Macrocyclic compounds as extensive RAS mutant inhibitors

Abstract

The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotope variant, tautomer or stereoisomer thereof, as a generic RAS mutant inhibitor. The invention also provides pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts, isotope variants, tautomers or stereoisomers thereof, and uses thereof in the treatment of cancer.

Description

[0001] This application claims the following priority: Chinese application 202411662635.8 filed on November 20, 2024; Chinese application 202411695004.6 filed on November 25, 2024; and Chinese application 202411928613.1 filed on December 25, 2024. Technical Field

[0002] This invention belongs to the pharmaceutical field, specifically relating to RAS mutant inhibitors, more specifically to compounds of formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers or stereoisomers thereof, pharmaceutical compositions thereof, and their use in the treatment of cancer. Background Technology

[0003] The human RAS gene family comprises three classes of RAS genes: KRAS, NRAS, and HRAS, encoding four different RAS proteins (KRAS-4A, KRAS-4B, NRAS, and HRAS). RAS proteins belong to the GTPase protein family. They are inactive when bound to GDP but active when bound to GTP, leading to the activation of downstream signaling pathways such as RAF-MAPK and PI3K-Akt, resulting in cell anti-apoptosis and proliferation (Nat Rev Drug Discov, 2020; 19(8):533-552.). Activating mutations in RAS genes are the most common oncogene drivers in human cancers, with KRAS being the most frequently mutated. For example, the mutation rate of KRAS is 86-96% in pancreatic cancer, 40-54% in colorectal cancer, and 27-39% in lung cancer (PNAS, 2019; 116(32):15823-15829; Nature, 2014; 511,543–550).

[0004] Oncogenic driver mutations can occur at multiple sites in the KRAS gene. The most common mutations occur at the G12 site, including G12C, G12D, and G12V. These mutations can reduce the GTPase activity of the KRAS protein, thereby causing the KRAS protein to remain in an active state for a long time, leading to malignant transformation of cells and cancer (Cell, 2017; 170(1):17-33; Nat RevDrug Discov, 2020; 19(8):533-552). The types of KRAS mutations that frequently occur vary across different cancer types. For example, approximately 13% of lung cancer patients have the G12C mutation (N Engl Med J, 2021; 384(25):2382-2393); while in pancreatic cancer, 33.8% of patients have the G12D mutation and 40% have the G12V mutation, but only 1.7% have the G12C mutation; in colorectal cancer, approximately 10-12% of patients have the G12D mutation, while the incidence of the G12C mutation is less than 3% (Nat Rev Cancer 2018; 18(12):767-777).

[0005] Unlike ATP-dependent protein kinases (where the affinity of proteins for ATP is at the micromolar level), KRAS proteins have an affinity for GDP / GTP at the picomolar level. Compounds struggle to effectively compete with GDP / GTP to inhibit the KRAS signaling pathway, severely hindering the development of KRAS inhibitors (Nat Rev Drug Discov, 2020; 19(8):533-552). In recent years, allosteric binding cavities that can effectively bind to small molecules without competing with GDP / GTP have been discovered on the KRAS protein. These findings have greatly facilitated the development of targeted drugs that target KRAS mutation-driven tumors. Currently, MRTX-849 (Adagrasib) and AMG510 (Sotorasib), which target KRAS G12C, have demonstrated excellent efficacy in clinical studies (N Engl J Med. 2020; 383(13):1207-1217; Cancer Discov. 2020; 10(1):54-71), and AMG510 and MRTX-849 have successfully obtained FDA approval for marketing. Compared with the development of drugs targeting KRAS G12C, the development of drugs targeting more mutations such as KRAS G12D, G13D, G12V, G12R, and Q61H is still in its early stages, and only a few molecules have entered clinical trials. Therefore, the development of new types of panRAS inhibitors is needed to meet the needs of clinical patients. Summary of the Invention

[0006] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0007]

[0008] in,

[0009] X1 is selected from CH2, -CH(=C)H-, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe;

[0010] X2 is selected from CH2, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -N(R) a )-C(O), -NHC(O)-N(Me)-, NMe, C 3-6 Cycloalkyl or C 4-7 Metacyclic group; wherein C 3-6 Cycloalkyl or C 4-7 The heterocyclic group can be optionally C 1-6 Alkyl, halogen, C 1-6 Further substitution with haloalkyl groups and 5-6-membered heteroaryl groups;

[0011] X3 is selected from CH2, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe; X3 may optionally be further reacted with halogen or C 1-6 Alkyl substitution;

[0012] Ring A1 is selected from phenyl or 5-6-membered heteroaryl groups;

[0013] Ring A2 is selected from phenyl or 5-6-membered heteroaryl groups;

[0014] R1 is selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups;

[0015] L1 is selected from the following: -C(O)-, -C(S)-, O, S, NH, -NMe-, -C(O)NH, -NHC(O), -NHC(O)-N(Me)-C 1-6 Alkylene, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Halogenated alkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclic groups;

[0016] L2 is selected from the following groups: -C(O)-, -C(S)-, O, S, NH, -NMe-, -C(O)NH, -NHC(O), -NHC(O)-N(Me)-C 1-6 Alkylene, -CH2O-, -CH2S-, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 4-6 membered heterocyclic;

[0017] L1 and L2 can form 3-6 membered cycloalkyl groups or 4-10 membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group may optionally be surrounded by one, two or three R groups. x replace;

[0018] R x Selected from H, D, halogens, and -(CH2). p CN, -(CH2) p -OR a -(CH2) p -NH2、-C(O)R a -SR a -S(O)2R a -S(O)R a -S(O)2N(R) a (R) a '), -(CH2) p -C(O)OR a -(CH2) p -C(O)N(R a (R) a '), -(CH2) p -NHC(O)OR a -(CH2) p -OC(O)N(R a (R) a '), -O-phenyl-, -(CH2) p -Phenyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups;

[0019] R a and R a 'Independently selected from H, -L-CN, -(CH2)' p-OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic groups, -LC 6-10 Aryl or -L-5-10 heteroaryl;

[0020] R b Selected from H, D, halogen, -L-CN, -L-OR a or -LC(O)OR a ;

[0021] R c Selected from H, D, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy or -LC 3-8 cycloalkyl;

[0022] R d Selected from H, D, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl; or two R d Their atoms connect to form 4-6 membered rings;

[0023] R e Selected from H, D, halogens, C 2-6 alkenyl, C 2-6 alkynyl group, -C 2-6 alkynyl-L-4-8-membered heterocyclic group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 cycloalkyl or -L-4-8 membered heterocyclic group; R e It can be further divided into 1 or 2 Rs x replace;

[0024] R f Selected from H or C 1-6 alkyl;

[0025] R g Selected from H or C 1-6 Alkyl; R f and R g Connecting the carbon atom to it can form a 3-6 membered cycloalkyl group;

[0026] n is selected from 0, 1, 2, 3, 4, 5, or 6;

[0027] p is selected from 0, 1, 2, 3, 4, 5, or 6;

[0028] L is selected from bond, -C(O)-, -C(S)-, C 1-6 Alkylene or C 1-6 Halogenated alkyl groups.

[0029] In another aspect, the present invention provides the use of the compounds of the present invention in the preparation of medicaments for treating and / or preventing diseases mediated by RAS or its mutants.

[0030] In another aspect, the present invention provides compounds or compositions thereof for the treatment and / or prevention of diseases mediated by RAS or its mutants.

[0031] In a specific implementation, the disease treated by the present invention is cancer, including, for example, cancers selected from the following: colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), non-small cell lung cancer (NSCLC), or pancreatic cancer, etc.

