Macrocyclic derivatives and use thereof

Abstract

The present disclosure relates to a macrocyclic RAS inhibitor, a preparation method therefor, a pharmaceutical composition containing the inhibitor, and the pharmaceutical use thereof. Disclosed in the present disclosure are macrocyclic derivatives represented by general formula (I), or stereoisomers thereof, or a mixture of stereoisomers thereof, or pharmaceutically acceptable salts thereof, a preparation method therefor, and the use thereof as RAS inhibitors.

Description

Macrocyclic derivatives and uses thereof TECHNICAL FIELD

[0001] The present disclosure relates to a macrocyclic derivative, a method for preparing the same, a pharmaceutical composition containing the same, and uses thereof as a therapeutic agent, particularly as a RAS inhibitor. BACKGROUND

[0002] RAS family proteins play a crucial role in cell signaling, which are a class of GTPases (guanosine triphosphatase) that regulate cell growth, differentiation, proliferation, and apoptosis through the conversion between GTP and GDP (guanosine diphosphate). RAS gene mutations are one of the most common events in tumorigenesis, particularly in pancreatic cancer, colorectal cancer, and lung cancer. The RAS family includes KRAS, NRAS, and HRAS, with KRAS, NRAS, and HRAS mutant forms accounting for 85%, 11%, and 4% of mutations, respectively, making RAS an important target for tumor treatment.

[0003] The role of RAS proteins in tumor development has been extensively studied, but due to the lack of a clear drug binding pocket in RAS proteins and the extremely high binding affinity to GTP and GDP, the development of small molecule inhibitors directly targeting RAS proteins is a great challenge. For a long time, RAS has been considered as one of the "undruggable" targets.

[0004] In recent years, with the understanding of the structure and function of RAS proteins, some small molecule inhibitors targeting specific RAS mutations (such as KRASG12C) have been developed and have begun to show therapeutic effects in clinical practice. For example, AMG510 targeting KRASG12C mutation has been approved by FDA for marketing, for the treatment of locally advanced or metastatic non-small cell lung cancer. However, due to the variety of KRAS mutations, the current inhibitors on the market mainly target this specific G12C mutation, and there is still a lack of effective treatment for other types of KRAS mutations and other RAS family protein mutation types.

[0005] Therefore, the development of pan-RAS inhibitors that can target multiple RAS mutations, even broad-spectrum, is of great significance to meet the urgent needs of clinical RAS mutation tumor treatment. These inhibitors should be able to effectively block the activity of RAS proteins and inhibit their downstream signaling, thereby exerting an anti-tumor effect in multiple tumor types. The present disclosure is committed to developing new broad-spectrum RAS inhibitors in order to provide new treatment strategies for RAS mutation-related tumor treatment. SUMMARY

[0006] The present disclosure provides a compound having a structure represented by general formula (I), which has good RAS inhibitory activity and good known cancer cell proliferation activity.

[0007] Therefore, in a first aspect, there is provided a compound represented by general formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

[0008] In a second aspect, there is provided a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0009] In a third aspect, there is provided use of a compound or a pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating a disease or disorder associated with Ras mediation.

[0010] In a fourth aspect, there is provided a method of treating or preventing a disease or disorder associated with Ras mediation in a subject, the method comprising administering to the subject an effective amount of a compound or a pharmaceutical composition of the present disclosure.

[0011] In a fifth aspect, there is provided a method of preparing a compound of the present disclosure.

[0012] The above and other aspects of the present disclosure are described in more detail below. DETAILED DESCRIPTION

[0013] The present disclosure provides a compound having a structure represented by general formula (I):

[0014] or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof; wherein:

[0015] X1is selected from N or CH;

[0016] Cy1is selected from C6-C 10 aryl, 5-10 membered heteroaryl, C3-C 12 cycloalkyl or 3-12 membered heterocyclyl;

[0017] Cy2is selected from C6-C 10 aryl or 5-10 membered heteroaryl;

[0018] Cy3is selected from C6-C 10 aryl, 5-10 membered heteroaryl, C3-C 12 cycloalkyl or 3-12 membered heterocyclyl;

[0019] Cy4is selected from 6-12 membered nitrogen-containing spiroheterocyclyl, 6-12 membered nitrogen-containing bridged heterocyclyl or 6-12 membered nitrogen-containing fused heterocyclyl;

[0020] R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C10aryl, 5-10 membered heteroaryl, C1-C6alkoxy, C1-C6alkylamino, halo, cyano, nitro, hydroxyl, amino, carboxyl, or -CONH2, said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from halo, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, C1-C6alkylamino, haloC1-C6alkylamino, oxo, C6-C10aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, -ORa, -SRa, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -NRaC(O)Rb, -NRaC(O)NRaRb, -NRaC(O)ORa, -OC(O)Ra, -OC(O)NRaRb, -S(O)Rc, -S(O)2Rc, -S(O)2NRaRb, or -P(O)RdRe, wherein Ra, Rb, Rc, Rd, and Reare each independently H or C1-C6alkyl; 10 R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C 10 R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C g R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C g R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C g R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C g R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C g R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C x R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C y R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C x R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C y R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C g R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C x R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C y R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C x R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C x R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C y R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C x R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C g R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C g R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C x R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C x R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C y R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C x R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C x R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C y R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C x R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C g R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C g R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C g R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C x R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C y R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C x R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C y R1is selected from H, C1-C6alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C

[0021] R2 is selected from non-existent, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C8 cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, 3-8 membered heteroaryl, -SO2R2', -CO2NR2'R2", -COR2', -COOR2', -(CR 2c R 2d )u1-NR 2a R 2b 、-(CR 2c R 2d u2-C(O)-NR 2a R 2b 、-(CR 2c R 2d )u3-3-8-membered heterocyclic group, -(CR 2c R 2d )u4-C(O)-3-8-membered heterocyclic group, -C1-C3 alkylene-CN or -C1-C3 alkylene-C3-C6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic or heteroaryl group is optionally further selected from one or more of halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, C1-C6 alkylamino, haloC1-C6 alkylamino, oxo, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, C1-C8 alkylamino, C1-C8 haloalkylamino, -OR g -SR g -OC(O)R g -C(O)R g -C(O)OR g -C(O)N(R) x )R y -NR x R y -N(CH3)R g -N(R) x )C(O)R y -N(R) x )C(O)NR x R y -N(R) x )C(O)OR g -C1-C8 alkylene-R g -N(R) x )S(O)NR x Ry -N(R x )S(O)2NR x R y -N(R x )S(O)2R g -S(O)R g -S(O)2R g -S(O)2NR x R y or -P(O)R x R y substituted;

[0022] t is selected from 0, 1, 2, 3, or 4;

[0023] u1 is selected from 0, 1, 2, 3, or 4;

[0024] u2 is selected from 0, 1, 2, 3, or 4;

[0025] u3 is selected from 0, 1, 2, 3, or 4;

[0026] u4 is selected from 0, 1, 2, 3, or 4;

[0027] R 2a , R 2b are each independently selected from H, C1-C6alkyl, haloC1-C6alkyl, -S(O)2R g , -S(O)2NR x R y , -C1-C8alkylene-R g , C1-C6alkoxy, C3-C6cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, or 3-8 membered heteroaryl;

[0028] R 2c , R 2d are each independently selected from H, C1-C6alkyl, haloC1-C6alkyl, -S(O)2R g , -S(O)2NR x R y , C3-C6cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, or 3-8 membered heteroaryl;

[0029] R2’, R2” are each independently selected from H, C1-C6alkyl, C3-C8cycloalkyl, or 3-8 membered heterocyclyl;

[0030] or, R2’ and R2” together with the atom to which they are attached form a 3-12 membered ring; said 3-12 membered ring contains 0, 1, or 2 heteroatoms selected from N, O, S, P;

[0031] R3, R4, R5, and R6 are each independently selected from H, halogen, cyano, nitro, amino, hydroxyl, carboxyl, amide (C1-C6 alkyl-C(O)-NH-), oxo, and -P(O)R. 14 R 14’ Acyl (C1-C6 alkyl-C(O)-), -SO2, sulfonamide (H-SO2-NH), C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-sulfonamide, C3-C8 cycloalkyl, 3-8 membered heterocyclic, C3-C8 cycloalkoxy, C1-C6 alkylamino, C3-C8 cycloalkylamino, C1-C6 alkyl-SO2-, aminosulfonyl or carbamoyl, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally further selected from one or more groups selected from halogen, cyano, nitro, amino, hydroxy, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylamino, halogenated C1-C6 alkylamino, oxo, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, C1-C8 alkylamino, C1-C8 haloalkylamino, -OR g -SR g -OC(O)R g -C(O)R g -C(O)OR g -C(O)N(R) x )R y -NR x R y -N(CH3)R g -N(R) x )C(O)R y -N(R) x )C(O)NR x R y -N(R) x )C(O)OR g -C1-C8 alkylene-R g -N(R) x )S(O)NR x R y -N(R) x )S(O)2NR x R y -N(R) x )S(O)2R g -S(O)R g -S(O)2R g -S(O)2NR x R y or -P(O)R x R ySubstituents;

[0032] Alternatively, when two R5 atoms substitute for the same atom, the two R5 atoms together with the atoms they are attached to form a 3-6 membered ring; or, when two R5 atoms substitute for adjacent atoms, the two R5 atoms together with the atoms they are attached to form a 3-12 membered ring; the 3-12 membered ring contains 0, 1 or 2 heteroatoms selected from N, O, S, and P.

[0033] R7 is selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy or halo-C1-C6 alkyl;

[0034] R8 is selected from H, halogens, C1-C6 alkyl groups, or C1-C6 haloalkyl groups;

[0035] R 10 Selected from H, C1-C6 alkyl, or C1-C6 haloalkyl;

[0036] R 11a R 11b R 12a R 12b R 13a R 13b Each is independently selected from H, halogen, hydroxyl, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy, C1-C3 alkylamino or C1-C3 haloalkylamino;

[0037] R 12a With R 12b Or R 13a With R 13b It can form a 3-6 membered ring with the atoms it is connected to; the 3-6 membered ring contains 0, 1 or 2 heteroatoms selected from N, O, S and P;

[0038] R 12a With R 12b They can be combined to form carbonyl or thiocarbonyl groups;

[0039] G is selected from -X 11 -X 12 -X 13 -;

[0040] X 11 X 12 X 13 Each is independently selected from non-existent, -CR 21 R 21’ -、-O-、-CO- or -NR 21 -;

[0041] R 21 R 21’each independently is optionally selected from H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl;

[0042] X 18 is selected from a chemical bond, -O-, -NR 18a -, -OC(O)-, -NR 18a -C(O)-, -N(R 18a )C(O)NR 18a R 18b or -N(R 18a )C(O)OR 18b ;

[0043] R 18a , R 18b each independently is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, or C3-C8 halocycloalkyl;

[0044] Y is selected from -L1-L2-L3-L4-L5-L6-L7-L8-L9;

[0045] L1is selected from H, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C3-C8 cycloalkylene, 3-12 membered heterocyclylene, 5-10 membered heteroarylene, or phenylene, said alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, heteroarylene, or phenylene is optionally further substituted with one or more substituents selected from oxo, halogen, cyano, nitro, -OH, -NH2, C1-C6 alkyl, C2-C6 alkynyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkylamino, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 10 aryl, or 5-12 membered heteroaryl;

[0046] L2, L4, L6, L8are each independently selected from absent, H, -NR 22 -CO-, -CO-, -O-CO-, -NR 22 -CO-NR 22’ -, -O-CO-NR 22’ -, -NR 22 -CO-O-, -O-, -NR 22 -, -SO-, -SO2-, -NR 22 -SO2-, -SO2NR 22 -, or -NR 22 -SO2-NR 22 ’-;

[0047] L3, L5, L7, L9 are each independently selected from absent, H, C1-C6alkylene, C2-C6alkenylene, C2-C6alkynylene, C3-C8cycloalkylene, 3-12 membered heterocyclylene, 5-10 membered heteroarylene, or phenylene, the aforementioned alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, heteroarylene, or phenylene optionally further substituted with one or more substituents selected from oxo, halogen, cyano, -OH, -NH2, C1-C6alkyl, C2-C6alkynyl, C2-C6alkenyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6alkylamino, C1-C6haloalkoxy, C1-C6haloalkylamino, C3-C8cycloalkyl, or 3-8 membered heterocyclyl;

[0048] R 22 R 22’ are each independently selected from H, C1-C3alkyl, C1-C3haloalkyl, C3-C5cycloalkyl, C3-C5halocycloalkyl, 3-6 membered heterocyclyl, or 3-6 membered haloheterocyclyl;

[0049] s is selected from 0, 1, or 2;

[0050] m, n, p are each independently selected from 0, 1, 2, or 3;

[0051] R 14、 R 14’、 R g R x R y are each independently selected from H, deuterium, halogen, C1-C8alkyl, C1-C8alkoxy, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkenyloxy, C3-C8cycloalkyl, C3-C8cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, aminosulfonyl, C6-C10aryl, 5-12 membered heteroaryl, cyano, amino, nitro, hydroxyl, oxo, carboxyl, amide (C1-C8alkyl-C(O)-NH-), hydroxyC1-C8alkyl, aminoC1-C8alkyl, C1-C8alkylcarbonyl, C1-C8alkoxycarbonyl, C1-C8alkylamino, C1-C8haloalkylamino, -OR 12 Cycloalkyl, C3-C8cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, aminosulfonyl, C6-C10aryl, 5-12 membered heteroaryl, cyano, amino, nitro, hydroxyl, oxo, carboxyl, amide (C1-C8alkyl-C(O)-NH-), hydroxyC1-C8alkyl, aminoC1-C8alkyl, C1-C8alkylcarbonyl, C1-C8alkoxycarbonyl, C1-C8alkylamino, C1-C8haloalkylamino, -OR 10 , -SR s , -C1-C8alkylene-R s , -OC(O)R s , -C(O)R s , -C(O)OR s , -C(O)N(R s )R s )R t , -NR s R t , -N(CH3)R s , -N(Rs )C(O)R t , -N(R s )C(O)NR s R t , -N(R s )C(O)OR t , -N(R s )S(O)NR s R t , -N(R s )S(O)2NR s R t , -N(R s )S(O)2R t , -S(O)R s , -S(O)2R s , -S(O)2NR s R t , or -P(O)R s R t , said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally further substituted with one or more R r ;

[0052] or, when 2 R r substituents are on the same atom, 2 R r together with the atom to which they are attached form a 3-6 membered ring; or, when 2 R r substituents are on adjacent atoms, 2 R r together with the atoms to which they are attached form a 3-12 membered ring;

[0053] R r , R s , R t are each independently selected from H, deuterium, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, halogen, cyano, amino, nitro, hydroxyl, oxo, C1-C8alkoxy, C1-C8haloalkyl, hydroxyC1-C8alkyl, aminoC1-C8alkyl, C1-C8alkylamino, C1-C8alkylcarbonyl, C1-C8alkoxycarbonyl, haloC1-C8hydroxyalkyl, C1-C8haloalkylamino, C3-C 12 cycloalkyl, 3-12 membered heterocyclyl, carboxyl, amide (C1-C8alkyl-C(O)-NH-), C6-C 10 aryl or 5-12 membered heteroaryl;

[0054] when X 18For chemical bonds, when Cy3 is selected from C3-C6 cycloalkyl or 3-10 heterocyclic groups, R2 is selected from C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylamino, C3-C8 cycloalkyl, 3-8 heterocyclic, 6-10 aryl, 3-8 heteroaryl, -SO2R2', -CO2NR2'R2", -COR2', -COOR2', -(CR 2c R 2d )u1-NR 2a R 2b 、-(CR 2c R 2d u2-C(O)-NR 2a R 2b 、-(CR 2c R 2d )u3-3-8-membered heterocyclic group, -(CR 2c R 2d )u4-C(O)-3-8-membered heterocyclic group, -C1-C3 alkylene-CN or -C1-C3 alkylene-C3-C6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic or heteroaryl group is optionally further selected from one or more of halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, C1-C6 alkylamino, haloC1-C6 alkylamino, oxo, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, C1-C8 alkylamino, C1-C8 haloalkylamino, -OR g -SR g -OC(O)R g -C(O)R g -C(O)OR g -C(O)N(R) x )R y -NR x R y -N(CH3)R g -N(R) x )C(O)R y -N(R) x )C(O)NR x R y -N(R) x )C(O)OR g -C1-C8 alkylene-R g -N(R) x )S(O)NR x Ry -N(R x )S(O)2NR x R y -N(R x )S(O)2R g -S(O)R g -S(O)2R g -S(O)2NR x R y or -P(O)R x R y substituted, and are not the following compounds

[0055] In some embodiments, selected from:

[0056] X2is selected from CR 15 R 15 ', O, NH, SO or SO2;

[0057] R 15 , R 15 are each independently selected from H, halogen, cyano, Ci-C6alkyl or halogenated Ci-C6alkyl;

[0058] R7is selected from H, halogen, cyano, Ci-C6alkyl or halogenated Ci-C6alkyl;

[0059] R 7a is selected from halogen, cyano, Ci-C6alkyl or halogenated Ci-C6alkyl;

[0060] q, r are selected from 0, 1, 2, 3 or 4, and r and q cannot be selected from 0 at the same time;

[0061] m is selected from 0, 1, 2 or 3.

[0062] In some specific embodiments, selected from:

[0063] R 7a is selected from F, CI, Br, cyano or methyl.

[0064] In some embodiments, R2is selected from -(CR 2c R 2d )u3-3-8 membered heterocyclyl, which 3-8 membered heterocyclyl can be, for example, 3 membered, 4 membered, 5 membered, 6 membered, 7 membered, 8 membered heterocyclyl.

[0065] In some embodiments, R2is selected from: absent, halogen, C1-C6alkyl optionally substituted with 1, 2, or 3 halogen atoms, C1-C3alkoxy, CH3-C(O)-, CH3-SO2-, C3-C8cycloalkyl, NH-S(O)2-CH3,

[0066] In some embodiments, Cy3is selected from C6-C 10 aryl, for example, can be C6, C7, C8, C9, or C 10 aryl.

[0067] In some embodiments, Cy3is selected from 5-10 membered heteroaryl, for example, can be 5 membered, 6 membered, 7 membered, 8 membered, 9 membered, 10 membered heteroaryl.

[0068] In some embodiments, Cy3is selected from C3-C 12 cycloalkyl, for example, can be C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 cycloalkyl.

[0069] In some embodiments, Cy3is selected from 3-12 membered heterocyclyl, for example, can be 3 membered, 4 membered, 5 membered, 6 membered, 7 membered, 8 membered, 9 membered, 10 membered, 11 membered, 12 membered heterocyclyl.

[0070] In some embodiments, Cy3is selected from C3-C7cycloalkyl, 3-10 membered heterocyclyl containing 1 or 2 ring-forming heteroatoms selected from N and / or O, 5-8 membered heteroaryl containing 1, 2, or 3 ring-forming heteroatoms selected from N.

[0071] In some specific embodiments, Cy3is selected from

[0072] * indicates attachment to ring Cy2or X 18 .

