3-C 10 cycloalkyl)C1-C6 alkylene, (4-10 membered heterocyclic)C1-C6 alkylene, or R 9 and R 10 The N atom to which it is connected together forms a substituted or unsubstituted 4-10 membered heterocyclic group; wherein the substitution refers to substitution by one or more R; Unless otherwise specified, the substitution refers to substitution by one or more R, each R being the same or different and independently selected from the group consisting of: H, deuterium, halogen, nitro, hydroxyl, oxo (=O), cyano, amino, C1-C6 alkyl, =CH2, halogenated =CH2, ≡CH, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C2-C6 alkenyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, hydroxy-substituted C3-C6 cycloalkyl, hydroxy-substituted 4-7 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -N(C1-C6 alkyl)2, -N(C1-C6 alkyl)(C3-C6 cycloalkyl), C3-C6 cycloalkyl-O-, 4-7 membered heterocyclyl-O-, C3-C6 cycloalkyl(C1-C6 alkylene)-, 4-6 membered heterocyclyl(C1-C6 alkylene)-, C3-C6 cycloalkyl-O-(C1-C6 alkylene)-, 4-6 membered heterocyclyl-O-(C1-C6 alkylene)-, (C C-C6 alkyl)-C≡C-, (deuterated C1-C6 alkyl)-C≡C-, (halogenated C1-C6 alkyl)-C≡C-, (C3-C6 cycloalkyl)-C≡C-, (4-6 membered heterocyclyl)-C≡C-, C1-C6 ester group, amino group, amide group, sulfonamide group, sulfone group or urea group.

2. The compound according to claim 1, wherein The compound has a structure shown in formula (II): in, R 5 Selected from the following substituted or unsubstituted groups: C 1-6 Alkyl, halogenated C 1-6 Alkyl or C1-C6 alkoxy; R 6 Selected from the following substituted or unsubstituted groups: C 3-7 Cycloalkyl, or 4-7 membered saturated or unsaturated heterocyclic group; Or, R 6 and R 5 The N atom connected thereto forms a ring B, wherein the ring B is selected from the following substituted or unsubstituted groups: C3-C 10 Cycloalkyl, 4-10 membered saturated or partially saturated heterocyclic group; The substitution mentioned herein refers to one or more R substitutions; Y, Z, R, R 2 、V 1 、V 2 and V 3 As claimed in claim 1.

3. The compound according to claim 1, wherein The ring W1 is selected from the following groups: substituted or unsubstituted 4-7 membered monocyclic heterocyclic group, substituted or unsubstituted C 3-6 substituted or unsubstituted 6-10 membered bicyclic spirocyclic heterocyclic group, substituted or unsubstituted 6-9 membered bicyclic cyclic heterocyclic group, substituted or unsubstituted 9-12 membered tricyclic heterocyclic group, substituted or unsubstituted 9-12 membered bridged heterocyclic group, substituted or unsubstituted 11-14 membered tetracyclic heterocyclic group, substituted or unsubstituted C7-C 10 Bridged cycloalkyl; wherein the substitution refers to substitution by one or more R; wherein the tricyclic heterocyclic group and the tetracyclic heterocyclic group are spirocyclic and / or cyclic; Preferably, The middle ring W1 is selected from a substituted or unsubstituted 4-7 membered monocyclic nitrogen-containing heterocyclic group, a substituted or unsubstituted 8-9 membered bicyclic N-containing fused heterocyclic group, a substituted or unsubstituted 8-9 membered bicyclic N-containing spirocyclic heterocyclic group, or a substituted or unsubstituted 10 membered tricyclic nitrogen-containing heterocyclic group, or a substituted or unsubstituted 11 membered tetracyclic heterocyclic group, wherein the substitution refers to substitution with one or more R, and R is defined as described in claim 1; The monocyclic nitrogen-containing heterocyclic group, bicyclic N-containing fused heterocyclic group, bicyclic N-containing spirocyclic heterocyclic group, tricyclic nitrogen-containing heterocyclic group and tetracyclic heterocyclic group optionally contain 0-3 heteroatoms independently selected from the following group: N, S or O; the tricyclic nitrogen-containing heterocyclic group and tetracyclic heterocyclic group are spirocyclic and annular; More preferably, Select from the following groups: wherein n' is 0, 1, 2, 3, 4, 5 or 6; R, R 4 and n are as defined in claim 1, R, R 4 Located on any ring or alkylene chain of a polycyclic ring (such as a bridged ring or a spiro ring); More preferably, Selected from: wherein n' is an integer of 0, 1, 2, 3, 4, 5 or 6; R, R 4 and n are as defined in claim 1, and R is located on any ring of a polycyclic ring (such as a bridged ring or a spiro ring) or an alkylene chain.