[0032] Other objects and advantages of the invention will become apparent to those skilled in the art from the following detailed embodiments, examples and claims.

[0033] definition

[0034] Chemical definition

[0035] The definitions of specific functional groups and chemical terms are described in more detail below.

[0036] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0037] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl and C 1-2 Alkyl groups are preferred. C 1-6Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term "C" is used in conjunction with the preceding text. 1-6 "Alkyl" also includes heteroalkyl, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3) or i-Bu(-CH2CH(CH3)2).

[0038] “C 2-6 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl groups are preferred. C 2-6 Examples of alkenyl groups include: vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and so on. The term "C" is used in conjunction with these groups. 2-6 "Alkenyl" also includes heteroalkenyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0039] “C 2-6 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 Alkyne groups are preferred. C 2-6 Examples of alkynyl groups include, but are not limited to: ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentyynyl (C5), hexynyl (C6), etc. The term "C" is used in conjunction with other alkynyl groups. 2-6"Alkyne" also includes heteroyne, wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0040] “C 1-6 "Alkylene" refers to the removal of C 1-6 The alkyl group is a divalent group formed by another hydrogen atom, and can be substituted or unsubstituted. In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylenes are preferred. Unsubstituted alkylenes include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and so on. Exemplary substituted alkylenes, for example, those substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylidenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0041] “C 1-6 "Halogenated alkyl" refers to the alkyl group that has had its C4 atoms removed. 1-6 A divalent group formed by the other hydrogen atom of a haloalkyl group, and it can be substituted or unsubstituted.

[0042] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0043] Therefore, "C" 1-6 "Halogenated alkyl" refers to the above "C 1-6 "alkyl" is substituted with one or more halogen groups. In some embodiments, C 1-4 Halogenated alkyl groups are particularly preferred, and C4 groups are more preferred. 1-2Halogenated alkyl groups. Exemplary alkyl halogenated groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. The alkyl halogenated group can be substituted at any available connection point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0044] "Deuteration" or "D-substitution" refers to the substitution of one or more hydrogen atoms in a compound or group by deuterium; deuteration can be mono-substitution, di-substitution, poly-substitution, or total substitution.

[0045] Therefore, "C" 1-6 "Deuterated alkyl" refers to the above "C 1-6 "alkyl", which is substituted with one or more deuterium.

[0046] “C 1-6 "Alkoxy" refers to the -OR group, where R is C as defined above. 1-6 Alkyl group. C 1-4 Alkyl groups are preferred.

[0047] “C 1-6 "Haloalkoxy" refers to "C 1-6 "Alkoxy" is substituted with one or more halogen groups. In some embodiments, C 1-4 Halogenated alkoxyalkyl groups are particularly preferred, and C4 is more preferred. 1-2 Halogenated alkoxyalkyl groups.

[0048] “C 3-12 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 12 ring carbon atoms and zero heteroatoms. In some embodiments, C 4-10 cycloalkyl, C 5-10 cycloalkyl, C 4-7 cycloalkyl, C 3-8 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyl and C 3-4 Cycloalkyl groups are particularly preferred, and C10 is more preferred. 5-6Cycloalkyl groups. Cycloalkyl groups also include ring systems in which the aforementioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the linkage is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), etc. The cycloalkyl group may optionally be substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0049] "3-12 membered heterocyclic groups" refer to groups with a 3- to 12-membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclic groups containing one or more nitrogen atoms, the linkage can be a carbon or nitrogen atom, provided that the valence allows. In some embodiments, a 4-12 membered heterocyclic group is preferred, which is a 4-12 membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 5-12 membered heterocyclic group is preferred, which is a 5-12 membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 3-10 membered heterocyclic group is preferred, which is a 3-10 membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 4-10 membered heterocyclic group is preferred, which is a 4-10 membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 5-8 membered heterocyclic group is preferred, which is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms; in some embodiments, a 5-7 membered heterocyclic group is preferred, which is a 5-7 membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms. In some embodiments, a 4-8 membered heterocyclic group is preferred, which is a 4-8 membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms; in some embodiments, a 3-7 membered heterocyclic group is preferred, which is a 3-7 membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms; a 3-6 membered heterocyclic group is preferred, which is a 3-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; a 4-7 membered heterocyclic group is preferred, which is a 4-7 membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms; a 4-6 membered heterocyclic group is preferred, which is a 4-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; a 5-6 membered heterocyclic group is preferred, which is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; a 3-5 membered heterocyclic group is preferred, which is a 3-5 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms. Heterocyclic groups also include ring systems in which the aforementioned heterocyclic ring is fused with one or more cycloalkyl groups, wherein the linking point is on the cycloalkyl ring, or ring systems in which the aforementioned heterocyclic ring is fused with one or more aryl or heteroaryl groups, wherein the linking point is on the heterocyclic ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirropropyl, oxetane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirrobutyl, oxetane, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione.Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxasulfuranyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, disulfuranyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxasulfuranyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinoneyl, etc. Exemplary 6-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrobenzopyranyl, tetrahydropyranopyridyl, etc. The heterocyclic group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0050] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). Aryl also includes a ring system in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the connection point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0051] "5-14 membered heteroaryl" refers to a 4n+2 aromatic ring system of a 5-14 membered monocyclic or bicyclic ring (e.g., having 6, 10, or 14 shared π electrons arranged in a ring) having a ring carbon atom and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the bonding point is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-10 membered heteroaryl is preferred, which is a 4n+2 aromatic ring system of a 5-10 membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms. In some embodiments, 5-10-membered heteroaryl groups are preferred, which are 4n+2 aromatic ring systems of 6-10-membered monocyclic or bicyclic rings having a cyclic carbon atom and 1-4 cyclic heteroatoms. In some embodiments, 5-9-membered heteroaryl groups are preferred, which are 4n+2 aromatic ring systems of 5-9-membered monocyclic or bicyclic rings having a cyclic carbon atom and 1-4 cyclic heteroatoms. In other embodiments, 5-6-membered heteroaryl groups are particularly preferred, which are 4n+2 aromatic ring systems of 5-6-membered monocyclic or bicyclic rings having a cyclic carbon atom and 1-4 cyclic heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrole, furanyl, and thiophene. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to: triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azirheptatrienyl, oxaheptatrienyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphridinyl, pteridinyl, quinolinyl, isoquinolinyl, zolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.The heteroaryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0052] "Cycloalkylene", "heterocyclic", "aryl", or "heteroaryl" refers to a divalent group formed by removing one hydrogen atom from "cycloalkyl", "heterocyclic", "aryl", or "heteroaryl" as defined above, and can be substituted or unsubstituted. For example, "C 5-7 "Cycloalkylene" refers to the removal of C246 atoms. 5-7 The divalent group formed by removing another hydrogen from a cycloalkyl group, "5-8 membered heterocyclic group" refers to the divalent group formed by removing another hydrogen from a 5-8 membered heterocyclic group, "C 6-10 "Aromatic" refers to the removal of C 6-10 A divalent group formed by removing another hydrogen atom from an aryl group; "5-6-membered heteroaryl" refers to a divalent group formed by removing another hydrogen atom from a 5-6-membered heteroaryl group.

[0053] The alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined in this article are optional substituted groups.