[0073] In some embodiments, R5is selected from hydrogen, amino, methyl, ethyl, propyl, isopropyl, cyano, halogen, hydroxyl, methoxy, trifluoromethyl, CH2F-, or C1-C3hydroxyalkyl, t is selected from 0, 1, or 2;

[0074] or, when 2 R5substitutions are on the same atom, the 2 R5together with the atom to which they are attached form a 3-6 membered ring; or, when 2 R5substitutions are on adjacent atoms, the 2 R5together with the atoms to which they are attached form a 3-12 membered ring; said 3-12 membered ring containing 0, 1, or 2 heteroatoms selected from N, O, S, P.

[0075] In some embodiments, is selected from:

[0076] In some embodiments, Y is selected from:

[0077] R 25 ,

[0078] R 23 is selected from -CH3, -CH2CH3, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl;

[0079] R 24 is selected from: absent, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-6 membered heterocyclyl; said alkyl, cycloalkyl, heterocyclyl optionally further substituted with one or more substituents selected from halogen, cyano, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, haloC1-C3 alkyl, haloC1-C3 alkoxy, C1-C3 alkylamino, haloC1-C3 alkylamino, oxo, C3-C6 cycloalkyl, or 4-6 membered heterocyclyl;

[0080] R 25 is selected from C1-C4 alkyl, C3-C8 cycloalkyl, C1-C4 alkylene-C3-C8 cycloalkyl, C1-C4 alkylene-3-8 membered cycloalkyl, or 3-8 membered heterocyclyl; said alkyl, cycloalkyl, heterocyclyl, alkylene optionally further substituted with one or more substituents selected from halogen, cyano, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, haloC1-C3 alkyl, haloC1-C3 alkoxy, C1-C3 alkylamino, haloC1-C3 alkylamino, oxo, C3-C6 cycloalkyl, or 4-6 membered heterocyclyl;

[0081] R 26 and R 27each independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, or heterocycloalkyl optionally further substituted by one or more substituents selected from halogen, cyano, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, haloC1-C3 alkyl, haloC1-C3 alkoxy, C1-C3 alkylamino, haloC1-C3 alkylamino, oxo, C3-C6 cycloalkyl, or 4-6 membered heterocyclyl;

[0082] R 28 selected from H or C1-C4 alkyl;

[0083] X 14 selected from: absent, C1-C4 alkylene, C1-C4 alkylene-N(R 29 )-CO-, C3-C8 cycloalkylene, C3-C8 cycloalkylene-N(R 29 )-CO-, 3-8 membered heterocyclylene, 3-8 membered heterocyclylene-N(R 29 )-CO-; said alkylene, cycloalkylene, heterocyclylene optionally further substituted by one or more substituents selected from halogen, cyano, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, haloC1-C3 alkyl, haloC1-C3 alkoxy, C1-C3 alkylamino, haloC1-C3 alkylamino, oxo, C3-C6 cycloalkyl, or 4-6 membered heterocyclyl;

[0084] R 29 selected from H or C1-C4 alkyl;

[0085] X4, X5, X6, X7, X8, X9, X 10 each independently selected from: absent, -CH2-, -CO-, N, -NH-, -O-, -SO-, -SO2-, or -CH2CH2-;

[0086] X 15 selected from -CH2-, -CO-, -C(O)O-, -C(O)NH-, -OC(O)-, -NHC(O)-, or -CH2CH2-;

[0087] Cy5is selected from 3-6 membered heterocyclyl, C3-C6 cycloalkyl, phenyl, or 5-6 membered heteroaryl;

[0088] v is selected from 0, 1, 2, or 3;

[0089] R 30 selected from absent, C1-C4 alkyl, haloC1-C4 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, -OR 31 , -CO-R 31, -C(O)O-R 31 , amino or hydroxy; said alkyl, cycloalkyl, heterocyclyl or phenyl is optionally further substituted with one or more substituents selected from halo, cyano, amino, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, haloC1-C3alkyl, haloC1-C3alkoxy, C1-C3alkylamino, haloC1-C3alkylamino, oxo, C3-C6cycloalkyl or 4-6 membered heterocyclyl;

[0090] R 31 selected from H, C1-C4alkyl, haloC1-C4alkyl, C3-C6cycloalkyl, 3-6 membered heterocyclyl or phenyl, said alkyl, cycloalkyl, heterocyclyl or phenyl is optionally further substituted with one or more substituents selected from halo, cyano, amino, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, haloC1-C3alkyl, -OC(O)-CH3, haloC1-C3alkoxy, C1-C3alkylamino, haloC1-C3alkylamino, oxo, C3-C6cycloalkyl or 4-6 membered heterocyclyl.

[0091] In some embodiments, Y is selected from:

[0092] In some embodiments, Cy1is selected from 3-12 membered heterocyclyl, for example, can be 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered heterocyclyl. In some embodiments, Cy1is selected from 3-10 membered heterocyclyl, 4-10 membered heterocyclyl, 5-10 membered heterocyclyl, 6-10 membered heterocyclyl, 4-9 membered heterocyclyl, 5-9 membered heterocyclyl, 6-9 membered heterocyclyl.

[0093] In some embodiments, Cy1is selected from phenyl, 5-8 membered heterocyclyl, 5-membered heteroaryl or 1,2,5,6-tetrahydropyridine.

[0094] In some embodiments, Cy1is selected from

[0095] In preferred embodiments of the present disclosure, Cy1is preferably selected from

[0096] In some embodiments, Cy2is selected from 5-10 membered heteroaryl, for example, can be 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered heteroaryl.

[0097] In some embodiments, selected from

[0098] Z1, Z 1a Z 1b Each is independently selected from N, CH, CF, or C-CN;

[0099] R1 is selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic, C6-C 10 aryl, 5-10-membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylamino, halogen, cyano, nitro, hydroxy, amino, carboxyl or -CONH2, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally further selected from one or more groups selected from halogen, cyano, nitro, amino, hydroxy, carboxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylamino, halogenated C1-C6 alkylamino, oxo, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, C1-C8 alkylamino, C1-C8 haloalkylamino, -OR g -SR g -OC(O)R g -C(O)R g -C(O)OR g -C(O)N(R) x )R y -NR x R y -N(CH3)R g -N(R) x )C(O)R y -N(R) x )C(O)NR x R y -N(R) x )C(O)OR g -C1-C8 alkylene-R g -N(R) x )S(O)NR x R y -N(R) x )S(O)2NR x R y -N(R) x )S(O)2R g -S(O)R g -S(O)2R g -S(O)2NR x R y or -P(O)R x R y Substituted by a substituent.

[0100] In some embodiments, Cy2is selected from

[0101] In some embodiments, R1is selected from C1-C3alkyl or -CONH2, said alkyl being optionally substituted with 1, 2 or 3 substituents selected from halogen, C1-C3alkoxy.

[0102] In some embodiments, R1is selected from

[0103] In some embodiments, R3, R4, R6are each independently selected from H, halogen, cyano or C1-C3alkyl, said alkyl being optionally substituted with 1, 2 or 3 substituents selected from F, Cl or Br.

[0104] In some embodiments, R8is selected from H or halogen.

[0105] In some embodiments, R 10 is selected from H.

[0106] In some embodiments, R 11a , R 11b , R 12a , R 12b , R 13a , R 13b are each independently selected from H or C1-C3alkyl.

[0107] In some embodiments, R 12a and R 12b together with the atom to which they are attached form a 3-membered ring.

[0108] In some embodiments, the compound has the structure according to general formula (II):

[0109] is selected from:

[0110] R7is selected from H, halogen, cyano, C1-C6alkyl or halogenated C1-C6alkyl;

[0111] R 7a is selected from halogen, cyano, C1-C6alkyl or halogenated C1-C6alkyl;

[0112] q, r are selected from 0, 1, 2, 3 or 4, and r and q cannot be selected from 0 at the same time;

[0113] m is selected from 0, 1, 2 or 3;

[0114] X1, Cy1, Cy3, R1, R2, R2’, R2”, R3, R4, R5, R6, R8, R10 , R 11a , R 11b , R 12a , R 12b , R 13a , R 13b , R 21 , R 21’ , R 22 , R 22’、 R g , R x , R y , R r , R s , R t , G, Y, X 11 , X 12 , X 13 , L1, L2, L3, L4, L5, L6, L7, L8, L9, s, n, t, p are as previously described.

[0115] In some embodiments, the compound has the structure of Formula (IV):

[0116] Cy3is selected from C3-C6cycloalkyl, 4-9 membered heterocyclyl, or 5-6 membered heteroaryl;

[0117] R2is selected from -(CR 2c R 2d )u1-NR 2a R 2b , -(CR 2c R 2d )u2-C(O)-NR 2a R 2b , -(CR 2c R 2d )u3-3-8 membered heterocyclyl, -(CR 2c R 2d )u4-C(O)-3-8 membered heterocyclyl, C3-C6cycloalkyl, -C1-C3alkylene-CN, or -C1-C3alkylene-C3-C6cycloalkyl, or heterocyclyl substituted with 1-3 substituents, said heterocyclyl or cycloalkyl optionally further substituted with one or more substituents selected from halogen, C1-C4alkyl, haloC1-C4alkyl, C1-C4hydroxyalkyl, C1-C4alkyl-O-C1-C4alkyl, C1-C4alkoxy, haloC1-C4alkoxy, C1-C4alkylamino, haloC1-C4alkylamino, oxo, C3-C6cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, or 5-6 membered heteroaryl, -OR g , -SR g , -OC(O)R g , -C(O)R g-C(O)OR g -C(O)N(R x )R y -NR x R y -N(CH3)R g -N(R x )C(O)R y -N(R x )C(O)NR x R y -N(R x )C(O)OR g -C1-C8alkylene-R g -N(R x )S(O)NR x R y -N(R x )S(O)2NR x R y -N(R x )S(O)2R g -S(O)R g -S(O)2R g -S(O)2NR x R y or -P(O)R x R y substituted;

[0118] R 2a , R 2b each independently is selected from H, halogen, C1-C3alkyl, halogenated C1-C3alkyl, C3-C6cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl, or 5-6 membered heteroaryl;

[0119] R 2c , R 2d each independently is selected from H, halogen, C1-C3alkyl, halogenated C1-C3alkyl, C3-C6cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl, or 5-6 membered heteroaryl;

[0120] u3is selected from 1, 2, 3, or 4;

[0121] u1, u2, u4are selected from 0, 1, 2, 3, or 4;

[0122] Cy1is selected from a phenyl ring, 5-8 membered heterocyclyl, 5 membered heteroaryl, or 1,2,5,6-tetrahydropyridine;

[0123] R1is selected from

[0124] R4is selected from ethyl or trifluoroethyl;

[0125] R5is selected from hydrogen, amino, methyl, ethyl, propyl, isopropyl, cyano, halogen, or C1-C3hydroxyalkyl; or, when two R5substitutions are on the same atom, the two R5together with the atom to which they are attached form a 3-6 membered ring; or, when two R5substitutions are on adjacent atoms, the two R5together with the atoms to which they are attached form a 3-12 membered ring; said 3-12 membered ring contains 0, 1, or 2 heteroatoms selected from N, O, S, P;

[0126] R6is selected from H, halogen, amino, hydroxyl, nitro, cyano, C1-C4alkyl, halogenated C1-C4alkyl, or C1-C4hydroxyalkyl;

[0127] R8is selected from hydrogen, halogen, C1-C3alkyl, or C1-C3haloalkyl;

[0128] R 10 is selected from hydrogen, C1-C3alkyl, or C1-C3haloalkyl;

[0129] Y, p, s, t, R x , R y , R g are as previously described.

[0130] In some aspects, the compound has the structure of Formula (V):

[0131] or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof; Cy3, R2, R4, R5, R8, Y, s, t are as previously described.

[0132] In some aspects, the compound has the structure of Formula (VI):

[0133] or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof;

[0134] R4is selected from ethyl or trifluoroethyl; Cy3, R2, R5, R8, Y, s, t are as previously described.

[0135] In some aspects, in the structure of Formula (VI), Cy3is selected from

[0136] Z2is selected from C, CH, or N;

[0137] Z3is selected from CH, CH2, N, NH, or O;

[0138] represents a single or double bond.

[0139] R5is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyano, halogen, or C1-C3hydroxyalkyl; or, when 2 R5substituents are on the same atom, the 2 R5together with the atom to which they are attached form a 3-6 membered ring; or, when 2 R5substituents are on adjacent atoms, the 2 R5together with the atoms to which they are attached form a 3-12 membered ring; said 3-12 membered ring contains 0, 1, or 2 heteroatoms selected from N, O, S, P;

[0140] t is selected from 0, 1, 2, 3, or 4.

[0141] In some embodiments, the structure of Formula (II), Cy3is selected from

[0142] * indicates attachment to ring Cy2;

[0143] R2is selected from C3-C6cycloalkyl, -methylene-C3-C6cycloalkyl, -(CR 2c R 2d )u1-NR 2a R 2b , -(CR 2c R 2d )u3-3-8 membered heterocyclyl, C3-C6heterocyclyl, -(CR 2c R 2d )u2-C(O)-NR 2a R 2b or -CH2CN,

[0144] said heterocyclyl or cycloalkyl is optionally substituted with one or two substituents selected from halogen, methyl, hydroxyl, hydroxymethyl, cyano, trifluoromethyl, difluoromethyl, -CH2F, C2-C3alkyl, and halogenated C2-C3alkyl;

[0145] R 2a , R 2b are each independently selected from H or methyl;

[0146] R 2c , R 2d are each independently selected from H;

[0147] u3is selected from 1;

[0148] u1, u2are selected from 0 or 1;

[0149] Y is selected from

[0150] R4is selected from ethyl or trifluoroethyl;

[0151] R5is selected from hydrogen or methyl;

[0152] R8is selected from hydrogen;

[0153] s, t are as previously described.

[0154] In some embodiments, C2-C3alkyl is selected from ethyl, propyl, isopropyl, ethenyl, ethynyl, allyl, propargyl, propenyl, propynyl.

[0155] In some embodiments, halogenated C2-C3alkyl is C2-C3alkyl substituted with one or more of F, Cl, Br, I, wherein the number of halogen substituents is 1, 2, 3, 4, or 5. As an example, halogenated C2-C3alkyl can be: -CH2CFH2, -CH2CF2H, -CH2CF3, -CH2CH2CFH2, -CH2CH2CF3, -CH=CFH, -CH2=CF2, -CF2CH=CH2, -CFHCH=CH2.

[0156] In some embodiments, the structure of Formula (II) is selected from: In some embodiments, the structure of Formula (II) is selected from:

[0157] In some embodiments, the structure of Formula (II) is selected from:

[0158] In some embodiments, the structure of Formula (II) is selected from:

[0159] In some embodiments, the structure of Formula (II) is selected from:

[0160] In some embodiments, the structure of Formula (II) is selected from:

[0161] In some embodiments, the compound has the structure of Formula (VIII):

[0162] Cy3is selected from C6-C10aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, or 3-12 membered heterocyclyl; 10 aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, or 3-12 membered heterocyclyl; 12 cycloalkyl, or 3-12 membered heterocyclyl;

[0163] Cy6is selected from C6-C10aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, or 3-12 membered heterocyclyl; 10 aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, or 3-12 membered heterocyclyl; 12 cycloalkyl, or 3-12 membered heterocyclyl;

[0164] R 2fSelected from: non-existent, halogen, cyano, nitro, amino, hydroxy, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, C1-C6 alkylamino, haloC1-C6 alkylamino, oxo, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, C1-C8 alkylamino, C1-C8 haloalkylamino, -OR g -SR g -OC(O)R g -C(O)R g -C(O)OR g -C(O)N(R) x )R y -NR x R y -N(CH3)R g -N(R) x )C(O)R y -N(R) x )C(O)NR x R y -N(R) x )C(O)OR g -C1-C8 alkylene-R g -N(R) x )S(O)NR x R y -N(R) x )S(O)2NR x R y -N(R) x )S(O)2R g -S(O)R g -S(O)2R g -S(O)2NR x R y or -P(O)R x R y ;

[0165] j can be 0, 1, 2, 3, or 4;

[0166] The definitions of R4, R5, R8, t, s, or Y are as described above.

[0167] In some of the schemes disclosed herein,

[0168] Selected from:

[0169] In some embodiments of the disclosure, preferably selected from

[0170] In some embodiments of the disclosure, R 2f preferably selected from: nothing, methyl, ethyl, propyl, isopropyl, halogen, cyano, nitro, hydroxyl, amino, methoxy, ethoxy, propoxy, cyclopropyl, cyclopropyloxy, trifluoromethyl, difluoromethyl, or trifluoromethoxy.

[0171] Specific structures of the compounds represented by general formula (I) of the disclosure include, but are not limited to:

[0172] or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

[0173] In the disclosure, if there is a difference between the structure drawn and the name given to the structure, the structure drawn will be given greater weight.

[0174] It is to be noted that when the present disclosure refers to a specific compound, the corresponding number below the compound (e.g. 498 in the above table) corresponds to the corresponding compound; when the present disclosure refers to the compound number in the rest of the text, it refers to the compound corresponding to the compound number, e.g. "compound 498" refers to the compound structure corresponding to the number 498.

[0175] Further, the present disclosure provides a method for preparing a compound represented by the structure of formula (I) or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0176] wherein Boc is an N-protecting group, X1, X 18 , Cy1, Cy2, Cy3, Cy4, R1, R2, R3, R4, R5, R6, R7, R8, R 10 , R 11a , R 11b , R 12a , R 12b , R 13a , R 13b , s, m, n, t, p are defined as described above. The N-protecting group is well known to those skilled in the art, and a group known in the art for protecting N atom can be used. In some embodiments, the method comprises the following steps:

[0177] wherein Boc is an N-protecting group, Cy1, Cy3, R5, R6, R7, R8, s, m, n, t, p are defined as described above.

[0178] The present disclosure provides a pharmaceutical composition comprising an effective amount of a compound represented by the general formula (I) or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0179] The present disclosure provides the use of a compound represented by the general formula (I) or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof disclosed herein in the preparation of a medicament for treating a disease mediated by Ras, wherein the medicament is preferably a broad-spectrum Ras inhibitor.

[0180] The present disclosure provides the use of a compound represented by the general formula (I) or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof disclosed herein in the preparation of a medicament for treating a disease mediated by Ras, wherein the disease mediated by Ras is preferably a solid tumor, a hematological malignancy.

[0181] The present disclosure provides a method of treating or preventing a Ras-mediated related disease or disorder in an individual, comprising administering to said individual an effective amount of a compound according to Formula (I) or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0182] The compounds according to Formula (I) or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, of the present disclosure can be used for the prevention, diagnosis, treatment of a Ras-mediated related disease or disorder. The Ras-mediated related disease or disorder includes pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myeloid leukemia multiple myeloma, thyroid adenocarcinoma, bone dysplasia syndrome, squamous cell lung cancer, esophageal cancer, ovarian cancer, uterine cancer, melanoma, bladder cancer or head and neck cancer.

[0183] Terminology

[0184] Unless otherwise indicated, the following terms used in the specification and claims have the following definitions:

[0185] "bond" means that the two moieties of the indicated substituent are directly connected by a bond.

[0186] "alkyl" when used as a group or part of a group refers to a straight or branched chain aliphatic group including C1-C 20 straight chain or branched chain aliphatic groups. Preferably, C1-C 10 alkyl, more preferably C1-C8alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group can be substituted or unsubstituted.