4. The compound according to claim 1, wherein when for hour, Y is selected from a bond, a substituted or unsubstituted C1-C6 alkylene group; Ring W2 is selected from the following groups: substituted or unsubstituted C3-C6 cycloalkylene, 4-7 membered saturated or unsaturated heterocyclylene; L4 is selected from the group consisting of a substituted or unsubstituted bond, a C1-C6 alkylene group, and a deuterated C1-C6 alkylene group; Q2 is selected from the following groups substituted or unsubstituted: 5-7 membered heterocyclyl, C1-C6 alkoxy, C3-C6 cycloalkyl-O-, 4-7 membered heterocyclyl-O-, deuterated C1-C6 alkoxy, C3-C6 cycloalkyl (C1-C6 alkylene) -O-, 4-7 membered heterocyclyl (C1-C6 alkylene) -O-, C3-C6 cycloalkyl C1-C6 alkyleneoxy, 4-7 membered heterocyclyl C1-C6 alkyleneoxy, C3-C7 cycloalkyl, phenyl, benzyl, NHR 9 NR 9 R 10 ; R 9 and R 10 Each is independently selected from the following groups: substituted or unsubstituted: C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, (C3-C6 cycloalkyl) C1-C6 alkylene, (4-7 membered heterocyclyl) C1-C6 alkylene, or R 9 and R 10 The N atom to which it is connected forms together a substituted or unsubstituted 4-8 membered heterocyclic group; wherein the substitution refers to substitution by one or more R; Preferably, Q2 is selected from the following substituted or unsubstituted groups: 5-7 membered heterocyclyl, C1-C6 alkoxy, C3-C6 cycloalkyl-O-, 4-7 membered heterocyclyl-O-, deuterated C1-C6 alkoxy, C3-C6 cycloalkyl (C1-C6 alkylene) -O-, 4-7 membered heterocyclyl (C1-C6 alkylene) -O-, C3-C7 cycloalkyl, NHR 9 NR 9 R 10 ; R 9 and R 10 Each is independently selected from the following groups: substituted or unsubstituted: C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, (C3-C6 cycloalkyl) C1-C6 alkylene, (4-7 membered heterocyclyl) C1-C6 alkylene, or R 9 and R 10 The N atom to which it is connected forms together a substituted or unsubstituted 4-8 membered heterocyclic group; wherein the substitution refers to substitution by one or more R; More preferably, Select from the following groups:

5. The compound according to claim 1, wherein R 2 is selected from substituted or unsubstituted 11-13 membered tricyclic heterocyclyl, or substituted or unsubstituted 7-9 membered bicyclic heterocyclyl, wherein the substitution is substituted by one or more groups selected from the group consisting of deuterium, halogen, hydroxyl, cyano, oxo (=O), -NH2, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl ... -C6 ester group, amino group, amide group, sulfone group, urea group, sulfonamide group, C3-C6 cycloalkyl-O-, 4-7 membered heterocyclyl-O-, -NH-(C1-C6 alkyl), -NH-(C3-C6 cycloalkyl), hydroxyl-substituted C3-C6 cycloalkyl, hydroxyl-substituted 4-6 membered heterocyclyl; the heterocyclyl contains 1, 2, 3, 4 or 5 heteroatoms independently selected from the following group: S, N or O; and the heterocyclyl is a spirocyclic and / or cyclic structure: Preferably, R 2 Select from the following groups: More preferably, R 2 Select from the following groups:

6. The compound according to claim 1, wherein Ring B is selected from the following group: C 3-7 cycloalkyl, 4-7 membered monocyclic heterocyclic group, 7-9 membered bridged heterocyclic group, 7-9 membered bridged heterocyclic alkenyl group, 7-10 membered spirocyclic heterocyclic group, 6-10 membered bicyclic fused heterocyclic group, wherein the substitution is substituted by one or more groups selected from the group consisting of halogen, hydroxy, cyano, -NH2, oxo (=O), thio (=S), C1-C6 alkyl, cyano-substituted C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 ester, amino, acyl, Amine, sulfone, urea, sulfonamide, C3-C6 cycloalkyl-O-, 4-6 membered heterocyclyl-O-, -C(O)-NRcRd, hydroxy-substituted C3-C6 cycloalkyl, hydroxy-substituted 4-6 membered heterocyclyl; Rc and Rd are each independently selected from the following group: H, C1-C6 alkyl, C3-C6 cycloalkyl, or Rc and Rd and the nitrogen atom to which they are commonly attached together form a substituted or unsubstituted 4-7 membered heterocyclyl; Preferably, ring B is selected from the following group: More preferably, Ring B is selected from the following group:

7. The compound according to claim 1, wherein The compound is selected from the group consisting of: Or choose from: Or choose from: Or choose from: Or choose from: Or choose from: Or choose from: Or choose from: Or choose from:

8. A pharmaceutical composition, characterized in that Comprising one or more compounds according to any one of claims 1 to 7, or stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof; and a pharmaceutically acceptable carrier.

9. A use of the compound according to any one of claims 1 to 7, or its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, or the pharmaceutical composition according to claim 8, characterized in that: Used for preparing a drug for preventing and / or treating a disease associated with the activity or expression of KRAS mutations, preferably, the disease is a tumor or a disorder.

10. A method for inhibiting KRAS mutation, characterized in that: Administering a therapeutically effective amount of the compound of any one of claims 1 to 7, or its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or the pharmaceutical composition of claim 8 to a subject in need thereof.

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