[0054] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa -ON(R) bb )2、-N(R bb )2、-N(R bb )3 + X - -N(OR) cc )R bb -SH, -SR aa -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR) cc )2、-CO2R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa -NR bb CO2R aa -NR bb C(=O)N(R bb )2、-C(=NR bb )R aa -C(=NR) bb OR aa、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(Rcc )3、-B(R aa 2. -B(OR) cc )2、-BR aa (OR cc ), alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0055] Or the two hydrogen-bearing groups on the carbon atom: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or = NOR cc replace;

[0056] R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R aa Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0057] R bb Each is independently selected from: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, or two R bb Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0058] R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R cc Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0059] R dd Each is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2,、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NR) ff OR ee-C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee 3. -OSi(R) ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. Alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently marked by 0, 1, 2, 3, 4, or 5 R groups. g g-group substitution, or two geminal R groups dd Substituents can combine to form =O or =S;

[0060] R ee Each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. g g-group substitution;

[0061] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R ff The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. g g-group substitution;

[0062] R gEach of g independently represents: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - -NH(C 1-6 Alkyl)2 + X - -NH2(C 1-6 alkyl) + X - -NH3 + X - -N(OC) 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1-6Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C) 1-6 Alkyl)3、-OSi(C 1-6 Alkyl)3, -C(=S)N(C 1-6 Alkyl)2、C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC (=S)SC 1-6 Alkyl group, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two ethryl groups g g-substituents can combine to form =O or =S; where X - It is a counterion.

[0063] Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) bb )R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SORaa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R atoms attached to a nitrogen atom. cc The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa R bb R cc and R dd As stated above.

[0064] Other definitions

[0065] As used herein, the term "pharmaceutically acceptable salt" refers to carboxylates and amino acid addition salts of the compounds of the present invention that are suitable for contact with patient tissues within the limits of reliable medical judgment, without producing undue toxicity, irritation, allergic reactions, etc., and are effective for their intended use in proportion to a reasonable benefit / risk ratio, including (where possible) zwitterionic forms of the compounds of the present invention.

[0066] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0067] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0068] Generally, the "effective amount" of a compound refers to the amount sufficient to elicit a target biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the administration method, and the age, health status, and symptoms of the subject. Effective amounts include therapeutic effective amounts and prophylactic effective amounts.

[0069] The term "combination" and related terms refer to the simultaneous or sequential administration of the compounds of the present invention and other therapeutic agents. For example, the compounds of the present invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form. Detailed Implementation

[0070] In one embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

[0071]

[0072] in,

[0073] X1 is selected from CH2, -CH(=C)H-, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe;

[0074] X2 is selected from CH2, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -N(R) a )-C(O), -NHC(O)-N(Me)-, NMe, C 3-6 Cycloalkyl or C 4-7 Metacyclic group; wherein C 3-6 Cycloalkyl or C 4-7 The heterocyclic group can be optionally C 1-6 Alkyl, halogen, C 1-6 Further substitution with haloalkyl groups and 5-6-membered heteroaryl groups;

[0075] X3 is selected from CH2, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe; X3 may optionally be further reacted with halogen or C 1-6 Alkyl substitution;

[0076] Ring A1 is selected from phenyl or 5-6-membered heteroaryl groups;

[0077] Ring A2 is selected from phenyl or 5-6-membered heteroaryl groups;

[0078] R1 is selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups;

[0079] L1 is selected from the following: -C(O)-, -C(S)-, O, S, NH, -NMe-, -C(O)NH, -NHC(O), -NHC(O)-N(Me)-C 1-6 Alkylene, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Halogenated alkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclic groups;

[0080] L2 is selected from the following groups: -C(O)-, -C(S)-, O, S, NH, -NMe-, -C(O)NH, -NHC(O), -NHC(O)-N(Me)-C 1-6 Alkylene, -CH2O-, -CH2S-, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 4-6 membered heterocyclic;

[0081] L1 and L2 can form 3-6 membered cycloalkyl groups or 4-10 membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group may optionally be surrounded by one, two or three R groups. x replace;

[0082] R x Selected from H, D, halogens, and -(CH2). p CN, -(CH2) p -OR a -(CH2) p -NH2、-C(O)R a -SR a -S(O)2R a -S(O)R a -S(O)2N(R) a (R) a '), -(CH2) p -C(O)OR a -(CH2) p -C(O)N(R a (R) a '), -(CH2) p -NHC(O)OR a -(CH2) p -OC(O)N(R a (R) a '), -O-phenyl-, -(CH2) p -Phenyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups;

[0083] R a and R a 'Independently selected from H, -L-CN, -(CH2)' p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic groups, -LC 6-10 Aryl or -L-5-10 heteroaryl;

[0084] R b Selected from H, D, halogen, -L-CN, -L-OR a or -LC(O)OR a ;

[0085] R c Selected from H, D, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy or -LC 3-8 cycloalkyl;

[0086] R d Selected from H, D, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl; or two R d Their atoms connect to form 4-6 membered rings;

[0087] R e Selected from H, D, halogens, C 2-6 alkenyl, C 2-6 alkynyl group, -C 2-6 alkynyl-L-4-8-membered heterocyclic group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 cycloalkyl or -L-4-8 membered heterocyclic group; R e It can be further divided into 1 or 2 Rs x replace;

[0088] R f Selected from H or C 1-6 alkyl;

[0089] R g Selected from H or C1-6 Alkyl; R f and R g Connecting the carbon atom to it can form a 3-6 membered cycloalkyl group;

[0090] n is selected from 0, 1, 2, 3, 4, 5, or 6;

[0091] p is selected from 0, 1, 2, 3, 4, 5, or 6;

[0092] L is selected from bond, -C(O)-, -C(S)-, C 1-6 Alkylene or C 1-6 Halogenated alkyl groups.

[0093] Any technical solution or any combination thereof in any of the above embodiments can be combined with any technical solution or any combination thereof in other embodiments. For example, any technical solution or any combination thereof of Z can be combined with X1-X2, R, R1-R2, ring A, ring B, R x R b R a and R a '、p、R c This invention aims to include combinations of all these technical solutions, but due to space limitations, they will not be listed individually.

[0094] In a more specific embodiment, the present invention relates to the following technical solutions:

[0095] Technical Solution 1. A compound of formula (II), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0096]

[0097] in,

[0098] X1 is selected from CH2, -CH(=C)H-, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe;

[0099] X3 is selected from CH2, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe; X3 may optionally be further reacted with halogen or C 1-6 Alkyl substitution;

[0100] Ring A1 is selected from phenyl or 5-6-membered heteroaryl groups;

[0101] Ring A2 is selected from phenyl or 5-6-membered heteroaryl groups;

[0102] R1 is selected from H and C.1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups;

[0103] L2 is selected from the following groups: -C(O)-, -C(S)-, O, S, NH, -NMe-, -C(O)NH, -NHC(O), -NHC(O)-N(Me)-C 1-6 Alkylene, -CH2O-, -CH2S-, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 4-6 membered heterocyclic;

[0104] Ring B1 is absent or ring B1 is selected from 4-10 member heterocyclic groups, wherein the heterocyclic group is optionally surrounded by 1, 2 or 3 R groups. x replace;

[0105] R x Selected from H, D, halogens, and -(CH2). p CN, -(CH2) p -OR a -(CH2) p -NH2、-C(O)R a -SR a -S(O)2R a -S(O)R a -S(O)2N(R) a (R) a '), -(CH2) p -C(O)OR a -(CH2) p -C(O)N(R a (R) a '), -(CH2) p -NHC(O)OR a -(CH2) p -OC(O)N(R a (R) a '), -O-phenyl-, -(CH2) p -Phenyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups;

[0106] R a and R a 'Independently selected from H, -L-CN, -(CH2)' p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic groups, -LC 6-10 Aryl or -L-5-10 heteroaryl;

[0107] R b Selected from H, D, halogen, -L-CN, -L-OR a or -LC(O)OR a ;

[0108] R c Selected from H, D, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy or -LC 3-8 cycloalkyl;

[0109] R d Selected from H, D, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl; or two R d Their atoms connect to form 4-6 membered rings;

[0110] R e Selected from H, D, halogens, C 2-6 alkenyl, C 2-6 alkynyl group, -C 2-6 alkynyl-L-4-8-membered heterocyclic group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 cycloalkyl or -L-4-8 membered heterocyclic group; R e It can be further divided into 1 or 2 Rs x replace;

[0111] n is selected from 0, 1, 2, 3, 4, 5, or 6;

[0112] p is selected from 0, 1, 2, 3, 4, 5, or 6;

[0113] L is selected from bond, -C(O)-, -C(S)-, C 1-6 Alkylene or C 1-6 Halogenated alkyl groups.