[0187] "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, preferably having 1 to 12 carbon atoms (i.e., C 1-12 alkylene), more preferably having 1 to 6 carbon atoms (i.e., C 1-6 alkylene), more preferably having 1 to 4 carbon atoms (i.e., C 1-4Alkylenes. Non-limiting examples of alkylenes include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), and 1,4-butylene (-CH2CH2CH2CH2-). Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. Substituents can be selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, and oxo.

[0188] "Alkenyl" refers to an aliphatic hydrocarbon group containing a single carbon-carbon double bond, which can be straight-chain or branched. C2-C is preferred. 10 Alkenyl, more preferably C2-C8 alkenyl. Representative examples include, but are not limited to, vinyl, The alkenyl group can be substituted or unsubstituted.

[0189] "Alkyne group" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which can be straight-chain or branched. C2-C is preferred. 10 The alkynyl group is more preferably C2-C8 alkynyl, and most preferably C2-C4 alkynyl. Examples of alkynyl groups include, but are not limited to, acetyleneyl, ... The alkynyl group can be substituted or unsubstituted.

[0190] "Ideinyl" refers to a divalent straight-chain or branched aliphatic hydrocarbon group containing one or more carbon-carbon double bonds, having a specified number of carbon atoms, such as 2 to 8 carbon atoms, for example -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, etc., and the imeneyl group may optionally be substituted by one or more (such as 1 to 3) identical or different substituents.

[0191] "Imyynyl" refers to a divalent straight-chain or branched hydrocarbon group having one or more carbon-carbon triple bonds, containing a specified number of carbon atoms, such as 2 to 8 carbon atoms, including but not limited to, etc., and the imynylyl group may optionally be substituted by one or more (such as 1 to 3) identical or different substituents.

[0192] "Hydrocarbon group" refers to a group containing only carbon and hydrogen atoms, generally referring to the group remaining after a corresponding hydrocarbon loses a hydrogen atom (H).

[0193] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused, bridged, or spirocyclic carbon ring. Preferably, it is C3-C.12 Cycloalkyl, more preferably C3-C8cycloalkyl, most preferably C3-C6cycloalkyl. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, preferably cyclopropyl, cyclohexenyl. Cycloalkyl groups can be substituted or unsubstituted.

[0194] "Cycloalkylene" refers to a divalent saturated or partially saturated monocyclic, fused, bridged, and spirocyclic carbocycle and is attached to a group by a single bond, to another group by a single bond, for example, C 3-10 Cycloalkylene containing 3-10 carbon atoms; C 3-6 Cycloalkylene containing 3-6 carbon atoms; common cycloalkylenes include, but are not limited to, cyclopropane-1,1-ylene, cyclopropane-1,2-ylene, cyclobutane-1,1-ylene, cyclobutane-1,2-ylene, cyclobutane-1,3-ylene, and the like.

[0195] "Heterocyclyl," "heterocycle," or "heterocyclic" are used interchangeably herein and refer to non-aromatic heterocyclic groups in which one or more of the ring atoms is a heteroatom, such as N, O, S, P, Se, including monocyclic, fused, bridged, and spirocyclic rings, which can contain 1 or more double bonds within the ring. Preferred are 3- to 12-membered rings, more preferably 4- to 7-membered monocyclic or 7- to 10-membered bi- or tricyclic rings, which can contain 1, 2, or 3 atoms selected from N, O, S(O) n (wherein n is selected from 0, 1, or 2), P(O) m (wherein m is selected from 0 or 1), Se. Examples of "heterocyclyl" groups include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, or 3,6-dihydro-2H-pyranyl. Heterocyclyl groups can be substituted or unsubstituted.

[0196] "Heterocyclyl" refers to a saturated or unsaturated non-aromatic ring radical wherein one or more of the ring atoms is a heteroatom, such as N, O, S, P, Se, including monocyclic, fused, bridged, and spiro rings, which can contain one or more double bonds within the ring, connected to a group by a single bond, and to other groups (or ring systems) by another single bond, for example, 3-10 membered heterocyclyl, 3-7 membered heterocyclyl, or 4-10 membered heterocyclyl; common heterocyclyl groups include, but are not limited to, oxirane-2,2-ylidene, oxirane-2,3-ylidene, azetidine-2,2-ylidene, azetidine-2,3-ylidene, azetidine-2,4-ylidene, tetrahydrofuran-2,5-ylidene, tetrahydro-2H-pyran-2,3-ylidene, tetrahydro-2H-pyran-2,4-ylidene, tetrahydro-2H-pyran-2,5-ylidene, tetrahydro-2H-pyran-2,6-ylidene, pyrrolidine-1,2-ylidene, pyrrolidine-1,3-ylidene, pyrrolidine-2,3-ylidene, pyrrolidine-2,4-ylidene, pyrrolidine-2,5-ylidene, piperidine-1,2-ylidene, piperidine-1,3-ylidene, piperidine-1,4-ylidene, piperidine-2,3-ylidene, piperidine-2,4-ylidene, piperidine-2,5-ylidene, piperidine-2,6-ylidene, and the like.

[0197] "Spiroheterocyclyl" refers to a 5- to 18-membered, polycyclic radical having two or more ring structures sharing a single atom between the rings, which can contain one or more double bonds within the ring, but no ring is aromatic, wherein one or more of the ring atoms is selected from N, O, S(O) n (wherein n is selected from 0, 1, or 2), P(O) m (wherein m is selected from 0 or 1), Se, and the remaining ring atoms are carbon. Preferably, 6- to 14-membered, more preferably 7- to 10-membered. Spiroheterocyclyl groups are classified as mono-, bi-, or polyspiroheterocyclyl groups, preferably mono- and bi-spiroheterocyclyl groups, depending on the number of spiro atoms shared between the rings. More preferably, 3 / 6-, 4 / 6-, 5 / 6-, 6 / 6-, 4 / 4-, 4 / 5-, 5 / 5-, or monospiroheterocyclyl groups. Examples of "spiroheterocyclyl" groups include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, and 5-oxaspiro[2.4]heptyl.

[0198] "Fused heterocyclyl" refers to a fully carbon polycyclic radical having two or more ring structures sharing a pair of atoms between the rings, one or more of which can contain one or more double bonds, but no ring is aromatic, wherein one or more of the ring atoms is selected from N, O, S(O) n (wherein n is selected from 0, 1, or 2), P(O) m(where m is selected from 0 or 1), Se heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 3 / 6, 4 / 6, 5 / 6, 6 / 6, 5 / 5 or 5 / 6 bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclic group" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrole, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin.

[0199] "Bridged heterocyclic groups" refer to polycyclic groups with 5 to 18 members, containing two or more ring structures that share two atoms that are not directly connected. One or more rings may contain one or more double bonds, but none of the rings are aromatic. One or more ring atoms are selected from N, O, and S(O). n (where n is selected from 0, 1, or 2), P(O) m (where m is selected from 0 or 1), Se heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Examples of “bridged heterocyclic groups” include, but are not limited to: 3,4-diazabicyclo[3.1.1]heptane, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-azabicyclo[3.3.2]decyl.

[0200] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be connected together in a fused manner. "Aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferably, the aryl group is C6-C. 10 Aryl, more preferably phenyl and naphthyl, most preferably phenyl. The aryl group can be substituted or unsubstituted.

[0201] "Arylidene" refers to an aryl group as defined herein, which has two monovalent group centers obtained by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent aryl group. Typical arylidene groups include, but are not limited to, phenylene and naphthylene.

[0202] "Heteroaryl," "heteroaromatic," and "heteroaromatic ring" are used interchangeably herein and refer to a monocyclic or polycyclic, aromatic ring group containing 5 to 14 ring atoms, which can contain 1 to 4 atoms selected from N, O, S, Se. Preferred are 5 to 12 ring atoms, more preferred are 5 to 6 membered monocyclic heteroaryl groups or 8 to 10 membered bicyclic heteroaryl groups. Examples of "heteroaryl" include, but are not limited to, furanyl, pyridinyl, 2-oxo-l,2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzoimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl, which can be substituted or unsubstituted.

[0203] "Heteroarylene" refers to a heteroaryl group as described above having two monovalent radical centers obtained by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent heteroaryl group or one hydrogen atom from a carbon atom and one hydrogen atom from a nitrogen atom.

[0204] "Alkoxy" refers to a group of the formula (alkyl-O-), wherein alkyl is as defined herein. C1-C8alkoxy groups are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, and the like. Alkoxy groups can be substituted or unsubstituted.

[0205] "Alkenyloxy" refers to a group of the formula (alkenyl-O-), wherein alkenyl is as defined herein. C2-C8alkenyloxy groups are preferred. Alkenyloxy groups can be substituted or unsubstituted.

[0206] "Alkylamino" refers to a group of the formula (alkyl-NH-), wherein alkyl is as defined herein. C1-C8alkylamino groups are preferred. Examples include, but are not limited to, methylamino, ethylamino, n-propylamino, isopropylamino, n-butoxy, isobutoxy, t-butoxy, and the like. Alkylamino groups can be substituted or unsubstituted, and the substituents can be on the alkyl group or on the N, such as in the case of dimethylamino, diethylamino.

[0207] "Aminoalkyl" refers to a group of the formula (-alkyl-NH2), wherein alkyl is as defined herein. Examples include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, aminopentyl, and the like. Aminoalkyl groups can be substituted or unsubstituted, and the substituents can be on the alkyl group or on the N, such as in the case of dimethylaminoalkyl.

[0208] "Alkylcarbonyl" means a group (alkyl-C(O)-). Alkyl is defined herein. Examples include, but are not limited to, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, and the like. The alkylcarbonyl group can be substituted or unsubstituted.

[0209] "Alkoxycarbonyl" means a group (alkyl-O-C(O)-). Alkyl is defined herein. Examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, and the like. The alkoxycarbonyl group can be substituted or unsubstituted.

[0210] "Haloalkyl" means an alkyl group substituted with halogen. Halogen and alkyl are defined herein.

[0211] "Haloalkoxy" means an alkoxy group substituted with halogen. Halogen and alkoxy are defined herein.

[0212] "Haloalkylamino" means an alkylamino group substituted with halogen. Halogen and alkylamino are defined herein.

[0213] "Cycloalkyloxy" means a group (cycloalkyl-O-). Cycloalkyl is defined herein.

[0214] "Heterocyclyloxy" means a group (heterocyclyl-O-). Heterocyclyl is defined herein.

[0215] "Hydroxy" means the -OH group.

[0216] "Halogen" means fluorine, chlorine, bromine, and iodine.

[0217] "Amino" means -NH2.

[0218] "Cyano" means -CN.

[0219] "Nitro" means -NO2.

[0220] "Carboxy" means -C(O)OH.

[0221] "W" means -C(O)NH2.

[0222] "Substituted" means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3, of a group are each, independently, replaced with the corresponding number of substituents. It will be understood that substituents are placed in their possible chemically-allowed positions, as can be determined by one skilled in the art (experimentally or theoretically) without undue devotion of resources. For example, an amino or hydroxyl group with a free hydrogen can not be stable when bound to a carbon atom with an unsaturation (e.g., an olefinic bond).

[0223] Unless otherwise specified, the terms "substituted" or "substituted" in this specification refer to the substitution of a group by one or more groups selected from the following: H, deuterium, halogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C2-C8 alkenyloxy, C3-C 12 Cycloalkyl, C3-C8 cycloalkoxy, 3-12 membered heterocyclic, 3-12 membered heterocyclic, aminosulfonyl, C6-C 10 Aryl, 5-12 heteroaryl, cyano, amino, nitro, hydroxy, oxo, carboxyl, amide, hydroxyalkyl, aminoalkyl, alkanecarbonyl, alkoxycarbonyl, C1-C8 alkylamino, C1-C8 haloalkylamino, -OR g -SR g -C1-C8 alkylene-R g -OC(O)R g -C(O)R g -C(O)OR g -C(O)N(R) x )R y -NR x R y -N(CH3)R g -N(R) x )C(O)R y -N(R) x )C(O)NR x R y -N(R) x )C(O)OR g -N(R) x )S(O)NR x R y -N(R) x )S(O)2NR x R y -N(R) x )S(O)2R g -S(O)R g -S(O)2R g -S(O)2NR x R y -P(O)R x R y The alkyl, alkylene, alkoxy, alkenyl, alkynyl, alkenyloxy, cycloalkyl, cycloalkoxy, heterocyclic, heterocyclic, aryl, heteroaryl, 3-12 membered ring, amino, hydroxyl, or amide may optionally be further surrounded by one or more R o replace;

[0224] When 2 R o When two R atoms are substituted on the same atom, oTogether with the atoms they are attached to, they form 3-6 membered rings, or when 2 R o When substitution occurs on adjacent atoms, 2 R o Together with the atoms it is attached to, they form 3-12 membered rings;

[0225] R g R x R y R o Each is independently selected from H, deuterium, halogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C2-C8 alkenyloxy, C3-C 12 Cycloalkyl, C3-C8 cycloalkoxy, 3-12 membered heterocyclic, 3-12 membered heterocyclic, aminosulfonyl, C6-C 10 Aryl, 5-12 heteroaryl, cyano, amino, nitro, hydroxy, oxo, carboxyl, amide, hydroxyalkyl, aminoalkyl, alkanecarbonyl, alkoxycarbonyl, C1-C8 alkylamino, C1-C8 haloalkylamino, -OR s -SR s -C1-C8 alkylene-R s -OC(O)R s -C(O)R s -C(O)OR s -C(O)N(R) s )R t -NR s R t -N(CH3)R s -N(R) s )C(O)R t -N(R) s )C(O)NR s R t -N(R) s )C(O)OR t -N(R) s )S(O)NR s R t -N(R) s )S(O)2NR s R t -N(R) s )S(O)2R t -S(O)R s -S(O)2R s -S(O)2NR s R t or -P(O)R s R t The alkyl, alkylene, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further modified by one or more R groups.r substituted;

[0226] when 2 R r substituted on the same atom, 2 R r together with the atom to which they are attached form a 3-6 membered ring, or when 2 R r substituted on adjacent atoms, 2 R r together with the atom to which they are attached form a 3-12 membered ring;

[0227] R r , R s , R t are each independently selected from H, deuterium, Ci-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, halogen, cyano, amino, nitro, hydroxyl, oxo, Ci-C8alkoxy, Ci-C8haloalkyl, hydroxyalkyl, aminoalkyl, Ci-C8alkylamino, alkylcarbonyl, alkoxycarbonyl, halo hydroxyalkyl, Ci-C8haloalkylamino, C3-C 12 cycloalkyl, 3-12 membered heterocyclyl, carboxyl, amide, C6-C 10 aryl, or 5-12 membered heteroaryl.

[0228] The compounds of the present disclosure can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present disclosure, including but not limited to, diastereomeric, enantiomeric, and atropisomeric forms, and geometric (conformational) isomers, and mixtures thereof, such as racemates, are within the scope of the present disclosure.

[0229] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (such as enantiomeric, diastereomeric, and atropisomeric, and geometric (conformational) isomeric) forms of the structure; for example, where a structure is depicted exclusively in one of its isomeric forms, this is intended to encompass all isomeric forms of the structure. Individual stereoisomers of the compounds of the present disclosure can be prepared by

[0230] The C, H, O, S, N, F, Cl, Br, I, etc. involved in the groups and compounds described in the present disclosure include their isotopic cases. Meanwhile, the C, H, O, S, N, F, Cl, Br, I involved in the groups and compounds described in the present disclosure can be optionally substituted by one or more of their corresponding isotopes, including but not limited to the isotopes of carbon 12 C, 13 C, 14 C, the isotopes of hydrogen protium (H), deuterium (D), tritium (T), the isotopes of oxygen 16 O, 17O, 18 O, isotopes of sulfur 32 S, 33 S, 34 S, 36 S, isotopes of nitrogen 14 N, 15 N, isotopes of fluorine 17 F, 19 F, isotopes of chlorine 35 Cl, 37 Cl, isotopes of bromine 79 Br, 81 Br and the like.

[0231] It should be understood that the general description and the detailed description are exemplary and explanatory only and are not restrictive of any claim. It should be noted that in this specification and in the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or" is intended to mean "and / or" unless the context clearly indicates otherwise. Further, the terms "comprises", "comprising", "includes", "including" and the like are inclusive of the terms "consisting of" and "consisting essentially of".

[0232] "Pharmaceutically acceptable salt" refers to those salts of the compounds described above which retain the biological activity of the parent compound and which are suitable for medical use. Pharmaceutically acceptable salts of the compounds represented by Formula (I) can be metal salts, salts with suitable acids or salts with suitable bases. One preferred class of salts is the salts of the compounds of the disclosure with acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid and the like inorganic acids, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, citraconic acid, isonicotinic acid, salicylic acid, ascorbic acid, gentisic acid, gluconic acid, pyruvic acid, naphthalenesulfonic acid, stearic acid, phenylacetic acid, p-aminobenzoic acid, isethionic acid, pamoic acid, tannic acid and the like organic acids; and aspartic acid, glutamic acid and the like acidic amino acids. One preferred class of salts is the salts of the compounds of the disclosure with bases, including but not limited to: sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate and the like inorganic bases, aqueous ammonia, triethylamine, diethylamine, piperazine, guanidine, diethanolamine and the like organic bases.

[0233] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any claim. It should be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the terms "or" and "and" as used herein represent "and / or" unless otherwise indicated. Furthermore, the terms "comprising," "including," and the like as used herein are not intended to exclude any element unless the context clearly dictates otherwise.

[0234] "Pharmaceutically acceptable salt" refers to those salts of the compounds described above which retain the biological activity of the parent compound and which are suitable for medical use. Pharmaceutically acceptable salts of the compounds represented by Formula (I) can be metal salts, salts formed with suitable organic or inorganic acids, or salts formed with suitable organic or inorganic bases. One preferred class of salts is the salts of the compounds of the disclosure with acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, and the like inorganic acids, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, embonic acid, isonicotinic acid, salicylic acid, ascorbic acid, gentisic acid, gluconic acid, pyruvic acid, naphthalenesulfonic acid, stearic acid, phenylacetic acid, p-aminobenzoic acid, hydroxyethanesulfonic acid, pamoic acid, tannic acid, and the like organic acids; and aspartic acid, glutamic acid, and the like acidic amino acids. One preferred class of salts is the salts of the compounds of the disclosure with bases, including but not limited to: sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, and the like inorganic bases, ammonia, triethylamine, diethylamine, piperazine, guanidine, diethanolamine, and the like organic bases.

[0235] "Administering," "administration," "treatment," and "treat" when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid means the contact of an exogenous agent, therapeutic agent, diagnostic agent, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of an agent with the cell, as well as contact of an agent with a fluid with which the cell is contacted. The terms "administering" and "treatment" also mean in vitro and ex vivo treatment of, for example, cells, by an agent, diagnostic agent, binding compound, or by another cell. The term "subject" herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit) and most preferably a human.

[0236] "Effective amount" or "therapeutically effective amount" refers to that amount of an active ingredient (such as a compound) which, when administered to a subject, is sufficient to effect such treatment for disease, or at least one clinical symptom of a disease or disorder. The "therapeutically effective amount" can vary depending on the compound, the disease, the disorder, and / or the symptom of the disease or disorder, the severity of the disease, disorder, and or symptom of the disease or disorder, the age of the subject to be treated, and / or the body weight of the subject to be treated. In any given case, an appropriate amount will be readily apparent to one skilled in the art, or can be determined using routine experimentation. In some embodiments, a "therapeutically effective amount" is the amount of at least one compound, and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, disclosed herein effective to "treat" (as defined above) a disease or disorder in a subject. In the case of combination therapy, "therapeutically effective amount" refers to the total amount of the combination that is effective for the treatment of a disease, disorder, or condition.

[0237] "Pharmaceutically acceptable carrier" refers to one or more solid or liquid filler substances or gel materials that are suitable for use in humans. The pharmaceutically acceptable carrier can be any conventional carrier and / or diluent used in the art of pharmaceutical formulations, preferably of sufficient purity and sufficiently low toxicity to be compatible with the active ingredients of the present disclosure and not to significantly reduce the efficacy of the active ingredients. For example, the pharmaceutically acceptable carrier can be a filler, a binder, a disintegrant, a lubricant, an aqueous solvent or a non-aqueous solvent, etc. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will generally be that amount of a compound that produces a therapeutic effect.

[0238] A "pharmaceutical formulation" refers to a preparation which is in a form to be administered to a patient or subject in need of such treatment in any suitable manner, for example, topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intra-pulmonary, intra-ocular, intra-venously, intra-muscularly, intra-arterially, intra-thecal, intra-cerebrospinal, intra-dermally, intra-peritoneally, subcutaneously, sub-keratinally, or by inhalation. The pharmaceutical composition containing the active ingredient can be in a form suitable for oral use, for example, as a tablet, troche, lozenge, aqueous or oily suspension, dispersible powder or granule, emulsion, hard or soft capsule, or syrup or elixir or solution or suspension. A tablet contains the active ingredient in admixture with non-toxic pharmaceutically acceptable carriers suitable for the manufacture of tablets. For parenteral administration, the pharmaceutical composition can be in the form of a solution, aqueous or oily suspension, concentrate, lyophilized powder, and the like. Preferably, the pharmaceutical formulation is selected from a tablet, coated tablet, capsule, suppository, nasal spray or injection, more preferably a tablet or capsule. The pharmaceutical composition can be in the form of single unit dosages having accurate dosages. In addition, the pharmaceutical composition can further comprise additional active ingredients. Dosage forms for topical or transdermal administration can include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants as can be required.

[0239] All formulations of the pharmaceutical compositions disclosed herein can be produced by conventional methods in the pharmaceutical art. For example, the active ingredient can be mixed with one or more excipients, and then the desired formulation prepared. A "pharmaceutically acceptable excipient" refers to a conventional pharmaceutical carrier suitable for the desired pharmaceutical formulation, for example: diluents, vehicles such as water, various organic solvents and the like, fillers such as starch, sucrose, etc., binders such as cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone (PVP); wetting agents such as glycerol; disintegrants such as agar-agar, calcium carbonate and sodium bicarbonate; absorption enhancers such as quaternary ammonium compounds; surfactants such as cetyl alcohol; absorption carriers such as kaolin and bentonite; lubricants such as talc, calcium stearate, magnesium stearate, polyethylene glycol and the like. In addition, the pharmaceutical composition further comprises other pharmaceutically acceptable excipients such as dispersing agents, stabilizers, thickening agents, complexing agents, buffers, penetration enhancers, polymers, fragrances, sweeteners and dyes.

[0240] The term "disease" refers to any illness, malaise, sickness, symptom or indication, and can be used interchangeably with the term "condition" or "disorder".

[0241] The compound of the present disclosure has good RAS inhibitory activity and good known cancer cell proliferation activity. The compound has KRAS / BRAF binding blocking activity and better selectivity, exerts good tumor inhibition activity while showing higher safety, and the compound has good pharmacokinetic properties.

[0242] It is proved by experiments that the compound of the present disclosure has obvious proliferation inhibition activity on NCI-H358(G12C) / Capan-1(G12V) / HPAF(G12D) cells.

[0243] EMBODIMENT

[0244] DETAILED DESCRIPTION

[0245] Chemical substances represented by abbreviations in the present disclosure:

[0246] EA: ethyl acetate

[0247] Na2SO4: sodium sulfate

[0248] DCM: dichloromethane

[0249] CAN: acetonitrile

[0250] NIS: iodobenzenesulfonyl imide

[0251] BINAP: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl

[0252] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium

[0253] Pd(dppf)Cl2: dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium

[0254] THF: tetrahydrofuran

[0255] DMF: dimethylformamide

[0256] Pd(PPh3)2Cl2: bis(triphenylphosphine)palladium chloride

[0257] TMSCl: chlorotrimethylsilane

[0258] DIPEA: N,N-diisopropylethylamine

[0259] HATU: 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0260] NaOH: sodium hydroxide

[0261] MEOH: methanol

[0262] Example 1: synthesis of intermediate A1

[0263] Synthesis Step 1: Synthesis of A1-1

[0264] 3-Bromo-2-[(1S)-1-methoxyethyl]pyridine (10.0 g, 46.28 mmol) was dissolved in THF (200 mL) and stirred at room temperature for 15 min. Then, pinacol diboronate (17.6 g, 69.42 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (1.9 g, 6.94 mmol), and methoxy(cyclooctadiene)iridium(I) dimer (1.5 g, 2.31 mmol) were added sequentially, and the mixture was stirred at 75 °C for 16 h. After the reaction was complete, the mixture was quenched with water, extracted with EA, washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure, and purified by column chromatography to give product Al₁-1 12 g; yield 76%. ESI-MS (M+H) + =260.9.

[0265] Synthesis Step 2: Synthesis of A1-2

[0266] A1-1 (11.5 g, 33.62 mmol) was dissolved in acetonitrile (200 mL) and stirred at room temperature for 15 min. NIS (19.0 g, 84.05 mmol) was added in portions, and the mixture was stirred at 90 °C for 40 h. After the reaction was complete, the mixture was quenched with water, extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography to give product A1-2 3.5 g; yield 30%. ESI-MS (M+H) + =343.0.

[0267] Synthesis Step 3: Synthesis of A1-3

[0268] A1-2 (3.0 g, 8.77 mmol) was dissolved in toluene (50 mL) and stirred at room temperature for 10 min. Piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester (1.9 g, 10.52 mmol), cesium carbonate (5.7 g, 17.54 mmol), BINAP (548 mg, 0.88 mmol), and Pd2(dba)3 (402 mg, 0.44 mmol) were added sequentially, and the mixture was stirred at 100 °C for 16 h. After the reaction was complete, the mixture was quenched with water, extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography to give product A1-3 2.5 g; yield 71%. ESI-MS (M+H) + =401.3.

[0269] Synthesis Step 4: Synthesis of A1-4

[0270] A1-3 (2.4 g, 6.0 mmol) was dissolved in 1.4 dioxane (24 ml), hydrochloric acid dioxane solution 24 ml was added, and the reaction was stirred at room temperature for 12 h. After the reaction was completed, it was concentrated under reduced pressure to obtain the product A1-4 2.1 g; yield was 95%, ESI-MS (M+H) + = 301.2.

[0271] Synthesis step 5: synthesis of A1-5

[0272] A1-4 (2.0 g, 5.94 mmol) was dissolved in dichloromethane (20 ml), formaldehyde (353 mg, 17.85 mmol), sodium triacetoxy cyanoborohydride (3.7 g, 17.85 mmol) were added in turn, and the reaction was stirred at room temperature for 8 h. After the reaction was completed, it was quenched with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by column chromatography, the product A1-5 1.8 g was obtained; yield was 96%, ESI-MS (M+H) + = 315.1.

[0273] Synthesis step 6: synthesis of A1

[0274] A1-5 (1.5 g, 4.78 mmol) was dissolved in toluene (20 ml), and the reaction was stirred at room temperature for 10 min. Pinacol diboronic acid (1.8 g, 7.16 mmol), potassium acetate (1.4 g, 14.33 mmol), Pd(dppf)Cl2 (351 mg, 0.48 mmol) were added in turn, and the reaction was stirred at 90°C for 16 h. After the reaction was completed, it was quenched with water, extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by column chromatography, the product 1.0 g was obtained; yield was 75%, ESI-MS (M+H) + = 280.1.

[0275] Referring to the synthesis route and method of intermediate A1, the following intermediate compounds were synthesized:

[0276] Example 2: synthesis of intermediate A2

[0277] Synthesis step 1: synthesis of A2-1

[0278] A1-2 (2.0 g, 5.85 mmol) was dissolved in toluene (50 ml) and stirred at room temperature for 10 min, and then 4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1, 2, 3, 6-tetrahydropyridine-1- carboxylic acid-2-methylprop-2-yl ester (2.2 g, 8.78 mmol), sodium carbonate (1.9 g, 17.55 mmol), Pd(dppf)Cl2(424 mg, 0.58 mmol) were added successively, and stirred at 80 °C for 16 h. After the reaction was completed, water was added for quenching, extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then the product A2-1 was obtained by column chromatography purification. Yield: 1.5 g, 64%, ESI-MS (M+H) + = 398.3.

[0279] Synthesis Step 2-4: Synthesis of A2

[0280] The synthesis methods of A2-2, A2-3 and A2 refer to the synthesis steps 4-6 of intermediate A1.

[0281] Referring to the synthesis route and method of intermediate A2, the following intermediate compounds were synthesized:

[0282] Example 3: Synthesis of intermediate A3

[0283] Synthesis Step 1: Synthesis of A3-1

[0284] A1-2 (3.0 g, 8.77 mmol) was dissolved in toluene (50 ml) and stirred at room temperature for 10 min, and then (hexahydropyridin-4-yl)dimethoxymethane (1.7 g, 10.52 mmol), cesium carbonate (5.7 g, 17.54 mmol), BINAP (548 mg, 0.88 mmol), Pd2(dba)3(402 mg, 0.44 mmol) were added successively, and stirred at 100 °C for 16 h. After the reaction was completed, water was added for quenching, extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then the product A3-1 was obtained by column chromatography purification. Yield: 2.2 g, 67%, ESI-MS (M+H) + = 374.1.

[0285] Synthesis Step 2: Synthesis of A3-2

[0286] A3-1 (2.0 g, 5.36 mmol) was dissolved in tetrahydrofuran (20 ml), 2N hydrochloric acid aqueous solution (24 ml) was added, and the reaction was stirred at room temperature for 12 h at 50 °C. After the reaction was completed, it was concentrated under reduced pressure, extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by column chromatography, the product A3-2 1.5 g was obtained; the yield was 89%, ESI-MS (M+H) + = 314.2.

[0287] Synthesis step 3: synthesis of A3-3

[0288] A3-2 (1.3 g, 4.15 mmol) was dissolved in dichloromethane (13 ml), 3-fluoroazetidine (467 mg, 6.23 mmol), sodium triacetoxy cyanoborohydride (1.7 g, 8.31 mmol) were added in turn, and the reaction was stirred at room temperature for 8 h. After the reaction was completed, it was quenched with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by column chromatography, the product A3-3 1.1 g was obtained; the yield was 71%, ESI-MS (M+H) + = 373.3.

[0289] Synthesis step 4: synthesis of A3

[0290] The synthesis method of A3 refers to the synthesis step 6 in intermediate A1.

[0291] Referring to the synthesis route and method of intermediate A3, the following intermediate compounds were synthesized:

[0292] Example 4: synthesis of intermediate A34

[0293] Synthesis step 1: synthesis of A34-1

[0294] 3-bromo-2-[1-methoxyethyl]pyridine (10.0 g, 46.28 mmol) was dissolved in THF (200 mL), stirred at room temperature for 15 min, and then pinacol diborane (17.6 g, 69.42 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (1.9 g, 6.94 mmol), methoxy(cyclooctadiene)iridium(I) dimer (1.5 g, 2.31 mmol) were added in turn, and the reaction was stirred at 75 °C for 16 h. After the reaction was completed, it was quenched with water, extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by column chromatography, the product A34-1 was obtained; ESI-MS (M+H) + = 260.0.

[0295] Synthesis Step 2: synthesis of A34-2

[0296] A34-1 (11.5 g, 33.62 mmol) was dissolved in AcN (200 mL), stirred at room temperature for 15 min, NIS (19.0 g, 84.05 mmol) was added in portions, stirred at 90°C for 12 h. After the reaction was completed, quenched with water, extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, purified by column chromatography to give the product A34-2, ESI-MS (M+H) + = 341.9.

[0297] Synthesis Step 3: synthesis of A34-3

[0298] A34-2 (3.0 g, 8.77 mmol) was dissolved in toluene (50 mL), stirred at room temperature for 10 min, 2-methylprop-2-yl piperazine-1-carboxylate (1.9 g, 10.52 mmol), cesium carbonate (5.7 g, 17.54 mmol), BINAP (548 mg, 0.88 mmol), Pd2(dba)3 (402 mg, 0.44 mmol) were added in turn, stirred at 100°C for 16 h. After the reaction was completed, quenched with water, extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, purified by column chromatography to give the product A34-3, ESI-MS (M+H) + = 414.1.

[0299] Synthesis Step 4: synthesis of A34-4

[0300] A34-3 (2.4 g, 6.0 mmol) was dissolved in 1,4-dioxane (24 mL), 24 mL of hydrochloric acid dioxane solution was added, stirred at room temperature for 12 h, the reaction was completed, concentrated under reduced pressure to give the product A34-4, ESI-MS (M+H) + = 314.1.

[0301] Synthesis Step 5: synthesis of A34-5

[0302] A34-4 (2.0 g, 5.94 mmol) was dissolved in DCM (20 mL), cyclopropanone (1.0 g, 17.85 mmol), sodium triacetoxy cyanoborohydride (3.7 g, 17.85 mmol) were added in turn, stirred at room temperature for 8 h. After the reaction was completed, quenched with water, extracted with DCM, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, purified by column chromatography to give the product A34-5; ESI-MS (M+H) + = 354.1.

[0303] Synthesis Step 5: synthesis of A34-6

[0304] A34-5 (1.8 g, 5.10 mmol) was dissolved in DCM (20 mL), triethylamine (1.0 g, 10.19 mmol) was added, benzyl chloroformate (1.3 g, 7.65 mmol) was added under ice bath, and stirring was performed at room temperature for 2 h. After the reaction was completed, water was added for quenching, DCM was added for extraction, saturated brine was added for washing, anhydrous Na2SO4 was added for drying, filtration was performed, and concentration was performed under reduced pressure. Purification by column chromatography yielded the product A34-6; ESI-MS (M+H) + = 488.1.

[0305] Synthesis Step 6: synthesis of A34

[0306] A34-6 (1.5 g, 4.41 mmol) was dissolved in toluene (20 mL), stirring was performed at room temperature for 10 min, pinacol diboronic acid (1.7 g, 6.59 mmol), potassium acetate (1.3 g, 13.18 mmol), Pd(dppf)Cl2 (323 mg, 0.44 mmol) were sequentially added, and stirring was performed at 90 °C for 16 h. After the reaction was completed, water was added for quenching, EA was added for extraction, saturated brine was added for washing, anhydrous Na2SO4 was added for drying, filtration was performed, and concentration was performed under reduced pressure. Purification by column chromatography yielded the product A34, ESI-MS (M+H) + = 454.2.

[0307] The following intermediate compounds were synthesized according to the synthetic route and method of intermediate A34:

[0308] The following intermediate compounds were synthesized according to the synthetic route and method of intermediate A34:

[0309] The following intermediate compounds were synthesized according to the synthetic route and method of intermediate A34:

[0310] The following intermediate compounds were synthesized according to the synthetic route and method of intermediate A34:

[0311] The following intermediate compounds were synthesized according to the synthetic route and method of intermediate A34:

[0312] Example 5: Synthesis of intermediate A35

[0313] Synthesis step 1: Synthesis of A35-1

[0314] 1-methyl-3-hydroxyazetidine (10.0 g, 0.115 mol) was dissolved in DCM (100 mL), p-toluenesulfonyl chloride (43.85 g, 0.23 mol) was added, and the mixture was cooled to 0 °C. Triethylamine (29.35 g, 0.29 mol) was added dropwise, and the mixture was stirred at room temperature for 12 h. After the reaction was completed, water was added for quenching, and the mixture was extracted with DCM. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product A35-1. ESI-MS (M+H) + = 242.1.

[0315] Synthesis step 2: Synthesis of A35-2

[0316] A35-1 (3.0 g, 12.4 mmol) was dissolved in DMF (15 mL), and cesium carbonate (8.1 g, 24.8 mmol) was added. 4-bromopyrazole (2.7 g, 18.6 mmol) was added, and the mixture was stirred at 60 °C for 1 h. After the reaction was completed, water was added for quenching, and the mixture was extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product A35-2. ESI-MS (M+H) + = 216.0.

[0317] Synthesis step 3: Synthesis of A35-3

[0318] A mixture of A35-2 (3 g, 13.95 mmol), bis(pinacolato)diboron (5.32 g, 20.93 mmol), Pd(dppf)Cl2 (1.0 g, 1.39 mmol), potassium acetate (6.2 g, 62.79 mmol) in toluene (60 mL) was stirred at 95 °C for 3 h under nitrogen protection. The reaction solution was added with EA (500 mL) and washed with water. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give the product A35-3 2.8 g; ESI-MS (M+H) + = 264.2.

[0319] Synthesis step 4: Synthesis of A35-4

[0320] A35-3 (2.0 g, 5.85 mmol) was dissolved in toluene (50 mL) and stirred at room temperature for 10 min, A34-2 (2.3 g, 8.78 mmol), sodium carbonate (1.9 g, 17.55 mmol), Pd(dppf)Cl2(424 mg, 0.58 mmol) were added successively, and stirred at 80 °C for 16 h. After the reaction was completed, water was added for quenching, extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the product A35-4 was obtained after purification by column chromatography. ESI-MS (M+H) + = 351.1.

[0321] Synthesis Step 5: Synthesis of A35

[0322] The synthesis method of A35 refers to the synthesis step 7 of intermediate A34.

[0323] Referring to the synthesis route and method of intermediate A35, the following intermediate compounds were synthesized:

[0324] Referring to the synthesis route and method of steps 3-4 of intermediate A35, the following intermediate compounds were synthesized:

[0325] Example 6: Synthesis of intermediate A36

[0326] Synthesis Step 1: Synthesis of A36-1

[0327] A34-1 (10.0 g, 38.6 mmol) was dissolved in AcN (100 mL) and cooled to 0 °C, and hydrogen peroxide (3.9 g, 1.2 mol) was added dropwise, and the reaction was stirred at room temperature for 3 h. After the reaction was completed, saturated sodium sulfite solution was added for quenching, concentrated under reduced pressure, extracted with DCM, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the product A36-1 was obtained after purification by column chromatography. ESI-MS (M+H) + = 232.0.