[0114] Technical Solution 2. A compound of formula (III), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0115]

[0116] in,

[0117] X1 is selected from CH2, -CH(=C)H-, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe;

[0118] X3 is selected from CH2, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe; X3 may optionally be further reacted with halogen or C 1-6 Alkyl substitution;

[0119] Ring A1 is selected from phenyl or 5-6-membered heteroaryl groups;

[0120] Ring A2 is selected from phenyl or 5-6-membered heteroaryl groups;

[0121] R1 is selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups;

[0122] L2 is selected from the following groups: -C(O)-, -C(S)-, O, S, NH, -NMe-, -C(O)NH, -NHC(O), -NHC(O)-N(Me)-C 1-6 Alkylene, -CH2O-, -CH2S-, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 4-6 membered heterocyclic;

[0123] R x Selected from H, D, halogens, and -(CH2). p CN, -(CH2) p -OR a -(CH2) p -NH2、-C(O)R a -SR a -S(O)2R a -S(O)R a -S(O)2N(R) a (R) a '), -(CH2) p -C(O)ORa -(CH2) p -C(O)N(R a (R) a '), -(CH2) p -NHC(O)OR a -(CH2) p -OC(O)N(R a (R) a '), -O-phenyl-, -(CH2) p -Phenyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups;

[0124] R a and R a 'Independently selected from H, -L-CN, -(CH2)' p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic groups, -LC 6-10 Aryl or -L-5-10 heteroaryl;

[0125] R b Selected from H, D, halogen, -L-CN, -L-OR a or -LC(O)OR a ;

[0126] R c Selected from H, D, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy or -LC 3-8 cycloalkyl;

[0127] R d Selected from H, D, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl; or two R d Their atoms connect to form 4-6 membered rings;

[0128] R e Selected from H, D, halogens, C 2-6 alkenyl, C2-6 alkynyl group, -C 2-6 alkynyl-L-4-8-membered heterocyclic group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 cycloalkyl or -L-4-8 membered heterocyclic group; R e It can be further divided into 1 or 2 Rs x replace;

[0129] n is selected from 0, 1, 2, 3, 4, 5, or 6;

[0130] p is selected from 0, 1, 2, 3, 4, 5, or 6;

[0131] L is selected from bond, -C(O)-, -C(S)-, C 1-6 Alkylene or C 1-6 Halogenated alkyl groups.

[0132] Technical Solution 3. The compound of Technical Solution 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, having the structure of formula (II-1) or formula (III-1):

[0133]

[0134] in,

[0135] X1 is selected from CH2, -CH(=C)H-, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe;

[0136] X3 is selected from CH2, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe; X3 may optionally be further reacted with halogen or C 1-6 Alkyl substitution;

[0137] Ring A1 is selected from phenyl or 5-6-membered heteroaryl groups;

[0138] R1 is selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups;

[0139] L2 is selected from the following groups: -C(O)-, -C(S)-, O, S, NH, -NMe-, -C(O)NH, -NHC(O), -NHC(O)-N(Me)-C 1-6 Alkylene, -CH2O-, -CH2S-, C 1-6 Alkyl, C 1-6 Alkylene, C1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 4-6 membered heterocyclic;

[0140] Ring B1 is absent or ring B1 is selected from 4-10 member heterocyclic groups, wherein the heterocyclic group is optionally surrounded by 1, 2 or 3 R groups. x replace;

[0141] R x Selected from H, D, halogens, and -(CH2). p CN, -(CH2) p -OR a -(CH2) p -NH2、-C(O)R a -SR a -S(O)2R a -S(O)R a -S(O)2N(R) a (R) a '), -(CH2) p -C(O)OR a -(CH2) p -C(O)N(R a (R) a '), -(CH2) p -NHC(O)OR a -(CH2) p -OC(O)N(R a (R) a '), -O-phenyl-, -(CH2) p -Phenyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups;

[0142] R a and R a 'Independently selected from H, -L-CN, -(CH2)' p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic groups, -LC 6-10 Aryl or -L-5-10 heteroaryl;

[0143] R c Selected from H, D, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy or -LC 3-8 cycloalkyl;

[0144] R e Selected from H, D, halogens, C 2-6 alkenyl, C 2-6 alkynyl group, -C 2-6 alkynyl-L-4-8-membered heterocyclic group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 cycloalkyl or -L-4-8 membered heterocyclic group; R e It can be further divided into 1 or 2 Rs x replace;

[0145] p is selected from 0, 1, 2, 3, 4, 5, or 6;

[0146] L is selected from bond, -C(O)-, -C(S)-, C 1-6 Alkylene or C 1-6 Halogenated alkyl groups.

[0147] Technical Solution 4. The compound of Technical Solution 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the structure of formula (II-2) or (II-3):

[0148]

[0149] in,

[0150] X1 is selected from CH2, -CH(=C)H-, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe;

[0151] X3 is selected from CH2, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe; X3 may optionally be further reacted with halogen or C 1-6 Alkyl substitution;

[0152] R1 is selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups;

[0153] L2 is selected from the following groups: -C(O)-, -C(S)-, O, S, NH, -NMe-, -C(O)NH, -NHC(O), -NHC(O)-N(Me)-C 1-6 Alkylene, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 4-6 membered heterocyclic;

[0154] R x Selected from H, D, halogens, and -(CH2). p CN, -(CH2) p -OR a -(CH2) p -NH2、-C(O)R a -SR a -S(O)2R a -S(O)R a -S(O)2N(R) a (R) a '), -(CH2) p -C(O)OR a -(CH2) p -C(O)N(R a (R) a '), -(CH2) p -NHC(O)OR a -(CH2) p -OC(O)N(R a (R) a '), -O-phenyl-, -(CH2) p -Phenyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups;

[0155] R a and R a 'Independently selected from H, -L-CN, -(CH2)' p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy, -LC 3-8Cycloalkyl, -L-4-8 membered heterocyclic groups, -LC 6-10 Aryl or -L-5-10 heteroaryl;

[0156] R e Selected from H, D, halogens, C 2-6 alkenyl, C 2-6 alkynyl group, -C 2-6 alkynyl-L-4-8-membered heterocyclic group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 cycloalkyl or -L-4-8 membered heterocyclic group; R e It can be further divided into 1 or 2 Rs x replace;

[0157] p is selected from 0, 1, 2, 3, 4, 5, or 6;

[0158] L is selected from bond, -C(O)-, -C(S)-, C 1-6 Alkylene or C 1-6 Halogenated alkyl groups.

[0159] Technical Solution 5. The compound of Technical Solution 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the structure of formula (IV):

[0160]

[0161] in,

[0162] X1 is selected from CH2, -CH(=C)H-, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe;

[0163] X3 is selected from CH2, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe; X3 may optionally be further reacted with halogen or C 1-6 Alkyl substitution;

[0164] Ring A1 is selected from phenyl or 5-6-membered heteroaryl groups;

[0165] Ring A2 is selected from phenyl or 5-6-membered heteroaryl groups;

[0166] L1 is selected from the following: -C(O)-, -C(S)-, O, S, NH, -NMe-, -C(O)NH, -NHC(O), -NHC(O)-N(Me)-C 1-6 Alkylene, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6Halogenated alkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclic groups;

[0167] L2 is selected from the following groups: -C(O)-, -C(S)-, O, S, NH, -NMe-, -C(O)NH, -NHC(O), -NHC(O)-N(Me)-C 1-6 Alkylene, -CH2O-, -CH2S-, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 4-6 membered heterocyclic;

[0168] L1 and L2 can form 3-6 membered cycloalkyl groups or 4-10 membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group may optionally be surrounded by one, two or three R groups. x replace;

[0169] R x Selected from H, D, halogens, and -(CH2). p CN, -(CH2) p -OR a -(CH2) p -NH2、-C(O)R a -SR a -S(O)2R a -S(O)R a -S(O)2N(R) a (R) a '), -(CH2) p -C(O)OR a -(CH2) p -C(O)N(R a (R) a '), -(CH2) p -NHC(O)OR a -(CH2) p -OC(O)N(R a (R) a '), -O-phenyl-, -(CH2) p -Phenyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups;

[0170] Ra and R a 'Independently selected from H, -L-CN, -(CH2)' p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic groups, -LC 6-10 Aryl or -L-5-10 heteroaryl;

[0171] R b Selected from H, D, halogen, -L-CN, -L-OR a or -LC(O)OR a ;

[0172] R c Selected from H, D, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy or -LC 3-8 cycloalkyl;

[0173] R d Selected from H, D, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl; or two R d Their atoms connect to form 4-6 membered rings;

[0174] R e Selected from H, D, halogens, C 2-6 alkenyl, C 2-6 alkynyl group, -C 2-6 alkynyl-L-4-8-membered heterocyclic group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 cycloalkyl or -L-4-8 membered heterocyclic group; R e It can be further divided into 1 or 2 Rs x replace;

[0175] n is selected from 0, 1, 2, 3, 4, 5, or 6;

[0176] p is selected from 0, 1, 2, 3, 4, 5, or 6;

[0177] L is selected from bond, -C(O)-, -C(S)-, C 1-6 Alkylene or C 1-6 Halogenated alkyl groups.

[0178] Technical Solution 6. The compound of Technical Solution 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, having the structure of formula (IV-1):

[0179]

[0180] in,

[0181] X1 is selected from CH2, -CH(=C)H-, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe;

[0182] X3 is selected from CH2, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe; X3 may optionally be further reacted with halogen or C 1-6 Alkyl substitution;

[0183] L1 is selected from the following: -C(O)-, -C(S)-, O, S, NH, -NMe-, -C(O)NH, -NHC(O), -NHC(O)-N(Me)-C 1-6 Alkylene, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Halogenated alkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclic groups;

[0184] L2 is selected from the following groups: -C(O)-, -C(S)-, O, S, NH, -NMe-, -C(O)NH, -NHC(O), -NHC(O)-N(Me)-C 1-6 Alkylene, -CH2O-, -CH2S-, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 4-6 membered heterocyclic;

[0185] L1 and L2 can form 3-6 membered cycloalkyl groups or 4-10 membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group may optionally be surrounded by one, two or three R groups. x replace;

[0186] R x Selected from H, D, halogens, and -(CH2). p CN, -(CH2) p -OR a -(CH2) p -NH2、-C(O)R a -SR a -S(O)2Ra -S(O)R a -S(O)2N(R) a (R) a '), -(CH2) p -C(O)OR a -(CH2) p -C(O)N(R a (R) a '), -(CH2) p -NHC(O)OR a -(CH2) p -OC(O)N(R a (R) a '), -O-phenyl-, -(CH2) p -Phenyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups;

[0187] R a and R a 'Independently selected from H, -L-CN, -(CH2)' p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic groups, -LC 6-10 Aryl or -L-5-10 heteroaryl;

[0188] R b Selected from H, D, halogen, -L-CN, -L-OR a or -LC(O)OR a ;

[0189] R d Selected from H, D, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl; or two R d Their atoms connect to form 4-6 membered rings;

[0190] R e Selected from H, D, halogens, C 2-6 alkenyl, C 2-6 alkynyl group, -C 2-6alkynyl-L-4-8-membered heterocyclic group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 cycloalkyl or -L-4-8 membered heterocyclic group; R e It can be further divided into 1 or 2 Rs x replace;

[0191] n is selected from 0, 1, 2, 3, 4, 5, or 6;

[0192] p is selected from 0, 1, 2, 3, 4, 5, or 6;

[0193] L is selected from bond, -C(O)-, -C(S)-, C 1-6 Alkylene or C 1-6 Halogenated alkyl groups.

[0194] Technical Solution 7. A compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein the compound is selected from:

[0195]

[0196]

[0197]

[0198]

[0199]

[0200] Technical Solution 8. A compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein the compound is selected from:

[0201]

[0202] Technical Solution 9. A compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein the compound is selected from:

[0203]

[0204]

[0205] Technical Solution 10. A compound of any one of Technical Solutions 7-9 or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, for the treatment and / or prevention of RAS-mediated diseases.

[0206] Technical Solution 11. In Technical Solution 10, the RAS-mediated disease is cancer, preferably, the cancer is selected from: colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), non-small cell lung cancer (NSCLC), or pancreatic cancer, etc.

[0207] The compounds of this invention may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0208] The compounds of this invention may also exist as tautomers. A compound is not limited to any particular tautomer, but is intended to encompass all tautomer forms.

[0209] The present invention also includes isotopically labeled compounds (isotopic variants) that are equivalent to those described in formula (A), but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Other isotopes of the present invention containing the aforementioned isotopes and / or other atoms, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e.,2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotopically labeled compounds of formula (A) of the present invention and their prodrugs can generally be prepared by using readily available isotopically labeled reagents instead of non-isotopically labeled reagents when performing the processes described below and / or the techniques disclosed in the examples and preparation examples.

[0210] Pharmaceutical Compositions and Kits

[0211] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as the "active component") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a preventatively effective amount of the compound of the present invention.

[0212] Pharmaceutically acceptable excipients used in this invention refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0213] The present invention also includes a kit (e.g., a pharmaceutical package). The provided kit may include the compounds of the present invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compounds of the present invention and other therapeutic agents. In some embodiments, the provided kit may optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the present invention and / or other therapeutic agents. In some embodiments, the compounds of the present invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0214] Dosage

[0215] The pharmaceutical compositions provided by this invention can be administered via a variety of routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration via implantation, or other routes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intramenstrual administration, intralesional administration, and intracranial injection or infusion techniques.

[0216] Typically, an effective amount of the compound described herein is administered. The actual amount of compound administered may be determined by the physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0217] When used to prevent the conditions described in this invention, the compounds provided herein are administered to subjects at risk of developing the conditions, typically based on a physician's advice and under physician supervision, at the dosage levels described above. Subjects at risk of developing a specific condition generally include subjects with a family history of the condition, or those identified through genetic testing or screening as particularly susceptible to developing the condition.

[0218] The pharmaceutical compositions provided herein can also be administered long-term (“long-term administration”). Long-term administration means administering the compound or a pharmaceutical composition thereof over a prolonged period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be administered indefinitely, such as for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of said compound in the blood over a prolonged period of time, such as within a therapeutic window.