[0328] Synthesis Step 2: Synthesis of A36-2

[0329] A36-1 (5.0 g, 21.6 mmol) was dissolved in THF (50 mL), cooled to 0 °C, triphenylphosphine (7.4 g, 28.1 mmol) was added, cooled to 0 °C, diisopropyl azodicarboxylate (4.4 g, 21.6 mmol) was added dropwise, stirred for 10 min, 2-hydroxycyclobutanone (1.8 g, 21.6 mmol) was added dropwise, and stirred at room temperature for 12 h. The reaction was quenched by adding water, extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product A36-2 was obtained after purification by column chromatography. ESI-MS (M+H) + = 300.0.

[0330] Synthesis Step 3-4: Synthesis of A36

[0331] The synthesis of A36-3, A36 was performed according to the synthesis of intermediates A34, synthesis steps 5 and 7.

[0332] Example 7: Synthesis of intermediate A38

[0333] Synthesis Step 1: Synthesis of A38-1

[0334] A34-2 (10.0 g, 29.3 mmol) was dissolved in DMSO (100 mL), 1H-pyrazole-4-carbaldehyde (3.1 g, 32.2 mmol) was added, cesium carbonate (19.1 g, 58.6 mmol) was added, copper oxide (0.23 g, 2.93 mmol) was added, and the mixture was stirred at 100 °C for 24 h under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, diluted with DCM, filtered through celite, the filtrate was dried over anhydrous Na2SO4, filtered and concentrated. The product A38-1 was obtained after purification by column chromatography. ESI-MS (M+H) + = 310.0.

[0335] Synthesis Step 2-3: Synthesis of A38

[0336] The synthesis of A38-2, A38 was performed according to the synthesis of intermediates A34, synthesis steps 5 and 7.

[0337] The following intermediate compounds were synthesized according to the synthesis route and method of intermediate A38:

[0338] The following intermediate compounds were synthesized according to the synthesis route and method of intermediate A38, steps 1 and 3:

[0339] Example 8: Synthesis of intermediate A39

[0340] Synthesis Step 1: synthesis of A39-1

[0341] A34-2 (2.0 g, 5.85 mmol) was dissolved in toluene (50 mL) and stirred at room temperature for 10 min, and then 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-3-ene-1-carboxylic acid ethyl ester (2.3 g, 8.78 mmol), sodium carbonate (1.9 g, 17.55 mmol), Pd(dppf)Cl2(424 mg, 0.58 mmol) were added successively, and the mixture was stirred at 80 °C for 16 h. After the reaction was completed, water was added for quenching, and the mixture was extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product A39-1. ESI-MS (M+H) + = 340.0.

[0342] Synthesis Step 2: synthesis of A39-2

[0343] A39-1 (5.0 g, 14.7 mmol) was dissolved in methanol (50 mL), and platinum carbon (50 mg, 1%) was added. The mixture was stirred at room temperature for 12 h under hydrogen gas protection. After the reaction was completed, the mixture was filtered, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure to give the product A39-2. ESI-MS (M+H) + = 342.1.

[0344] Synthesis Step 3: synthesis of A39-3

[0345] A39-2 (3.0 g, 8.7 mmol) was dissolved in THF (30 mL), and a solution of diisobutylaluminum hydride (34.8 mL, 17.4 mmol) was added dropwise at 0 °C under nitrogen gas protection. The mixture was stirred at 0 °C for 6 h. After the reaction was completed, a saturated ammonium chloride solution was added dropwise at 0 °C, and the mixture was extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product A39-3. ESI-MS (M+H) + = 312.0.

[0346] Synthesis Step 4-5: synthesis of A39

[0347] A39-4, A39 was synthesized according to the synthesis steps 5 and 7 of intermediate A34.

[0348] According to the synthesis routes and methods of intermediate A39, the following intermediate compounds were synthesized:

[0349] Example 9: synthesis of intermediate A40

[0350] Synthesis Step 1: synthesis of A40-1

[0351] Methyl 3-bromocyclobutane carboxylate (10.0 g, 51.8 mmol) was dissolved in THF (100 mL), protected by nitrogen replacement, cooled to -70 °C, and n-butyllithium in n-hexane (26.0 mL, 2.0 M) was added dropwise. The temperature was raised to -20 °C and reacted for 30 min. Zinc chloride (8.5 g, 62.2 mmol) was added, and the reaction was maintained for 20 min. A solution of A34-2 (13.6 g, 39.9 mmol) in acetonitrile (100 mL) was added dropwise, and Pd(PPh3)4 (1.2 g, 1.03 mmol) was added. The temperature was raised to 50 °C, and the reaction was maintained for 5 h. After the reaction was completed, water was added for quenching, and the mixture was filtered, extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product A40-1 was obtained after purification by column chromatography. ESI-MS (M+H) + = 328.0.

[0352] Synthesis Step 2: synthesis of A40-2

[0353] A40-1 (5.0 g, 15.3 mmol) was dissolved in methanol (50 mL), cooled to 0 °C, and sodium borohydride (2.3 g, 61.2 mmol) was added in portions. The temperature was raised to room temperature, and the reaction was stirred for 12 h. After the reaction was completed, water was added for quenching, and the mixture was extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product A40-2 was obtained. ESI-MS (M+H) + = 300.0.

[0354] Synthesis Step 3-4: synthesis of A40-4

[0355] The synthesis method of A40-3, A40-4 was referred to the synthesis steps 2-3 of intermediate A35.

[0356] Synthesis Step 5: synthesis of A40

[0357] The synthesis method of A40 was referred to the synthesis step 7 of intermediate A34.

[0358] According to the synthesis route and method of intermediate A40, the following intermediate compounds were synthesized:

[0359] Example 10: synthesis of intermediate A217

[0360] Synthesis Step 1: synthesis of A217-1

[0361] The synthesis method of A217-1 was referred to the synthesis step 1 of intermediate A38.

[0362] Synthesis Step 2-4: Synthesis of A217

[0363] The synthesis method of A217 refers to the synthesis steps 4 and 6-7 of intermediate A34.

[0364] Example 11: Synthesis of intermediate A218

[0365] Synthesis Step 1-2: Synthesis of A218-2

[0366] The synthesis method of A218-1, A218-2 refers to the synthesis steps 1-2 of intermediate A38.

[0367] Synthesis Step 3-4: Synthesis of A218

[0368] The synthesis method of A218-3, A218 refers to the synthesis steps 6-7 of intermediate A34.

[0369] Referring to the synthesis route and method of intermediate A218 steps 1-2 and 4, the following intermediate compounds are synthesized:

[0370] Example 12: Synthesis of intermediate A220

[0371] Synthesis Step 1: Synthesis of A220-1

[0372] A94-2 (2.0 g, 5.88 mmol) was dissolved in toluene (50 mL) and stirred at room temperature for 10 min, then 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.7 g, 8.82 mmol), sodium carbonate (1.9 g, 17.55 mmol), Pd(dppf)Cl2 (424 mg, 0.58 mmol) were added successively, and stirred at 80°C for 16 h. After the reaction was completed, water was added for quenching, extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain the product A220-1, ESI-MS (M+H) + = 397.1.

[0373] Synthesis Step 2: Synthesis of A220-2

[0374] A220-1 (1.0 g, 2.5 mmol) was dissolved in methanol (10 mL), and platinum carbon (10 mg, 1%) was added, and the reaction was protected by hydrogen exchange, and stirred at room temperature for 12 h. After the reaction was completed, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure to obtain the product A220-2, ESI-MS (M+H)+ = 399.1.

[0375] Synthesis of A220-3, A220-4, A220

[0376] The synthesis method of A220-3, A220-4, A220 refers to the synthesis steps 4-5 and 7 of intermediate A34.

[0377] The following intermediate compounds were synthesized according to the synthesis route and method of steps 1 and 3-5 of intermediate A220

[0378] Example 13: Synthesis of intermediate A222

[0379] Synthesis of A222-1, A222-2

[0380] The synthesis method of A222-1, A222-2 refers to the synthesis steps 1-2 of intermediate A220.

[0381] Synthesis of A222-3, A222-4, A222

[0382] The synthesis method of A222-3, A222-4, A222 refers to the synthesis steps 4 and 6-7 of intermediate A34.

[0383] Example 14: Synthesis of intermediate H1

[0384] Synthesis of H1-1

[0385] A94-2 (3.0 g, 8.77 mmol) was dissolved in toluene (50 mL) and stirred at room temperature for 10 min, and then tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (2.0 g, 10.52 mmol), cesium carbonate (5.7 g, 17.54 mmol), BINAP (548 mg, 0.88 mmol), Pd2(dba)3 (402 mg, 0.44 mmol) were added in turn, and stirred at 100°C for 16 h. After the reaction was completed, water was added for quenching, extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain the product H1-3, ESI-MS (M+H) + = 426.1.

[0386] Synthesis of H1-2

[0387] H1-1 (2.4 g, 6.0 mmol) was dissolved in 1,4-dioxane (24 mL), and hydrochloric acid dioxane solution 24 mL was added, and stirred at room temperature for 12 h. After the reaction was completed, it was concentrated under reduced pressure to obtain the product H1-4, ESI-MS (M+H) += 326.1.

[0388] Synthesis Step 3: Synthesis of H1-3

[0389] H1-2 (2.0 g, 5.94 mmol) was dissolved in DCM (20 mL), 3-methyl-3- formyl-1-oxetane (1.0 g, 17.85 mmol), sodium triacetoxy cyanoborohydride (3.7 g, 17.85 mmol) were added successively, stirred at room temperature for 8 h. After the reaction was completed, quenched with water, extracted with DCM, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, purified by column chromatography to give the product H1-5; ESI-MS (M+H) + = 410.1.

[0390] Synthesis Step 4: Synthesis of H1

[0391] H1-3 (1.5 g, 4.41 mmol) was dissolved in toluene (20 mL), stirred at room temperature for 10 min, pinacol diboronic acid (1.7 g, 6.59 mmol), potassium acetate (1.3 g, 13.18 mmol), Pd(dppf)Cl2 (323 mg, 0.44 mmol) were added successively, stirred at 90 °C for 16 h. After the reaction was completed, quenched with water, extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, purified by column chromatography to give the product H1, ESI-MS (M+H) + = 376.2.

[0392] The following intermediate compounds were synthesized according to the synthesis route and method of intermediate H1:

[0393] Example 15: Synthesis of intermediate H14

[0394] Synthesis Step 1: Synthesis of H14-1

[0395] 3-Methyloxetane-3-ol (10.0 g, 0.115 mol) was dissolved in DCM (100 mL), p-toluenesulfonyl chloride (43.85 g, 0.23 mol) was added, and the mixture was cooled to 0 °C. Triethylamine (29.35 g, 0.29 mol) was added dropwise, and the mixture was heated to room temperature and stirred for 12 h. After the reaction was complete, the mixture was quenched with water, extracted with DCM, washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure, and purified by column chromatography to give product H₁₄⁻. ESI-MS (M+H) + =243.1.

[0396] Synthesis Step 2: Synthesis of H14-2

[0397] H14-1 (3.0 g, 12.4 mmol) was dissolved in DMF (15 mL), cesium carbonate (8.1 g, 24.8 mmol) was added, and H1-4 (6.1 g, 18.6 mmol) was added. The mixture was heated to 80 °C and stirred for 12 h. After the reaction was completed, the mixture was quenched with water, extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain product H14-2. ESI-MS (M+H) + =396.1.

[0398] Synthesis Step 3: Synthesis of H14

[0399] The synthesis method for H14 is the same as step 6 in the synthesis of intermediate H1.

[0400] Following steps 2 and 3 of the synthesis of intermediate H14, the following intermediate compounds were synthesized:

[0401] Example 16: Synthesis of intermediate H106

[0402] Synthesis Step 1: Synthesis of H106-1

[0403] 3-Bromooxetane-3-ol (5.0 g, 32.91 mmol) was dissolved in DCM (50 mL), and triethylamine (6.6 g, 65.81 mmol) and DMAP (402 mg, 3.29 mmol) were added. The mixture was cooled to 0 °C, and acetic anhydride (5.0 g, 49.36 mol) was added dropwise. The mixture was then heated to room temperature and stirred for 5 h. After the reaction was complete, the mixture was quenched with water, extracted with DCM, washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, concentrated under reduced pressure, and purified by column chromatography to give product H₁₀₆₁. ESI-MS (M+H) + =195.0.

[0404] Synthesis steps 2-3: Synthesis of H106

[0405] H106 synthesis route and method refer to synthesis steps 2-3 of intermediate H14.

[0406] Referring to the synthesis steps and methods of intermediate H106, the following intermediate compounds were synthesized:

[0407] Example 17: Synthesis of intermediate J1

[0408] Synthesis step 1: synthesis of J1-1

[0409] (3-oxycyclobutyl)acetic acid (7.8 g, 61.27 mmol) was dissolved in DCM (100 mL), (4R)-4-benzyl-1,3-oxazolidin-2-one (11.9 g, 67.40 mmol), 4-dimethylaminopyridine (750 mg, 6.13 mmol) and triethylamine (18.6 g, 184 mmol) were added in turn, and then 2-chloro-1-methylpyridine (salt) iodide (26.6 g, 104 mmol) was added in portions. Stirring at room temperature for 1 hour. After the reaction was completed, DCM was added for extraction, and the organic phase was dried over anhydrous Na2SO4. The filtrate was concentrated and purified by column chromatography to obtain the product J1-1, ESI-MS (M+H) + = 288.1.

[0410] Synthesis step 2: synthesis of J1-2

[0411] J1-1 (4.4 g, 15.3 mmol) and acetic acid (1.8 g, 30.6 mmol) were added in turn to THF (50 mL), and sodium borohydride (463 mg, 12.2 mmol) was slowly added in portions to the above solution at 0°C. Stirring was continued at 0°C for 2 hours. After the reaction was completed, saturated aqueous ammonium chloride solution was slowly added dropwise, concentrated under reduced pressure, and extracted with EA. The organic phase was washed with saturated NaHCO3 until the pH was about 8. The organic phase was dried over anhydrous Na2SO4. The filtrate was concentrated and purified by column chromatography to obtain the product J1-2 ESI-MS (M+H) + = 290.1.

[0412] Synthesis step 3: synthesis of J1-3

[0413] Compound J1-2 (4 g, 13.82 mmol) was dissolved in DCM (40 mL), cooled to 0 °C, and 4-dimethylaminopyridine (1.35 g, 11.06 mmol) and N,N- diisopropylethylamine (2.7 g, 20.73 mol) were added successively, and then p-toluenesulfonyl chloride (2.9 g, 15.21 mmol) was added portionwise to the above solution, and stirred at 25 °C for 3 h. After the reaction was completed, DCM was added for extraction, and the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The filtrate was purified by column chromatography to obtain the product J1-3, ESI-MS (M+H) + = 444.1.

[0414] Synthesis Step 4: Synthesis of J1-4

[0415] J1-3 (4.5 g, 10.15 mmol) and lithium bromide (1.7 g, 20.29 mmol) were added successively to 1-methyl-2-pyrrolidinone (45 mL), and stirred at 90 °C for 13 h. After the reaction was completed, saturated brine was added for dilution, and EA was added for extraction. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The filtrate was purified by column chromatography to obtain the product J1-4, ESI-MS (M+H) + = 352.1.

[0416] Synthesis Step 5: Synthesis of J1-5

[0417] J1-4 (2 g, 5.01 mmol) was dissolved in THF (20 mL), cooled to -78 °C, and lithium diisopropylamide 2M tetrahydrofuran n-heptane mixed solution (3.26 mL, 6.51 mmol) was added dropwise slowly, and stirred for half an hour under a nitrogen atmosphere. Di-tert-butyl hydrazine dicarboxylate (1.4 g, 6.01 mmol) in DCM (50 mL) was added to the above solution at once, and stirring was continued for half an hour. 1.3-dimethyl-tetrahydro-2-pyrimidinone (19.2 g, 154.08 mmol) was added slowly to the above reaction solution, and the temperature was allowed to rise to room temperature naturally, and stirring was continued for 13 h. After the reaction was completed, 20 mL of water was added for extraction, and lithium hydroxide monohydrate (632 mg, 15.03 mmol) was added, and stirred at room temperature for 1 h. After concentration under reduced pressure, saturated brine was added for dilution, and EA was added for extraction. The organic phase was discarded, and the aqueous phase was adjusted to pH 5 with 1N hydrochloric acid, and then extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The filtrate was purified by column chromatography to obtain the product J1-5, ESI-MS (M+H) + = 343.2.

[0418] Synthesis Step 6: Synthesis of J1-6

[0419] J1-5 (500 mg, 1.46 mmol) was dissolved in MeOH (20 mL), and trimethylsilyldiazomethane 2M in n-hexane (3.65 mL, 7.3 mmol) was added dropwise slowly. The reaction was stirred at room temperature for 10 min. After the reaction was completed, 0.1 mL of acetic acid was added to quench the reaction. The product J1-6 was obtained by concentration under reduced pressure. ESI-MS (M+H) + = 357.2.

[0420] Synthesis Step 7: Synthesis of J1

[0421] J1-6 (100 mg, 0.28 mmol) was dissolved in DCM (2 mL), and 1 mL of trifluoroacetic acid was added. The reaction was stirred at room temperature for 12 h. After the reaction was completed, 5 mL of methyl tert-butyl ether was added, and the mixture was stirred at room temperature for 10 min. The product J1 was obtained by filtration and drying of the filter cake. ESI-MS (M+H) + = 157.1.

[0422] Example 18: Synthesis of Intermediate J2

[0423] Synthesis Step 1: Synthesis of J2-1

[0424] J1 (2 g, 10.78 mmol) was dissolved in DCM (40 mL), and DMAP (2.6 g, 20.76 mmol) and Et3N (4 g, 41.53 mmol) were added to the system. (Boc)2O (8 g, 41.53 mmol) was added dropwise slowly, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, water was added to quench the reaction, and DCM was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Compound J2-1 was obtained by column chromatography. ESI-MS (M+H) + = 357.2.

[0425] Synthesis Step 2: Synthesis of J2-2

[0426] J2-1 (500 mg, 1.4 mmol) was dissolved in THF (5 mL), and the temperature was lowered to -70°C. LiHMDS (2.1 mL, 2.1 mmol) was added to the system, and the internal temperature was controlled below -60°C. After the dropwise addition was completed, the reaction was stirred for 1 h. Iodomethane (500 mg, 3.5 mmol) was added dropwise, and the internal temperature was controlled below -70°C. After the dropwise addition was completed, the reaction was carried out at room temperature for 1 h. After the reaction was completed, water was added to quench the reaction, and EA was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Compound J2-2 was obtained by column chromatography. ESI-MS (M+H) + = 371.2.

[0427] Synthesis Step 3: Synthesis of J2

[0428] J2-2 (200 mg, 0.54 mmol) was dissolved in DCM (5 mL), TFA (1 mL) was added, and the reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain compound J2, ESI-MS (M+H) + = 171.1.

[0429] Example 19: Synthesis of intermediate K1

[0430] Synthesis Step 1: Synthesis of K1-1

[0431] 3-hydroxy-2,2-dimethylpropionic acid (100 g, 847.40 mmol), benzoyl chloride (220 g, 1.69 mol), and imidazole (74 g, 1.10 mol) were dissolved in DCM (2000 mL), and the mixture was stirred at room temperature for 20 h. After the reaction was completed, the reaction mixture was extracted with DCM, and the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product K1-1 was obtained after purification by column chromatography, ESI-MS (M+H) + = 357.2.