[0219] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by bolus injection, for instance, to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active component through the body; for example, an intramuscular or subcutaneous bolus dose results in a slow release of the active component, while a bolus dose delivered directly to a vein (e.g., via IV intravenous infusion) allows for a more rapid delivery, causing the concentration of the active component in the blood to rapidly increase to an effective level. In other embodiments, the pharmaceutical composition can be administered in the form of a continuous infusion, for example, via IV intravenous infusion, thereby providing a steady-state concentration of the active component in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0220] Oral compositions may be in the form of bulk liquid solutions, suspensions, or bulk powders. However, more commonly, the compositions are provided in unit dose form for the purpose of precise dosing. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined quantity of active substance and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect. Typical unit dose forms include pre-filled, pre-measured ampoules or syringes for liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is typically a smaller component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients useful for forming the desired dosage form, as well as processing aids.

[0221] For oral dosage, a typical regimen is one to five oral doses daily, particularly two to four oral doses, typically three oral doses. Using these dosage regimens, each dose provides approximately 0.01 to approximately 20 mg / kg of the compound of the invention, with preferred doses each providing approximately 0.1 to approximately 10 mg / kg, particularly approximately 1 to approximately 5 mg / kg.

[0222] To provide blood levels similar to or lower than those achieved with an injection dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, more preferably about 0.1 to about 10% by weight, and even more preferably about 0.5 to about 15% by weight.

[0223] From approximately 1 to approximately 120 hours, especially 24 to 96 hours, the injection dose level ranges from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour. To obtain adequate steady-state levels, a preload bolus of approximately 0.1 mg / kg to approximately 10 mg / kg or more may also be administered. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed approximately 2 g / day.

[0224] Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers, as well as buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following components, or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavorings.

[0225] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art. As previously described, in such compositions, the active compound is typically a smaller component, often about 0.05 to 10% by weight, with the remainder being injectable excipients, etc.

[0226] Transdermal compositions are typically formulated as topical ointments or creams containing an active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water emulsion base. Such transdermal formulations are well known in the art and generally include other components to enhance stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of this invention.

[0227] The compounds of this invention can also be administered via transdermal devices. Therefore, transdermal drug delivery can be achieved using reservoirs or porous membrane types, or patches with various solid matrices.

[0228] The above-described components for oral, injectable, or topical administration are merely representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0229] The compounds of this invention can also be administered in a sustained-release form or from a sustained-release drug delivery system. Descriptions of representative sustained-release materials can be found at Remington's Pharmaceutical Sciences.

[0230] This invention also relates to pharmaceutically acceptable formulations of the compounds of this invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, respectively, composed of 6, 7, and 8 α-1,4-linked glucose units, optionally including one or more substituents on the linked sugar moieties, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfonyl ether substituted groups. In some embodiments, the cyclodextrin is a sulfonyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US 5,376,645. In some embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0231] Example

[0232] The reagents used in this invention are commercially available reagents that are purchased directly or synthesized using common methods known in the art.

[0233] Notes on commonly used abbreviations:

[0234]

[0235]

[0236] Example 1: Preparation of intermediates

[0237] Preparation of intermediates a1, a3-a8, a25-a26

[0238]

[0239] Step 1: Under nitrogen protection, starting material a1-1 (2.0 g, 9.3 mmol) and starting material pinacol diborate (3.54 g, 14.0 mmol) were dissolved in 31 mL of anhydrous tetrahydrofuran. Catalyst [Ir(COD)Cl]₂ (187 mg, 0.28 mmol) and ligand BBBPY (375 mg, 1.4 mmol) were added. The mixture was reacted at 80 °C for 12 hours, and then the reaction was stopped. 50 mL of saturated ammonium chloride aqueous solution was added to the mixture, and the mixture was extracted with MTBE, dried over anhydrous sodium sulfate, and concentrated to give compound a1-2 (1.2 g), yield: 50%. LCMS ESI-MS m / z: 260 [M+H] + .

[0240] Step 2: Under nitrogen protection, intermediate a1-2 (95 g, 230.53 mmol) from the previous step was dissolved in 1000 mL of a mixed solution of acetonitrile and water (v / v, 1 / 1). NIS (57.05 g, 253.58 mmol) and CuI (131.7 g, 691.59 mmol) were slowly added. The mixture was reacted at 90 °C for 12 hours and then filtered. 1000 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (PE / EA, 3 / 1) to give a yellow oily substance a1-3 (64.5 g), yield: 77%. LCMS ESI-MS m / z: 341.7 [M+H] + .

[0241] 1H NMR (400MHz, CDCl3) δ8.80(d,J=1.67Hz,1H),8.18(d,J=1.79Hz,1H),4.86(q,J=6.44Hz,1H),3.31(s,3H),1.47(d,J=6.44Hz,3H).

[0242] Step 3: Under nitrogen protection, intermediate a1-3 (500 mg, 1.47 mmol) and starting material a1-4 (647 mg, 2.94 mmol) from the previous step were dissolved in 25 mL of anhydrous toluene. Catalyst Pd(OAc)2 (34 mg, 0.15 mmol) and ligand R-BINAP (93 mg, 0.15 mmol) were added. The mixture was reacted at 105 °C for 12 hours, and then the reaction was stopped. 40 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (PE / EA, 1 / 1) to obtain a yellow solid a1 (310 mg), yield: 49%. LCMS ESI-MS m / z: 434 [M+H] + .

[0243] Following the synthetic route of intermediate a1, and using similar starting materials, the following intermediate was synthesized:

[0244]

[0245] Preparation of intermediate a27

[0246]

[0247] Step 1: Under nitrogen protection, starting material a1-1 (50.0 g, 231.40 mmol) and starting material pinacol diborate (61.7 g, 242.97 mmol) were dissolved in 600 mL of anhydrous tetrahydrofuran. Catalyst Ir(OMe)(COD)2 (1.55 g, 2.31 mmol) and ligand dtbbpy (7.45 g, 27.77 mmol) were added. The mixture was reacted at 75 °C for 3 hours, and then the reaction was stopped. The mixture was cooled to room temperature and concentrated. The crude product was separated by column chromatography (nHex / EA, 6 / 1) to give a yellow oily substance a27-1 (90.0 g, Purity: 82%), yield: 93%. LCMS ESI-MS m / z: 343.9 [M+H] + .

[0248] Step 2: Dissolve the intermediate a27-1 (80.0 g, 191.79 mmol, Purity: 82%) from the previous step in a mixed solution of acetonitrile and water (v / v, 1 / 1). Slowly add N-chlorosuccinimide NCS (26.89 g, 201.38 mmol) and CuCl (56.96 g, 575.37 mmol). Slowly heat the mixture to 90 °C and react for 2.5 hours, then stop the reaction. Add 1000 mL of water to the reaction solution, extract with ethyl acetate, dry to anhydrous sodium sulfate, concentrate, and separate the crude product by column chromatography (nHex / EA, 9 / 1) to obtain a colorless, transparent oil a27 (43.2 g, Purity: 95%), yield: 85%. LCMS ESI-MS m / z: 251.9 [M+H] + .

[0249] 1 H NMR (400MHz, CDCl3) δ8.59 (d, J = 1.91Hz, 1H), 7.88 (d, J = 2.03Hz, 1H), 4.90 (q, J = 6.40Hz, 1H), 3.32 (s, 3H), 1.48 (d, J = 6.44Hz, 3H).

[0250] Preparation of intermediates a2, a9-a14, a28-a30

[0251]

[0252] Step 1: Under nitrogen protection in an ice bath, intermediate a1 (2.9 g, 6.7 mmol) and trimethylsilylacetylene a2-1 (788 mg, 8.1 mmol) were dissolved in 20 mL of anhydrous DMF. TEA (2.7 g, 26.8 mmol), CuI (2.2 g, 16.9 mmol), and catalyst Pd(PPh3)Cl2 (470 mg, 0.67 mmol) were added dropwise. The mixture was heated to 100 °C and reacted for 12 hours, after which the reaction was stopped. 100 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (PE / EA, 1 / 1) to give a white solid a2-2 (2.08 g), yield: 69%. LCMS ESI-MS m / z: 452 [M+H] + .

[0253] Step 2: Dissolve intermediate a2-2 (2.08 g, 4.62 mmol) and KF (1.3 g, 23.0 mmol) in 11 mL of methanol. React the mixture at room temperature for 12 hours, then stop the reaction. Add 50 mL of ice water to the reaction solution, extract with dichloromethane, dry to anhydrous sodium sulfate, concentrate, and separate the crude product by column chromatography (PE / EA, 1 / 1) to obtain a white solid a2 (1.5 g), yield: 89%. LCMS ESI-MS m / z: 380 [M+H] + .

[0254] Following the synthetic route of intermediate a2, and using similar starting materials, the following intermediate was synthesized:

[0255]

[0256] intermediate a30 1 H NMR (400MHz, CDCl3) δ8.58(d,J=2.4Hz,1H),7.76(d,J=2.4Hz,1H),4.98-4.91(m,1H),3.49(s,1H),3.32-3.31(m,3H),1.51-1.49(m,3H)

[0257] Preparation of intermediates a15-a21, a31-a33

[0258]

[0259] Step 1: Under nitrogen protection, intermediate a2 (1.5 g, 4.1 mmol), triethylamine (1.6 g, 16.4 mmol), and starting material a15-1 (2.07 g, 6.1 mmol) were dissolved in 20 mL of anhydrous DMF. CuI (105 mg, 0.41 mmol) and catalyst Pd(PPh3)Cl2 (390 mg, 0.41 mmol) were added. The mixture was heated to 100 °C and reacted for 12 hours, after which the reaction was stopped. 100 mL of ice water was added to the reaction solution, followed by extraction with dichloromethane, washing with saturated brine, drying with anhydrous sodium sulfate, and concentration. The crude product was separated by column chromatography (PE / EA, 3 / 2) to obtain a yellow solid a15-2 (1.57 g), yield: 65%. LCMS ESI-MS m / z: 589 [M+H] + .

[0260] Step 2: Under nitrogen protection, the intermediate a15-2 (1.57 g, 2.67 mmol) and the catalyst PdCl2 (49 mg, 0.27 mmol) from the previous step were dissolved in 15 mL of DMF. The mixture was heated to 70 °C and reacted for 12 hours, after which the reaction was stopped. 100 mL of ice water was added to the reaction solution, followed by extraction with dichloromethane, washing with saturated brine, drying over anhydrous sodium sulfate, and concentration. The crude product was separated by flash reversed-phase column chromatography (column: C18; CH3CN / H2O, 3 / 2) to obtain a white solid a15 (267 mg), yield: 30%. LCMSESI-MS m / z: 589 [M+H] + .

[0261] Following the synthetic route of intermediate a15, and using similar starting materials, the following intermediate was synthesized:

[0262]

[0263] intermediate a31 1 H NMR (400MHz, CDCl3) δ8.91(br dd,1H,J=1.9,5.0Hz),7.64(s,1H),7.48(br s,1H),7.18(s,1H),6.44(s,1H),4.5-4.6(m,1H),3.7-3.9(m,10H),3.28(brs,3H),3.0-3.1(m,2H),2.94(s,3H),2.2-2.3(m,2H),1.42(br d,3H,J=5.2Hz).

[0264] intermediate a33 1 H NMR (400MHz, CDCl3) δ8.74(d,J=2.38Hz,1H),7.63(dd,J=6.38,1.97Hz,2H),7.13(s,1H),6.39(s,1H),4.48(q,J =6.24Hz,1H),3.78-3.93(m,2H),3.18(s,3H),3.02(t,J=6.08Hz,2H),2.13-2.30(m,2H),1.44(d,J=6.32Hz,3H).

[0265] Preparation of intermediates a22-a24, a34-a36

[0266]

[0267] Step 1: Under nitrogen protection in an ice bath, POCl3 (688 mg, 4.5 mmol) was dissolved in 3 mL of anhydrous DMF and stirred for 30 minutes. Then, a DMF solution (3 mL) of intermediate a15 (267 mg, 0.45 mmol) was added dropwise to the reaction mixture. After the addition was complete, the mixture was heated to 40 °C and reacted for 1 hour, at which point the reaction was stopped. 100 mL of ice water was added to the reaction mixture, and the pH was adjusted to approximately 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed-phase column chromatography (column: C18; CH3CN / H2O, 1 / 1) to obtain a white solid a22-1 (152 mg), yield: 55%. LCMS ESI-MS m / z: 617 [M+H] + .

[0268] Step 2: Under nitrogen protection at -78℃, methyl isobutyrate a22-2 (127 mg, 1.25 mmol) was dissolved in 3 mL of anhydrous tetrahydrofuran. LDA (1.25 mL, 1 M) was added dropwise. After the addition was complete, intermediate a22-1 (152 mg, 0.25 mmol) from the previous step was added. The mixture was slowly heated to room temperature and reacted for 1 hour, then the reaction was stopped. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed-phase column chromatography (column: C18; CH3CN / H2O, 1 / 2) to give a white solid a22-3 (82 mg), yield: 46%. LCMS ESI-MS m / z: 719 [M+H] + .

[0269] Step 3: Under nitrogen protection and in an ice bath, dissolve the intermediate a22-3 (82 mg, 0.11 mmol) and Et3SiH (102 mg, 0.88 mmol) from the previous step in 5 mL of dichloromethane. Add TFA (125 mg, 1.1 mmol) dropwise, heat to room temperature, and react for 16 hours. Stop the reaction. Add 40 mL of ice water to the reaction solution, adjust the pH to approximately 9 with saturated sodium bicarbonate solution, extract with ethyl acetate, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by flash reversed column chromatography (column: C18; CH3CN / H2O, 1 / 1) to obtain a white solid a22-4 (55 mg), yield: 71%. LCMS ESI-MS m / z: 703 [M+H] + .

[0270] Step 4: Under nitrogen protection, the intermediate a22-4 (55 mg, 0.078 mmol) from the previous step was dissolved in 5 mL of tetrahydrofuran solution (0.78 mL, 0.78 mmol) of LiBH4. The reaction was carried out at room temperature for 3 hours, and then the reaction was stopped. 40 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 9 with saturated sodium bicarbonate aqueous solution. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (DCM / MeOH, 20 / 1) to give a white solid a22 (35 mg), yield: 66%. LCMS ESI-MS m / z: 675 [M+H] + .

[0271] Following the synthetic route of intermediate a22, and using similar raw materials, the following intermediate was synthesized:

[0272]

[0273] intermediate a36 1 H NMR (400MHz, CDCl3) δ8.76(d,J=2.27Hz,1H),7.64-7.72(m,2H),7.10(s,1H),4.13(q,J=7.07Hz,1H),3.71-3.85(m,2H),3.21 -3.34(m,2H),2.95-3.07(m,5H),2.72(d,J=14.19Hz,1H),2.10-2.32(m,3H),1.48(d,J=6.20Hz,3H),0.80(d,J=3.22Hz,6H).