[0432] Synthesis Step 2: Synthesis of K1-2

[0433] K1-1 (100 g, 499.80 mmol) and DMF (3.8 mL, 50.0 mmol) were dissolved in DCM (1000 mL), and oxalyl chloride (74 mL, 849.6 mmol) was slowly added to the system at 0°C. The mixture was stirred at room temperature for 5 h. The product K1-2 was obtained after concentration under reduced pressure. ESI-MS (M+H) + = 375.1.

[0434] Synthesis Step 3: Synthesis of K1-3

[0435] 5-bromoindole (40.0 g, 201.20 mmol) was dissolved in DCM (800 mL), and tin tetrachloride (24.2 mL, 201.20 mmol) was slowly added to the mixture at 0°C. The mixture was stirred under a nitrogen atmosphere for 30 min. A 400 mL DCM solution of K1-2 (80.0 g, 372.0 mmol) was slowly added to the above reaction mixture at 0°C. The reaction mixture was stirred at 0°C under a nitrogen atmosphere for 1 h. After the reaction was completed, the reaction was quenched by adding 1000 mL of water, and the mixture was filtered. The filtrate was allowed to stand and separate into an aqueous phase and an organic phase. The organic phase was combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product K1-3 was obtained after purification by column chromatography, ESI-MS (M+H) + = 534.1.

[0436] Synthesis Step 4: Synthesis of K1-4

[0437] K1-3 (37.0 g, 93.90 mmol) was dissolved in THF (400 mL), and lithium borohydride THF solution (1 M, 200 mL) was slowly added dropwise into the reaction solution at 0 °C under nitrogen atmosphere. After the dropwise addition was completed, the temperature was increased to 60 °C, and stirring was performed for 15 h. After the reaction was completed, the temperature was cooled to room temperature, 100 mL of saturated aqueous ammonium chloride solution was slowly added dropwise, followed by the addition of 500 mL of EA, 40 mL of saturated brine, and the organic phase was collected, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purification by column chromatography, the product K1-4 was obtained, ESI-MS (M+H) + = 520.2.

[0438] Synthesis Step 5: Synthesis of K1-5

[0439] K1-4 (24 g, 46.15 mmol) was dissolved in tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 250 mL), and stirring was performed at 60 °C for 3 h. After the reaction was completed, 500 mL of water was added, and extraction was performed with 500 mL of EA. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purification by column chromatography, the product K1-5 was obtained, ESI-MS (M+H) + = 282.0.

[0440] Synthesis Step 6: Synthesis of K1-6

[0441] K1-5 (10 g, 35.46 mmol) was dissolved in DCM (100 mL), and triethylamine (9.0 g, 88.65 mmol) and acetyl chloride (4.2 g, 53.19 mmol) were sequentially added under ice bath conditions, and stirring was performed at room temperature for 30 min. After the reaction was completed, washing was performed with saturated sodium bicarbonate (200 mL), and the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. After purification by column chromatography, the product K1-6 was obtained, ESI-MS (M+H) + = 324.1.

[0442] Synthesis Step 7: Synthesis of K1-7

[0443] A mixture of K1-6 (8 g, 24.77 mmol), bis(pinacolato)diboron (9.44 g, 37.15 mmol), Pd(dppf)Cl2 (1.8 g, 2.48 mmol), potassium acetate (7.3 g, 74.30 mmol), and toluene (80 mL) was stirred at 95 °C for 3 h under nitrogen protection. The reaction solution was added with EA (500 mL), and washing was performed with water (30 mL x 3). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. After purification by column chromatography, the product K1-7 was obtained, ESI-MS (M+H) + = 372.2.

[0444] Synthesis Step 8: Synthesis of K1-8

[0445] A mixture of K1-7 (7 g, 18.82 mmol), (2S)-3-(4-bromo-1,3-thiazol-2-yl)-2-({[(2- methylpropan-2-yl)oxy]carbonyl}amino)propanoic acid methyl ester (12.3 g, 37.63 mmol), [1,1’-bis(ditert-butylphosphino)ferrocene]dichloropalladium (1.37 g, 1.88 mmol), potassium phosphate (12 g, 56.45 mmol) in dioxane (140 mL), toluene (70 mL) and water (70 mL) was stirred at 100 °C for 2 h under nitrogen atmosphere. After the reaction was completed, EA (200 mL) was added and washed with saturated brine (200 mL). The organic phase was dried over anhydrous Na2SO4and concentrated after filtration. The product K1-8 was obtained after purification by column chromatography, ESI-MS (M+H) + = 530.2.

[0446] Synthesis Step 9: Synthesis of K1-9

[0447] A solution of iodine (3.5 g, 13.99 mmol) in THF (35 mL) was added to a mixture of compound K1-8 (6 g, 13.99 mmol), silver trifluoroacetate (3.4 g, 15.38 mmol) in THF (60 mL) under ice-bath condition and stirred for 0.5 h. After the reaction was completed, the reaction was quenched with a solution of sodium thiosulfate (100 mL) and extracted with EA (100 mL). The organic phase was dried over anhydrous Na2SO4and concentrated after filtration. The product K1-9 was obtained after purification by column chromatography, ESI-MS (M+H) + = 656.1.

[0448] Synthesis Step 10: Synthesis of K1-10

[0449] K1-9 (4 g, 6.11 mmol) was dissolved in THF (50 mL) and water (10 mL) and anhydrous lithium hydroxide (439 mg, 18.32 mmol) was added and stirred at room temperature for 5 h. After the reaction was completed, the pH was adjusted to 6 with 1 N dilute hydrochloric acid and extracted with EA (50 mL). The organic phase was dried over anhydrous Na2SO4and concentrated after filtration to obtain K1-10, ESI-MS (M+H) + = 642.1.

[0450] Synthesis Step 11: Synthesis of K1-11

[0451] K1-10 (3 g, 5.01 mmol), intermediate J1 (940 mg, 6.01 mmol), N, N, N', N' tetramethylchloroformamidium hexafluorophosphate (2.8 g, 7.51 mmol), N-methylmorpholine (1.5 g, 15.2 mmol) in AcN (30 mL) was stirred at room temperature for 2 h. After the reaction was completed, it was diluted with EA (100 mL) and washed with water (100 mL). The organic phase was dried over anhydrous Na2SO4and filtered and concentrated to give K1-11 3.2 g, ESI-MS (M+H) + = 738.2.

[0452] Synthesis Step 12: synthesis of K1-12

[0453] K1-11 (3 g, 4.07 mmol) was dissolved in THF (30 mL) and water (10 mL), and anhydrous lithium hydroxide (293 mg, 12.21 mmol) was added, and stirred at room temperature for 1 h. After the reaction was completed, the pH was neutralized to 6 with 1N dilute hydrochloric acid, and extracted with EA (50 mL). The organic phase was dried over anhydrous Na2SO4and filtered and concentrated to give K1-12, ESI-MS (M+H) + = 724.2.

[0454] Synthesis Step 13: synthesis of K1

[0455] K1-12 (2.2 g, 3.04 mmol) was dissolved in DCM (220 mL), and N, N-diisopropylethylamine (15.1 g, 121.71 mmol), 1-hydroxybenzotriazole (4.1 g, 30.43 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23.2 g, 121.71 mmol) were added in turn, and stirred at room temperature for 12 h. After the reaction was completed, the reaction liquid was washed with 0.5N dilute hydrochloric acid (100 mL x 3), the organic phase was dried over anhydrous Na2SO4and filtered and concentrated to give K1, ESI-MS (M+H) + = 706.2.

[0456] Referring to the synthesis route and method of intermediate K1, the following intermediate compounds were synthesized:

[0457] Example 20: synthesis of compound 474

[0458] Synthesis Step 1: synthesis of 474-1

[0459] Intermediate H1 (2.0 g, 6.82 mmol) was dissolved in 1,4-dioxane (50 mL) and water (10 mL), and then intermediate K1 (7.4 g, 10.23 mmol), potassium carbonate (2.8 g, 20.46 mmol), Pd(dppf)Cl2(240 mg, 0.34 mmol) were added successively, and stirred at 80 °C for 4 h. After the reaction was completed, water was added for quenching, extracted with EA, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain 474-1, ESI-MS (M+H) + = 909.5.

[0460] Synthesis Step 2: Synthesis of 474-2

[0461] 474-1 (2.0 g, 2.37 mmol) was dissolved in DMF (20 mL), and then cesium carbonate (1.2 g, 3.55 mmol) and iodoethane (370 mg, 2.37 mmol) were added successively, and stirred at room temperature for 5 h. After the reaction was completed, extracted with EA, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain 474-2, ESI-MS (M+H) + = 937.5.

[0462] Synthesis Step 3: Synthesis of 474-3

[0463] 474-2 (1.0 g, 1.17 mmol) was dissolved in 1,4-dioxane (10 mL), and then hydrochloric acid dioxane solution (4.0 M, 10 mL) was added dropwise, and stirred at room temperature for 2 h. After the reaction was completed, concentrated under reduced pressure to obtain 474-3, ESI-MS (M+H) + = 837.4.

[0464] Synthesis Step 4: Synthesis of 474-4

[0465] (1R,5S,6r)-rel-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid (42 mg, 0.33 mmol) was dissolved in DMAC (5 mL), and then DIPEA (107 mg, 0.83 mmol), HATU (157 mg, 0.51 mmol) were added successively, and stirred at room temperature for 30 min, and then 474-3 (220 mg, 0.28 mmol) was dissolved in DMAC (5 mL), and added dropwise into the above solution, and stirred at room temperature for 12 h. After the reaction was completed, extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then purified by column chromatography to obtain 474-4, ESI-MS (M+H) + = 947.5.

[0466] Synthesis step 5: synthesis method parameters of 474:

[0467] The 474-4 was chiral resolution, as follows (Column: (R, R) Whelk-O 1 (250mm x 50mm, 10um);

[0468] Mobile phase: A for CO2 and B for (MeOH: ACN = 1:1); Gradient: B 50% in 9min FlowRate (mL / min) 140), to obtain the product compound 474, ESI-MS (M+H) + = 947.5.

[0469] Referring to the synthesis route and method of compound 474, the following compounds were synthesized:

[0470] Similarly, referring to the above synthesis route and method, the following compounds were obtained:

[0471] Example 21: synthesis of compound 187

[0472] Synthesis step 1-4: synthesis of 187-4

[0473] The synthesis route and operation of 187-4 refer to the synthesis route and operation of compound 474 synthesis step 1-4.

[0474] Synthesis step 5: synthesis of 187

[0475] Dissolve 187-4 (100 mg, 0.1 mmol) in a mixed solution of methanol (2 mL) and THF (2 mL), add Pd / C (20 mg, WM 10%), and react under hydrogen atmosphere at room temperature for 12 h. After the reaction is completed, filter and concentrate under reduced pressure, and after semi-preparation purification, obtain the product compound 187 50 mg, ESI-MS (M+H) + = 863.5.

[0476] Referring to the synthesis steps and methods of compound 187, the following intermediate compounds were synthesized:

[0477] Similarly, with reference to the above synthetic routes and methods, the following compounds can be obtained:

[0478] Example 22: Synthesis of compound 96

[0479] Synthesis step 1: synthesis of 96-1

[0480] [5-(4-cyclopropylpiperazin-1-yl)-2-(1-methoxyethyl)pyridin-3-yl]boronic acid (2 g, 6.56 mmol) was dissolved in 1.4 dioxane (50 ml) and water (10 ml), and 5-bromo-3-(2,2-dimethyl-3-{[(sulfinyl-λ4-boryl)(2H1)-λ5-methylphosphoryl](3H1)-λ3- oxy}propyl)-1-ethyl-2-iodoindole (5.0 g, 9.84 mmol), potassium carbonate (2.7 g, 19.67 mmol), Pd(dppf)Cl2(240 mg, 0.33 mmol) were added in turn, and stirred at 80°C for 4 h. After the reaction was completed, water was added for quenching, extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the product 96-1 2.5 g was obtained after purification by column chromatography; yield was 57%, ESI-MS (M+H) + = 648.2.

[0481] Synthesis step 2: synthesis of 96-2

[0482] 96-1 (2.3 g, 3.6 mmol) was dissolved in 1.4 dioxane (20 ml) and water (4 ml), and (2R)-3-(4-bromo-1,3-thiazol-2-yl)-2-({[(2-methylpropan-2-yl)oxy]carbonyl}amino)propanoic acid methyl ester (1.3 g, 3.6 mmol), potassium carbonate (1.5 g, 10.81 mmol), Pd(dppf)Cl2(263 mg, 0.36 mmol) were added in turn, and stirred at 90°C for 12 h. After the reaction was completed, water was added for quenching, extracted with EA, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the product 96-2 2.4 g was obtained after purification by column chromatography; yield was 76%, ESI-MS (M+H) + = 854.4.

[0483] Synthesis step 3: synthesis of 96-3

[0484] Dissolve 96-2 (2.3 g, 2.64 mmol) in a mixture of tetrahydrofuran (20 ml), methanol and water (20 ml), add lithium hydroxide (317 mg, 13.23 mmol), stir at room temperature for 12 h. After the reaction is completed, adjust PH = 7, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the product 96-3 2.1 g; yield 91%, ESI-MS (M+H) + = 840.4.

[0485] Synthesis step 4: synthesis of 96-4

[0486] Dissolve 96-3 (2 g, 2.39 mmol) in dichloromethane (20 ml), add 3,4-diazabicyclo[3.1.1]heptane-2-carboxylic acid methyl ester (344 mg, 9.84 mmol), triethylamine (725 mg, 7.16 mmol), HATU (1.4 g, 3.58 mmol) in sequence, stir at room temperature for 12 h. After the reaction is completed, extract with dichloromethane, wash with saturated brine, dry with anhydrous Na2SO4, filter and concentrate under reduced pressure, purify by column chromatography to obtain the product 96-4 1.2 g; yield 51%, ESI-MS (M+H) + = 978.5.

[0487] Synthesis step 5: synthesis of 96-5

[0488] Dissolve 96-4 (1.1 g, 1.12 mmol) in tetrahydrofuran (10 ml), add tetrabutylammonium fluoride (2.5 g, 2.24 mmol), stir at room temperature for 5 h. After the reaction is completed, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter and concentrate under reduced pressure, purify by column chromatography to obtain the product 96-5 829 mg; yield 82%, ESI-MS (M+H) + = 899.5.

[0489] Synthesis step 6: synthesis of 96-6

[0490] Dissolve 96-5 (790 mg, 0.88 mmol) in a mixture of tetrahydrofuran (10 ml), methanol and water (10 ml), add lithium hydroxide (106 mg, 4.42 mmol), stir at room temperature for 12 h. After the reaction is completed, adjust PH = 7, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the product 96-6 670 mg; yield 83%, ESI-MS (M+H) + = 885.5.

[0491] Synthesis step 7: synthesis of 96-7

[0492] To a solution of 96-6 (600 mg, 0.67 mmol) in dichloromethane (60 ml), DCC (208 mg, 1.01 mmol), DMAP (9 mg, 0.07 mmol) were added successively and stirred at room temperature for 12 h. After the reaction was completed, dichloromethane was added for extraction, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product 96-7 was obtained by column chromatography in 312 mg; the yield was 53%, ESI-MS (M+H) + = 867.5.

[0493] Synthesis Step 8: synthesis of 96-8

[0494] To a solution of 96-7 (295 mg, 0.34 mmol) in 1.4 dioxane (3 ml), hydrochloric acid dioxane solution 3 ml was added, stirred at room temperature for 12 h. After the reaction was completed, it was concentrated under reduced pressure to obtain the product 96-8 252 mg; the yield was 84%, ESI-MS (M+H) + = 767.4.

[0495] Synthesis Step 9: synthesis of compound 96-9

[0496] To a solution of 96-8 (215 mg, 0.28 mmol) in dichloromethane (5 ml), (2S)-2-(7-{[(2R)-1-{[(2-methylprop-2-yl)oxy]carbonyl}aziridin-2-yl]carbonyl}-1-oxo-2,7-diazaspiro[4.4]non-2-yl)-3-methylbutanoic acid (135 mg, 0.33 mmol), triethylamine (84 mg, 0.83 mmol), HATU (157 mg, 0.51 mmol) were added successively and stirred at room temperature for 12 h. After the reaction was completed, dichloromethane was added for extraction, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product compound 96-9 was obtained by column chromatography in 150 mg; the yield was 62%, ESI-MS (M+H) + = 1144.6.

[0497] Synthesis Step 10: synthesis of 96

[0498] To a solution of 96-9 (137 mg, 0.12 mmol) in 1.4 dioxane (3 ml), hydrochloric acid dioxane solution 3 ml was added, stirred at room temperature for 12 h. After the reaction was completed, it was concentrated under reduced pressure to obtain the product 96 103 mg; the yield was 82%, ESI-MS (M+H) + = 1044.6.

[0499] The following compounds were synthesized according to the synthesis route and method of compound 96: The following compounds were synthesized according to the synthesis route and method of compound 96:

[0500] Biological testing

[0501] Biological test 1: Evaluation of KRAS / BRAF binding blocking activity at the molecular level

[0502] The inhibitory activity of the compounds against KRAS and BRAF binding was determined using the AlphaScreen method. HIS-tagged wild-type and mutant KRAS proteins were compared with... Nickel chelate acceptor microbeads specifically bind, biotin-labeled BRAF specifically binds to streptavidin donor microbeads, and KRAS interacts with BRAF, causing the two magnetic beads to spatially approach each other and emit fluorescence at a specific wavelength. When the molecular gel, CYPA, and KRAS form a ternary complex, interfering with the KRAS-BRAF interaction, the signal value weakens. Changes in fluorescence signal at 570 nm were detected using an Envision fluorescence detector to characterize the compounds' blocking activity against KRAS-BRAF binding.

[0503] Compounds CYPA, BRAF, KRAS-WT, G12D, or G12V were added sequentially to a 384 reaction plate (ProxiPlate). TM Incubate in -384 Plus (PerkinElmer) at room temperature for two hours, then add The nickel chelate acceptor microbeads were incubated at room temperature for another hour before adding... Streptavidin donor microbeads were incubated at room temperature for half an hour, then treated with Envision. TM Fluorescence signals were detected at a wavelength of 570 nm. The final reaction volume was 10 μL, and the specific reaction system consisted of 2% DMSO, 100 nM KRAS-WT / G12D / G12V, 100 nM BRAF, 100 nM CYPA, 10 μM GMPPNP, 20 mM HEPES (pH 7.5), 150 mM NaCl, 5 mM MgCl2, 0.01% Tween 20, and 0.1% BSA. The final concentrations of RAS, BRAF, and CYPA were all 100 nM.

[0504] Data processing: IC50 of compounds was calculated using the software Graphpad Prism 9. 50 .

[0505] Table 1. Blocking activity of compounds against KRAS / BRAF binding. A: 1 < Selectivity (IC) 50 B: 5 < selectivity (IC) ≤ 5; 50 Ratio) ≤ 10; C: 10 < selectivity (IC) 50 ratio);

[0506] From Table 1, it can be seen that the compound of the present disclosure has good selectivity in wild type and mutant KRAS, and the inhibition activity of WT KRAS increases the risk of toxicity, and the compound of the present disclosure has higher selectivity, which shows better safety.

[0507] Compound a:

[0508] Compound b:

[0509] Biological test 2, compound activity test on HPAF-II (G12D) cells

[0510] (System: 100 μL complete medium + 80 μL cell suspension + 20 μL complete medium containing compound)

[0511] Step:

[0512] 1.1 Prepare complete medium: MEM medium (containing NEAA) + 10% cell cook + 1 mM sodium pyruvate solution

[0513] 1.2 Compound dilution: dilute the compound to 2000 nM (0.2% DMSO)

[0514] 1.3 Collect cells in a 15 mL centrifuge tube, centrifuge at 800 rpm for 3 min, discard the supernatant, add 2 mL medium to resuspend the cell pellet, count the cells, inoculate the cells, 80 μL / well, overnight adhesion, add the compound the next day, and incubate in the cell incubator for 5 days.

[0515] 1.4 Read value: add 10 μL CCK-8 reagent to each well, incubate in the incubator for 2 h, and read the value on the enzyme marker (SPECTRA MAX190 (Molecular Device))

[0516] 1.5 The difference between the absorbance values at 450 nm and 650 nm is used as the final data. Finally, the IC value of the compound is calculated by using the non-linear regression method of GraphPad 8.0 software. 50

[0517] Table 2 Proliferation inhibition activity of compounds on HPAF-II cells

[0518] From Table 2, it can be seen that the compound of the present disclosure has excellent proliferation inhibition activity on HPAF-II cells.

[0519] Biological test 3, compound activity test on Capan-1 (G12V) cells ​

[0520] (System: 100 μL complete medium + 80 μL cell suspension + 20 μL compound-containing complete medium)

[0521] Procedure:

[0522] 1.1 Preparation of complete medium: IMDM medium + 20% cellcook

[0523] 1.2 Compound dilution: Compound was diluted to 2000 nM (0.2% DMSO)

[0524] 1.3 Collection of cells in 15 mL centrifuge tube, centrifugation at 800 rpm for 3 min, discard supernatant. Add 2 mL medium to resuspend cell pellet, count cells, plating amount: 5000 cells / well Preparation of suspension: inoculate cells, 80 μL / well, overnight adhesion, add compound the next day, incubate in cell incubator for 5 days.

[0525] 1.4 Reading: Add 10 μL MTS reagent to each well, incubate in incubator for 2 h, read on microplate reader (SPECTRA MAX 190 (Molecular Device))

[0526] 1.5 Take the difference between the absorbance values at 450 nm and 650 nm as the final data. Finally, use the GraphPad 8.0 software to calculate the IC 50 value of the compound by nonlinear regression method.

[0527] Table 3 Proliferation inhibition activity of compounds on Capan-1 cells

[0528] As can be seen from Table 3, the compounds of the present disclosure have excellent proliferation inhibition activity on Capan-1 cells.

[0529] Biological test 4, hERG test

[0530] All tests were performed at room temperature. Cells were transferred to a perfusion chamber and perfused with extracellular solution. Electrodes were pulled with a PC-10 (Narishige, Japan). Whole-cell patch-clamp recordings were made, with noise filtered at one fifth of the sampling frequency. Cells were clamped at -80 mV, then depolarized to 40 mV with a 4 s square wave, then hyperpolarized to -40 mV with a 2 s square wave. The hERG tail current was obtained. This procedure was repeated every 20 s.

[0531] Electrophysiological test cell internal and external fluid formula: extracellular fluid (mM) is: sodium chloride, 137; potassium chloride, 4; calcium chloride, 1.8; magnesium chloride, 1; HEPES, 10; glucose, 10. Adjusted to 7.34 with sodium hydroxide. Stored at 2-8℃. Intracellular fluid (mM) is: potassium aspartate, 130; magnesium chloride, 5; ethylene glycol tetraacetic acid (EGTA), 5; N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), 10. Adjusted to 7.4 with potassium hydroxide. Stored at -80℃ refrigerator after dispensing in 1mL centrifuge tube. The test concentration of the compound is 10μM.

[0532] Data processing and fitting: data are analyzed using OriginPro 8.

[0533] Table 4 Inhibition activity of compounds on hERG ion channel

[0534] As can be seen from Table 4, the inhibition activity of the compounds of the present disclosure on hERG ion channel is low at a concentration of 10μM.

[0535] Biological test 5, PK-59 in vivo efficacy evaluation

[0536] 1, animal inoculation: PK-59 cells are subcutaneously injected at 5×10 6 cells / 0.1mL / each (1:1 mixed Matrigel) at the right axillary fat pad of 6-8 week old female Nu Nu mice (purchased from Vantian Li Hua).

[0537] 2, grouping: when the tumor volume of mice reaches 100-300mm 3 , they are randomly assigned to drug treatment group and solvent control group, 5 in each group.

[0538] 3, compound configuration: 10% DMSO + 10% Solutol HS15 (polyethylene glycol-15 hydroxystearate) + 80% H2O

[0539] 4, administration frequency: oral, daily, continuous administration for 7 days.

[0540] 5, weigh the tumor twice a week

[0541] 6, data calculation formula:

[0542] ①Tumor volume (TV) = (length x width x width) / 2

[0543] ②Relative tumor volume (RTV) = TV t / TV1

[0544] Note: TV1 is the tumor volume measured at the time of drug administration (i.e. D1), TVt Tumor volume at each measurement.

[0545] Tumor Inhibition Rate (TGI) = (RTV of tumor in control group - RTV of tumor in experimental group) / RTV of tumor in control group x 100%

[0546] Table 5 Compound in PK-59 in vivo efficacy A: T / C≤15% B: 15% < T / C≤30% C: 30% < T / C≤60% D: 60% < T / C

[0547] As shown in Table 5, the compound of the present disclosure has excellent tumor inhibition effect in PK-59 tumor model.

[0548] Biological test 6, mouse pharmacokinetic study

[0549] 1. Drug preparation

[0550] Dose 10 mg / kg

[0551] The drug was prepared in proportion (10% DMSO / 20% PEG400 / 10% Solutol HS15 / 60% physiological saline) to a concentration of solution, and the mice were gavaged (dose 1 mg / kg or 10 mg / kg), with 3 mice in parallel for each point.

[0552] 2. Fixed point blood sampling

[0553] After the mice were dosed, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h, 0.5 mL of orbital blood was taken with a capillary tube into an EP tube containing EDTA anticoagulant, shaken gently, centrifuged at 3500 rpm for 10 min at 4°C, and the supernatant was taken as plasma.

[0554] 3. Sample processing

[0555] 3.1. Standard curve and quality control sample preparation and processing

[0556] The drug stock solution (1 mg / mL) was diluted with acetonitrile to obtain standard working solutions with concentrations of 50 ng / mL, 100 ng / mL, 200 ng / mL, 500 ng / mL, 1000 ng / mL, 2000 ng / mL, 5000 ng / mL, 10000 ng / mL, and 20000 ng / mL, respectively, and quality control working solutions with concentrations of 100 ng / mL, 2000 ng / mL, and 10000 ng / mL. 47.5 uL of the blank matrix was taken and 2.5 uL of the standard curve working solution and the quality control working solution was added to prepare standard curves with concentrations of 2.5 ng / mL, 5 ng / mL, 10 ng / mL, 25 ng / mL, 50 ng / mL, 100 ng / mL, 250 ng / mL, 500 ng / mL, and 1000 ng / mL, and quality control samples with concentrations of 5 ng / mL, 100 ng / mL, and 500 ng / mL. 200 uL of acetonitrile (containing an internal standard montelukast 1 ng / mL) was added, vortexed for 3 min, centrifuged at 15000 rpm at 4°C for 10 min, and the supernatant was taken for LC-MS / MS analysis.

[0557] 3.2 Preparation and treatment of unknown samples

[0558] 50 uL of the plasma sample was taken, 200 uL of acetonitrile (containing an internal standard montelukast 1 ng / mL) was added, vortexed for 3 min, centrifuged at 15000 rpm at 4°C for 10 min, and the supernatant was taken for LC-MS / MS analysis.

[0559] Table 6: Results of mouse absorption of compounds DNAUC represents the ratio of AUC to the dose; A: DNAUC≤300; B: 300<DNAUC≤1000; C: 1000<DNAUC

[0560] As can be seen from the results in Table 6, the compounds of the present disclosure have excellent pharmacokinetic properties in mice.

Claims

1. A compound having the structure shown in general formula (I): or a stereoisomer thereof, or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof; wherein: X1is selected from N or CH; Cy1 is selected from C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl or 3-12 membered heterocyclic groups; Cy2is selected from C6-Ci0aryl or 5-10 membered heteroaryl; 10 aryl or 5-10 membered heteroaryl; Cy3 is selected from C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl or 3-12 membered heterocyclic groups; Cy4is selected from a 6-12 membered nitrogen-containing spiro heterocyclyl, a 6-12 membered nitrogen-containing bridged heterocyclyl, or a 6-12 membered nitrogen-containing fused heterocyclyl; R1 is selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic, C6-C 10 aryl, 5-10-membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylamino, halogen, cyano, nitro, hydroxy, amino, carboxyl or -CONH2, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally further selected from one or more groups selected from halogen, cyano, nitro, amino, hydroxy, carboxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylamino, halogenated C1-C6 alkylamino, oxo, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, C1-C8 alkylamino, C1-C8 haloalkylamino, -OR g -SR g -OC(O)R g -C(O)R g -C(O)OR g -C(O)N(R) x )R y -NR x R y -N(CH3)R g -N(R) x )C(O)R y -N(R) x )C(O)NR x R y -N(R) x )C(O)OR g -C1-C8 alkylene-R g -N(R) x )S(O)NR x R y -N(R) x )S(O)2NR x R y -N(R) x )S(O)2R g -S(O)R g -S(O)2R g -S(O)2NR x R y or -P(O)R x R y Substituents; R2 is selected from non-existent, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C8 cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, 3-8 membered heteroaryl, -SO2R2', -CO2NR2'R2", -COR2', -COOR2', -(CR 2c R 2d )u1-NR 2a R 2b 、-(CR 2c R 2d u2-C(O)-NR 2a R 2b 、-(CR 2c R 2d )u3-3-8-membered heterocyclic group, -(CR 2c R 2d )u4-C(O)-3-8-membered heterocyclic group, -C1-C3 alkylene-CN or -C1-C3 alkylene-C3-C6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic or heteroaryl group is optionally further selected from one or more of halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, C1-C6 alkylamino, haloC1-C6 alkylamino, oxo, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, C1-C8 alkylamino, C1-C8 haloalkylamino, -OR g -SR g -OC(O)R g -C(O)R g -C(O)OR g -C(O)N(R) x )R y -NR x R y -N(CH3)R g -N(R) x )C(O)R y -N(R) x )C(O)NR x R y -N(R) x )C(O)OR g -C1-C8 alkylene-R g -N(R) x )S(O)NR x R y -N(R x )S(O)2NR x R y -N(R x )S(O)2R g -S(O)R g -S(O)2R g -S(O)2NR x R y or -P(O)R x R y substituted by one or more substituents selected from the group consisting of t is selected from 0, 1, 2, 3, or 4; u1is selected from 0, 1, 2, 3, or 4; u2is selected from 0, 1, 2, 3, or 4; u3is selected from 0, 1, 2, 3, or 4; u4is selected from 0, 1, 2, 3, or 4; R 2a , R 2b each independently is selected from H, C1-C6alkyl, haloC1-C6alkyl, -S(O)2R g , -S(O)2NR x R y , -C1-C8alkylene-R g , C1-C6alkoxy, C3-C6cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, or 3-8 membered heteroaryl; R 2c , R 2d each independently is selected from H, C1-C6alkyl, haloC1-C6alkyl, -S(O)2R g , -S(O)2NR x R y , C3-C6cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, or 3-8 membered heteroaryl; R2', R2" are each independently selected from H, C1-C6alkyl, C3-C8cycloalkyl, or 3-8 membered heterocyclyl; or, R2' and R2" together with the atom to which they are attached form a 3-12 membered ring; said 3-12 membered ring contains 0, 1, or 2 heteroatoms selected from N, O, S, P; R3, R4, R5, and R6 are each independently selected from H, halogen, cyano, nitro, amino, hydroxyl, carboxyl, amide (C1-C6 alkyl-C(O)-NH-), oxo, and -P(O)R. 14 R 14’ Acyl (C1-C6 alkyl-C(O)-), -SO2, sulfonamide (H-SO2-NH), C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-sulfonamide, C3-C8 cycloalkyl, 3-8 membered heterocyclic, C3-C8 cycloalkoxy, C1-C6 alkylamino, C3-C8 cycloalkylamino, C1-C6 alkyl-SO2-, aminosulfonyl or carbamoyl, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally further selected from one or more groups selected from halogen, cyano, nitro, amino, hydroxy, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylamino, halogenated C1-C6 alkylamino, oxo, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, C1-C8 alkylamino, C1-C8 haloalkylamino, -OR g -SR g -OC(O)R g -C(O)R g -C(O)OR g -C(O)N(R) x )R y -NR x R y -N(CH3)R g -N(R) x )C(O)R y -N(R) x )C(O)NR x R y -N(R) x )C(O)OR g -C1-C8 alkylene-R g -N(R) x )S(O)NR x R y -N(R) x )S(O)2NR x R y -N(R) x )S(O)2R g -S(O)R g -S(O)2R g -S(O)2NR x R y or -P(O)R x R y substituted by one or more substituents; or, when 2 R5substitutions are on the same atom, 2 R5together with the atom to which they are attached form a 3-6 membered ring; or, when 2 R5substitutions are on adjacent atoms, 2 R5together with the atoms to which they are attached form a 3-12 membered ring; said 3-12 membered ring contains 0, 1, or 2 heteroatoms selected from N, O, S, P; R7is selected from H, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, or haloC1-C6alkyl; R8is selected from H, halogen, C1-C6alkyl, or C1-C6haloalkyl; R 10 selected from H, Ci-C6alkyl, or Ci-C6haloalkyl; R 11a , R 11b , R 12a , R 12b , R 13a , R 13b each independently is selected from H, halogen, hydroxyl, amino, C1-C3alkyl, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3alkoxy, C1-C3alkylamino, or C1-C3haloalkylamino; R 12a with R 12b or R 13a with R 13b together with the atom to which they are attached form a 3-6 membered ring; said 3-6 membered ring contains 0, 1 or 2 heteroatoms selected from N, O, S, P; R 12a with R 12b may be combined into a carbonyl or thiocarbonyl group; G is selected from -X 11 -X 12 -X 13 -; X 11 、X 12 、X 13 each independently is selected from the absence, -CR 21 R 21’ -, -O-, -CO- or -NR 21 -; R 21 , R 21’ each independently is optionally selected from H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl; X 18 is selected from a chemical bond, -O-, -NR 18a -, -OC(O)-, -NR 18a -C(O)-, -N(R 18a )C(O)NR 18a R 18b or -N(R 18a )C(O)OR 18b ; R 18a , R 18b each independently is selected from H, C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, or C3-C8halocycloalkyl; Y is selected from -L1-L2-L3-L4-L5-L6-L7-L8-L9; L1is selected from H, C1-C6alkylene, C2-C6alkenylene, C2-C6alkynylene, C3-C8cycloalkylene, 3-12 membered heterocyclylene, 5-10 membered heteroarylene, or phenylene, said alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, heteroarylene, or phenylene is optionally further substituted with one or more substituents selected from oxo, halogen, cyano, nitro, -OH, -NH2, C1-C6alkyl, C2-C6alkynyl, C2-C6alkenyl, C1-C6alkoxy, C1-C6alkylamino, C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6haloalkylamino, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C10aryl, or 5-12 membered heteroaryl; wherein each alkyl, alkenyl, alkynyl, alkoxy, alkylamino, haloalkyl, haloalkoxy, haloalkylamino, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, cyano, nitro, -OH, -NH2, C1-C6alkyl, C2-C6alkynyl, C2-C6alkenyl, C1-C6alkoxy, C1-C6alkylamino, C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6haloalkylamino, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C10aryl, or 5-12 membered heteroaryl; and 10 aryl or 5-12 membered heteroaryl substituent; L2, L4, L6, L8 are each independently selected from the group consisting of absent, H, -NR 22 -CO-, -CO-, -O-CO-, -NR 22 -CO-NR 22’ -, -O-CO-NR 22’ -, -NR 22 -CO-O-, -O-, -NR 22 -, -SO-, -SO2-, -NR 22 -SO2-, -SO2NR 22 - or -NR 22 -SO2-NR 22’ -; L3, L5, L7, L9are each independently selected from absent, H, C1-C6alkylene, C2-C6alkenylene, C2-C6alkynylene, C3-C8cycloalkylene, 3-12 membered heterocyclylene, 5-10 membered heteroarylene, or phenylene, said alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, heteroarylene, or phenylene is optionally further substituted with one or more substituents selected from oxo, halogen, cyano, -OH, -NH2, C1-C6alkyl, C2-C6alkynyl, C2-C6alkenyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6alkylamino, C1-C6haloalkoxy, C1-C6haloalkylamino, C3-C8cycloalkyl, or 3-8 membered heterocyclyl; R 22 , R 22’ each independently is selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C3-C5 cycloalkyl, C3-C5 halocycloalkyl, 3- to 6-membered heterocyclyl, or 3- to 6-membered haloheterocyclyl; s is selected from 0, 1, or 2; m, n, p are each independently selected from 0, 1, 2, or 3; R 14 R 14’ R g R x R y Each is independently selected from H, deuterium, halogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C2-C8 alkenyloxy, C3-C 12 Cycloalkyl, C3-C8 cycloalkoxy, 3-12 membered heterocyclic, 3-12 membered heterocyclic, aminosulfonyl, C6-C 10 Aryl, 5-12 heteroaryl, cyano, amino, nitro, hydroxy, oxo, carboxyl, amide (C1-C8 alkyl-C(O)-NH-), hydroxyC1-C8 alkyl, aminoC1-C8 alkyl, C1-C8 alkoxycarbonyl, C1-C8 alkamino, C1-C8 haloalkamino, -OR s -SR s -C1-C8 alkylene-R s -OC(O)R s -C(O)R s -C(O)OR s -C(O)N(R) s )R t -NR s R t -N(CH3)R s -N(R) s )C(O)R t -N(R) s )C(O)NR s R t -N(R) s )C(O)OR t -N(R) s )S(O)NR s R t -N(R) s )S(O)2NR s R t -N(R) s )S(O)2R t -S(O)R s -S(O)2R s -S(O)2NR s R t or -P(O)R s R t The alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be further modified by one or more R groups. r replace; or, when 2 R r substituted on the same atom, taken together with the atom to which they are attached, form a 3-6 membered ring; or, when 2 R r substituted on adjacent atoms, taken together with the atom to which they are attached, form a 3-12 membered ring; or, when 2 R r substituted on adjacent atoms, taken together with the atom to which they are attached, form a 3-12 membered ring; or, when 2 R r substituted on adjacent atoms, taken together with the atom to which they are attached, form a 3-12 membered ring; R r R s R t Each is independently selected from H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, halogen, cyano, amino, nitro, hydroxyl, oxo, C1-C8 alkoxy, C1-C8 haloalkyl, hydroxyC1-C8 alkyl, aminoC1-C8 alkyl, C1-C8 alkylamino, C1-C8 alkylcarbonyl, C1-C8 alkoxycarbonyl, haloC1-C8 hydroxyalkyl, C1-C8 haloalkylamino, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, carboxyl groups, amides (C1-C8 alkyl-C(O)-NH-), C6-C 10 Aryl or 5-12 heteroaryl groups; When X 18 For chemical bonds, when Cy3 is selected from C3-C6 cycloalkyl or 3-10 heterocyclic groups, R2 is selected from C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylamino, C3-C8 cycloalkyl, 3-8 heterocyclic, 6-10 aryl, 3-8 heteroaryl, -SO2R2', -CO2NR2'R2", -COR2', -COOR2', -(CR 2c R 2d )u1-NR 2a R 2b 、-(CR 2c R 2d u2-C(O)-NR 2a R 2b 、-(CR 2c R 2d )u3-3-8-membered heterocyclic group, -(CR 2c R 2d )u4-C(O)-3-8-membered heterocyclic group, -C1-C3 alkylene-CN or -C1-C3 alkylene-C3-C6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic or heteroaryl group is optionally further selected from one or more of halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, C1-C6 alkylamino, haloC1-C6 alkylamino, oxo, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, C1-C8 alkylamino, C1-C8 haloalkylamino, -OR g -SR g -OC(O)R g -C(O)R g -C(O)OR g -C(O)N(R) x )R y -NR x R y -N(CH3)R g -N(R) x )C(O)R y -N(R) x )C(O)NR x R y -N(R) x )C(O)OR g -C1-C8 alkylene-R g -N(R) x )S(O)NR x R y , -N(R x )S(O)2NR x R y , -N(R x )S(O)2R g , -S(O)R g , -S(O)2R g , -S(O)2NR x R y or -P(O)R x R y substituted, and is not 2. The compound according to claim 1, characterized in that: wherein selected from the group consisting of: X2is selected from CR 15 R 15 ', O, NH, SO, or SO2; R 15 , R 15 each independently is selected from H, halogen, cyano, Ci-C6alkyl or halogenated Ci-C6alkyl; R7is selected from H, halogen, cyano, C1-C6alkyl, or haloC1-C6alkyl; R 7a selected from halogen, cyano, C1-C6alkyl or halogenated C1-C6alkyl; q, r are selected from 0, 1, 2, 3, or 4, and r and q cannot be selected from 0 at the same time; m is selected from 0, 1, 2, or 3.

3. The compound according to claim 1 or 2, characterized in that: selected from the group consisting of: R 7a is selected from F, Cl, Br, cyano or methyl.

4. The compound according to any one of claims 1 to 3, characterized in that: R2is selected from the group consisting of: nothing, halogen, C1-C6alkyl optionally substituted with 1, 2, or 3 halogen atoms, C1-C3alkoxy, CH3-C(O)-, CH3-SO2-, C3-C8cycloalkyl, NH-S(O)2-CH3, 5. The compound according to any one of claims 1 to 4, characterized in that: Cy3is selected from C3-C7cycloalkyl, 3-10 membered heterocyclyl containing 1 or 2 ring-forming heteroatoms selected from N and / or O, 5-8 membered heteroaryl containing 1, 2, or 3 ring-forming heteroatoms selected from N.

6. The compound of any one of claims 1 to 5, wherein: Cy3 is selected from * denotes attachment to ring Cy2or X 18 .

7. The compound according to any one of claims 1 to 6, wherein: R5is selected from hydrogen, amino, methyl, ethyl, propyl, isopropyl, cyano, halogen, hydroxy, methoxy, trifluoromethyl, CH2F-, or C1-C3 hydroxyalkyl, t is selected from 0, 1 or 2; or, when 2 R5substituents are on the same atom, 2 R5together with the atom to which they are attached form a 3-6 membered ring; or, when 2 R5substituents are on adjacent atoms, 2 R5together with the atoms to which they are attached form a 3-12 membered ring; said 3-12 membered ring containing 0, 1 or 2 heteroatoms selected from N, O, S, P.

8. The compound according to any one of claims 1 to 7, wherein: selected from the group consisting of:

9. The compound of any one of claims 1 to 8, wherein, Y is selected from: R 25 、 R 23 is selected from -CH3, -CH2CH3, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl; R 24 is selected from: absent, H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 4-6 membered heterocyclyl; said alkyl, cycloalkyl, heterocyclyl optionally further substituted by one or more substituents selected from halogen, cyano, amino, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, halogenated C1-C3alkoxy, C1-C3alkylamino, halogenated C1-C3alkylamino, oxo, C3-C6cycloalkyl, or 4-6 membered heterocyclyl; R 25 is selected from C1-C4alkyl, C3-C8cycloalkyl, C1-C4alkylene-C3-C8cycloalkyl, C1-C4alkylene-3-8 membered cycloalkyl, or 3-8 membered heterocyclyl; said alkyl, cycloalkyl, heterocyclyl, alkylene groups are optionally further substituted with one or more substituents selected from halogen, cyano, amino, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, halogenated C1-C3alkyl, halogenated C1-C3alkoxy, C1-C3alkylamino, halogenated C1-C3alkylamino, oxo, C3-C6cycloalkyl, or 4-6 membered heterocyclyl; R 26 and R 27 each independently is selected from H, C1-C4alkyl, C3-C6cycloalkyl, or 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, or heterocycloalkyl optionally further substituted with one or more selected from halogen, cyano, amino, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, halogenated C1-C3alkyl, halogenated C1-C3alkoxy, C1-C3alkylamino, halogenated C1-C3alkylamino, oxo, C3-C6cycloalkyl, or 4-6 membered heterocyclyl substituents; R 28 selected from H or C1-C4alkyl; X 14 is selected from: absent, C1-C4alkylene, C1-C4alkylene-N(R 29 )-CO-, C3-C8cycloalkylene, C3-C8cycloalkylene-N(R 29 )-CO-, 3-8 membered heterocyclylene, 3-8 membered heterocyclylene-N(R 29 )-CO-; said alkylene, cycloalkylene, heterocyclylene groups are optionally further substituted by one or more substituents selected from halogen, cyano, amino, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propyloxy, isopropyloxy, halogenated C1-C3alkyl, halogenated C1-C3alkoxy, C1-C3alkylamino, halogenated C1-C3alkylamino, oxo, C3-C6cycloalkyl or 4-6 membered heterocyclyl; R 29 selected from H or C1-C4alkyl; X4, X5, X6, X7, X8, X9, X 10 each independently selected from: absent, -CH2-, -CO-, N, -NH-, -O-, -SO-, -SO2-, or -CH2CH2-; X 15 is selected from -CH2-, -CO-, -C(O)O-, -C(O)NH-, -OC(O)-, -NHC(O)- or -CH2CH2-; Cy5is selected from 3-6 membered heterocyclyl, C3-C6 cycloalkyl, phenyl or 5-6 membered heteroaryl; v is selected from 0, 1, 2 or 3; R 30 selected from the group consisting of absent, C1-C4alkyl, haloC1-C4alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, phenyl, -OR 31 , -CO-R 31 , -C(O)O-R 31 , amino or hydroxyl; said alkyl, cycloalkyl, heterocyclyl or phenyl is optionally further substituted with one or more substituents selected from halogen, cyano, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, haloC1-C3alkyl, haloC1-C3alkoxy, C1-C3alkylamino, haloC1-C3alkylamino, oxo, C3-C6cycloalkyl or 4-6 membered heterocyclyl; R 31 selected from H, C1-C4alkyl, haloC1-C4alkyl, C3-C6cycloalkyl, 3-6 membered heterocyclyl, or phenyl, said alkyl, cycloalkyl, heterocyclyl, or phenyl optionally further substituted with one or more substituents selected from halogen, cyano, amino, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, haloC1-C3alkyl, -OC(O)-CH3, haloC1-C3alkoxy, C1-C3alkylamino, haloC1-C3alkylamino, oxo, C3-C6cycloalkyl, or 4-6 membered heterocyclyl.

10. The compound of any one of claims 1 to 9, wherein Y is selected from:

11. The compound of any one of claims 1 to 10, wherein Cy1is selected from phenyl ring, 5-8 membered heterocyclyl, 5 membered heteroaryl or 1,2,5,6-tetrahydropyridine.

12. The compound of any one of claims 1 to 11, wherein, Cy1is selected from the group consisting of 13. The compound according to any one of claims 1 to 12, wherein: selected from the group consisting of Z1, Z 1a , Z 1b are each independently selected from N, CH, C-F or C-CN; R1 is selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic, C6-C 10 aryl, 5-10-membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylamino, halogen, cyano, nitro, hydroxy, amino, carboxyl or -CONH2, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally further selected from one or more groups selected from halogen, cyano, nitro, amino, hydroxy, carboxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylamino, halogenated C1-C6 alkylamino, oxo, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, C1-C8 alkylamino, C1-C8 haloalkylamino, -OR g -SR g -OC(O)R g -C(O)R g -C(O)OR g -C(O)N(R) x )R y -NR x R y -N(CH3)R g -N(R) x )C(O)R y -N(R) x )C(O)NR x R y -N(R) x )C(O)OR g -C1-C8 alkylene-R g -N(R) x )S(O)NR x R y -N(R) x )S(O)2NR x R y -N(R) x )S(O)2R g -S(O)R g -S(O)2R g -S(O)2NR x R y or -P(O)R x R y Substituted by a substituent.

14. The compound according to any one of claims 1 to 13, wherein: Cy2is selected from the group consisting of 15. The compound of any one of claims 1 to 14, wherein, R1is selected from C1-C3 alkyl or -CONH2, said alkyl being optionally substituted with 1, 2 or 3 substituents selected from halogen, C1-C3 alkoxy.

16. The compound of any one of claims 1 to 15, wherein R1is selected from 17. The compound according to any one of claims 1 to 16, wherein: R3, R4, R6are each independently selected from H, halogen, cyano or C1-C3 alkyl, said alkyl being optionally substituted with 1, 2 or 3 substituents selected from F, Cl or Br; R8is selected from H or halogen; R 10 selected from H; R 11a , R 11b , R 12a , R 12b , R 13a , R 13b each independently is selected from H or C1-C3alkyl; R 12a with R 12b together with the atom to which they are attached form a 3-membered ring.

18. The compound of any one of claims 1 to 17, wherein, having the structure of Formula (II): selected from the group consisting of: R7is selected from H, halogen, cyano, C1-C6 alkyl or halogenated C1-C6 alkyl; R 7a selected from halogen, cyano, C1-C6alkyl or halogenated C1-C6alkyl; q, r are selected from 0, 1, 2, 3 or 4, and r and q cannot be selected from 0 at the same time; m is selected from 0, 1, 2 or 3; X1, Cy1, Cy3, R1, R2, R2', R2", R3, R4, R5, R6, R8, R 10 , R 11a , R 11b , R 12a , R 12b , R 13a , R 13b , R 21 , R 21’ , R 22 , R 22’ , R g , R x , R y , R r , R s , R t , G, Y, X 11 , X 12 , X 13 , L1, L2, L3, L4, L5, L6, L7, L8, L9, s, n, t, p are defined as in claim 1.

19. The compound of claim 18, wherein having the structure of Formula (IV): Cy3is selected from C3-C6 cycloalkyl, 4-9 membered heterocyclyl or 5-6 membered heteroaryl; R2 is selected from -(CR) 2c R 2d )u1-NR 2a R 2b 、-(CR 2c R 2d u2-C(O)-NR 2a R 2b 、-(CR 2c R 2d )u3-3-8-membered heterocyclic group, -(CR 2c R 2d )u4-C(O)-3-8-membered heterocyclic group, C3-C6 cycloalkyl, -C1-C3 alkylene-CN or -C1-C3 alkylene-C3-C6 cycloalkyl or heterocyclic group substituted with 1-3 substituents, wherein the heterocyclic group or cycloalkyl group is optionally further substituted with one or more substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkoxy, C1-C4 alkylamino, halo-C1-C4 alkylamino, oxo, C3-C6 cycloalkyl, 3-8-membered heterocyclic group, 6-10-membered aryl or 5-6-membered heteroaryl, -OR g -SR g -OC(O)R g -C(O)R g -C(O)OR g -C(O)N(R) x )R y -NR x R y -N(CH3)R g -N(R) x )C(O)R y -N(R) x )C(O)NR x R y -N(R) x )C(O)OR g -C1-C8 alkylene-R g -N(R) x )S(O)NR x R y -N(R) x )S(O)2NR x R y -N(R) x )S(O)2R g -S(O)R g -S(O)2R g -S(O)2NR x R y or -P(O)R x R y substituted by substituents; R 2a , R 2b each independently is selected from H, halogen, C1-C3 alkyl, halo C1-C3 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl, or 5-6 membered heteroaryl; R 2c , R 2d each independently is selected from H, halogen, C1-C3 alkyl, halo C1-C3 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl, or 5-6 membered heteroaryl; u3is selected from 1, 2, 3 or 4; u1, u2, u4are selected from 0, 1, 2, 3 or 4; Cy1is selected from phenyl ring, 5-8 membered heterocyclyl, 5 membered heteroaryl or 1,2,5,6-tetrahydropyridine. R1is selected from R4is selected from ethyl or trifluoroethyl; R5is selected from hydrogen, amino, methyl, ethyl, propyl, isopropyl, cyano, halogen or C1-C3 hydroxyalkyl; or, when 2 R5substituents are on the same atom, 2 R5together with the atom to which they are attached form a 3-6 membered ring; or, when 2 R5substituents are on adjacent atoms, 2 R5together with the atoms to which they are attached form a 3-12 membered ring; said 3-12 membered ring containing 0, 1 or 2 heteroatoms selected from N, O, S, P. R6is selected from H, halogen, amino, hydroxyl, nitro, cyano, C1-C4 alkyl, halogenated C1-C4 alkyl or C1-C4 hydroxyalkyl; R8is selected from hydrogen, halogen, C1-C3 alkyl or C1-C3 halogenated alkyl; R 10 selected from hydrogen, C1-C3alkyl or C1-C3haloalkyl; Y, p, s, t, R x , R y , R g as defined in claim 1.

20. The compound of claim 19, wherein having the structure of Formula (V): or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof; Cy3, R2, R4, R5, R8, Y, s, t are as defined in claim 19.

21. The compound of claim 20, wherein having the structure of Formula (VI): or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof; R4is selected from ethyl or trifluoroethyl; Cy3, R2, R5, R8, Y, s, t are as defined in claim 20.

22. The compound of claim 21, wherein, Cy3 is selected from Z2 is selected from C, CH or N; Z3 is selected from CH, CH2, N, NH or O; represents a single or double bond. R5 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyano, halogen or C1-C3 hydroxyalkyl; or, when 2 R5 are substituted on the same atom, the 2 R5 together with the atom to which they are attached form a 3-6 membered ring; or, when 2 R5 are substituted on adjacent atoms, the 2 R5 together with the atoms to which they are attached form a 3-12 membered ring; said 3-12 membered ring contains 0, 1 or 2 heteroatoms selected from N, O, S, P; t is selected from 0, 1, 2, 3 or 4.

23. The compound of claim 18, wherein Cy3 is selected from * represents attachment to ring Cy2; R2is selected from C3-C6cycloalkyl, -methylene-C3-C6cycloalkyl, -(CR 2c R 2d )u1-NR 2a R 2b , -(CR 2c R 2d )u3-3-8 membered heterocyclyl, C3-C6heterocyclyl, -(CR 2c R 2d )u2-C(O)-NR 2a R 2b or -CH2CN, said heterocyclyl or cycloalkyl is optionally substituted with one or two substituents selected from halogen, methyl, hydroxyl, hydroxymethyl, cyano, trifluoromethyl, difluoromethyl, -CH2F, C2-C3 alkyl and halogenated C2-C3 alkyl; R 2a , R 2b are each independently selected from H or methyl; R 2c , R 2d are each independently selected from H; u3 is selected from 1; u1, u2 are selected from 0 or 1; Y is selected from R4 is selected from ethyl or trifluoroethyl; R5 is selected from hydrogen or methyl; R8 is selected from hydrogen; s, t are as defined in claim 19.

24. The compound of claim 23, wherein, selected from the group consisting of:

25. The compound of claim 24, wherein, selected from the group consisting of:

26. The compound of claim 25, wherein, selected from the group consisting of:

27. The compound of claim 20, wherein having the structure of Formula (VIII): Cy3 is selected from C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl or 3-12 membered heterocyclic groups; Cy6 is selected from C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl or 3-12 membered heterocyclic groups; R 2f Selected from: non-existent, halogen, cyano, nitro, amino, hydroxy, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, C1-C6 alkylamino, haloC1-C6 alkylamino, oxo, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic groups, C1-C8 alkylamino, C1-C8 haloalkylamino, -OR g -SR g -OC(O)R g -C(O)R g -C(O)OR g -C(O)N(R) x )R y -NR x R y -N(CH3)R g -N(R) x )C(O)R y -N(R) x )C(O)NR x R y -N(R) x )C(O)OR g -C1-C8 alkylene-R g -N(R) x )S(O)NR x R y -N(R) x )S(O)2NR x R y -N(R) x )S(O)2R g -S(O)R g -S(O)2R g -S(O)2NR x R y or -P(O)R x R y ; j is selected from 0, 1, 2, 3 or 4; R4, R5, R8, t, s or Y are as defined in claim 1.

28. The compound of any one of claims 1-27, wherein has the following compound structure:

29. A method of preparing a compound of structure (I) as described in any one of claims 1-28, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, comprising the step of: Wherein, Boc is an N protecting group, X1, X 18 , Cy1, Cy2, Cy3, Cy4, R1, R2, R3, R4, R5, R6, R7, R8, R 10 R 11a R 11b R 12a R 12b R 13a R 13b The definitions of s, m, n, t, and p are as described in claim 1.

30. The method of claim 29, wherein, comprising the steps of: wherein Boc is a N protecting group, and Cy1, Cy3, R5, R6, R7, R8, s, m, n, t, p are as defined in claim 1.

31. A pharmaceutical composition, characterized by, The pharmaceutical composition contains an effective dose of the compound according to any one of claims 1-28 or prepared by the method of any one of claims 29-30, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.

32. Use of the compound according to any one of claims 1-28 or prepared by the method of any one of claims 29-30, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 29 in the preparation of a medicament for treating a disease associated with Ras mediation.

33. The use according to claim 30, wherein The disease associated with Ras mediation is a solid tumor, a hematological malignancy.

34. Use of the compound according to any one of claims 1-28 or prepared by the method of any one of claims 29-30, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 29 in the preparation of a medicament for treating a solid tumor, a hematological malignancy.

35. A method of treating or preventing a disease or disorder associated with Ras mediation in an individual, the method comprising administering to the individual an effective amount of a compound of any one of claims 1-28 or a compound prepared by the method of any one of claims 29-30, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 29.

36. The use of any one of claims 32-34 or the treatment method of claim 35, wherein, The disease associated with Ras mediation includes pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myelogenous leukemia multiple myeloma, thyroid adenocarcinoma, bone dysplasia syndrome, squamous cell lung cancer, esophageal cancer, ovarian cancer, uterine cancer, melanoma, bladder cancer, or head and neck cancer.

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