[0274] Preparation of intermediate b1

[0275]

[0276] Step 1: Under nitrogen protection in an ice bath, dissolve raw material b1-1 (2.47 g, 3.4 mmol) in 30 mL of a mixture of methanol and water (v / v, 1 / 1). Stir for 5 minutes, then add 6 mL of LiOH aqueous solution (4N) dropwise to the reaction solution. Heat to room temperature and react for 1 hour, then stop the reaction. Add 100 mL of ice water to the reaction solution, adjust the pH to approximately 5 with dilute hydrochloric acid, extract with ethyl acetate, dry to anhydrous sodium sulfate, and concentrate to obtain a white solid b1-2 (1.53 g), yield: 80%. LCMS ESI-MS m / z: 562 [MH] - .

[0277] 1H NMR (400MHz, CD3OD) δ7.22(s,1H),7.10(d,J=2.03Hz,1H),6.89(s,1H),4.28(br dd,J=8.17,4.71Hz,1H),3.12(dd,J=13.77,4.83Hz,1H),2.88(br dd,J=13.59,8.34Hz,1H),1.40(s,9H),1.34(s,12H),1.22-1.27(m,3H),1.12(d,J=7.27Hz,18H).

[0278] Step 2: Under nitrogen protection and in an ice bath, intermediate b1-2 (1.53 g, 2.7 mmol), starting material b1-3 (600 mg, 3.0 mmol), and NMM (2.7 g, 27 mmol) from the previous step were dissolved in 53 mL of anhydrous dichloromethane. EDCI (778 mg, 4.1 mmol) and HOBT (554 mg, 4.1 mmol) were added, and the mixture was slowly heated to room temperature for 20 hours. The reaction was then stopped. 50 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed-phase column chromatography (column: C18; CH3CN / H2O, 1 / 2) to give a yellow oily substance b1 (760 mg), yield: 41%. LCMS ESI-MS m / z: 690 [M+H] + .

[0279] 1 H NMR (400MHz, CD3OD) δ7.19(s,1H),7.12(d,J=2.03Hz,1H),6.86(t,J=1.79Hz,1H),5.32-5.47(m,1H),4.06-4.20(m,1H),3.72(s,3H),2.92(br dd,J=12.99,7.15Hz,1H),2.73-2.81(m,3H),1.71-1.91(m,2H),1.52-1.63(m ,2H),1.40(s,9H),1.34(s,12H),1.23-1.29(m,3H),1.12(d,J=7.15Hz,18H).

[0280] Preparation of intermediate b2

[0281]

[0282] Step 1: Under nitrogen protection in an ice bath, dissolve starting material b2-1 (10.0 g, 45 mmol) and starting material b2-2 (12.8 g, 90 mmol) in 80 mL of anhydrous dichloromethane. After stirring for 5 minutes, add catalyst Rh2(OAc)4 (1016 mg, 2.3 mmol). Heat to room temperature and react for 24 hours, then stop the reaction. Filter, concentrate the filtrate under reduced pressure to obtain a colorless oily substance b2-3 (4.99 g), yield: 33%.

[0283] Step 2: In an ice bath, dissolve intermediate b2-3 (4.99 g, 14.85 mmol) from the previous step in a 1,4-dioxane solution of hydrogen chloride (8 mL, 4 M). React at room temperature for 2 hours, then stop the reaction. Add 50 mL of water to the reaction solution, adjust the pH to approximately 5 with saturated sodium bicarbonate, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to obtain a yellow oily substance b2-4 (2.9 g).

[0284] Step 3: The intermediate b2-4 (2.9 g, 10.3 mmol) from the previous step was dissolved in BH3-THF solution (18 mL, 1 M). The reaction was carried out at room temperature for 2 hours. The reaction was then stopped, and the solvent was removed by vacuum distillation. 50 mL of ice water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give a yellow oily substance b2-5 (1.5 g), yield: 55%. LCMS ESI-MS m / z: 267 [M+H] + .

[0285] Step 4: In an ice bath, dissolve intermediate b2-5 (1.5 g, 5.6 mmol) and TEA (1.13 g, 11.2 mmol) from the previous step in 12 mL of dichloromethane. Add methanesulfonyl chloride MsCl (766 mg, 6.7 mmol). React at room temperature for 2 hours, then stop the reaction and remove the solvent under reduced pressure. Add 50 mL of ice water, extract with ethyl acetate, dry to anhydrous sodium sulfate, and concentrate to obtain a yellow oil b2 (1.5 g), which can be used directly in the next step.

[0286] Preparation of intermediates b3 and b4

[0287]

[0288] Step 1: Under nitrogen protection in an ice bath, dissolve raw material b3-1 (20.0 g, 61.85 mmol) and DIEA (11.99 g, 92.78 mmol) in 50 mL of anhydrous dichloromethane. Add methyl trifluoromethanesulfonate (TfOMe) (15.22 g, 92.78 mmol) dropwise. React at room temperature for 1.5 hours, then stop the reaction. Add 50 mL of water to the reaction solution, adjust the pH to approximately 6 with dilute hydrochloric acid, extract with dichloromethane, dry to anhydrous sodium sulfate, concentrate, and wash with n-hexane to obtain a white solid b3-2 (18 g, Purity: 86%).

[0289] Step 2: Under nitrogen protection at -78℃, intermediate b3-2 (30.0 g, 88.92 mmol) from the previous step was dissolved in 500 mL of anhydrous tetrahydrofuran. KHMDS (225 mL, 1 M) was added dropwise. After the addition was complete, hexamethylphosphoric triamine (HMPA) (23.21 mL, 133.38 mmol) was added. After stirring for 15 minutes, allyl bromide (11.54 mL, 133.38 mmol) was added to the reaction mixture. The reaction was continued at -78℃ for 2 hours. The reaction was then stopped, and the solvent was removed by vacuum distillation. 100 mL of ice water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (nHex / EA, 2 / 5) to give yellow oily substances b3 (14.6 g) and b4, yield: 44%. LCMS ESI-MS m / z: 378 [M+H] + The structure of the compound was identified by two-dimensional NMR.

[0290] 1 H NMR (400MHz, CDCl3) δ7.33(br s,5H),5.87-5.68(m,1H),5.29(br d,J=8.8Hz,1H),5.20-5.10(m,2H),5.09-5.04(m,1H),4.65(br dd,J=4.9,8.5Hz,1H),3.68(s,2H),3.63(s,1H),3.07-2.87(m,1H),2.64-2.50(m,1H),2.46-2.27(m,1H),1.47-1.42(m,9H).

[0291] Preparation of intermediate b5

[0292]

[0293] Step 1: In an ice bath, intermediate b3 (14.6 g, 38.68 mmol) was dissolved in 250 mL of a mixture of methanol and water (v / v, 4 / 1). K2O5O4 (140 mg, 0.39 mmol) and NaIO4 (24.82 g, 116 mmol) were added. The mixture was heated to room temperature and reacted for 12 hours, then the reaction was stopped. 500 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and washed with n-hexane to obtain an oily substance b5-1 (15 g, Purity: 99%).

[0294] Step 2: Under nitrogen protection and in an ice bath, dissolve intermediate b5-1 (15.0 g, 39.54 mmol) and Et3SiH (18.95 mL, 118.62 mmol) in 200 mL of dichloromethane. Add trifluoroacetic acid (TFA) (5.87 mL, 79.08 mmol) dropwise. After the addition is complete, react in an ice bath for 3 hours, then remove the solvent under reduced pressure. Add 100 mL of ice water and adjust the pH to approximately 8 with saturated sodium bicarbonate solution. Extract with dichloromethane, dry over anhydrous sodium sulfate, concentrate, and separate the crude product by flash column chromatography (nHex / EA, 2 / 5) to obtain a yellow oil b5-2 (5.76 g, purity: 100%), yield: 40%. LCMS ESI-MS m / z: 264.3 [M+H-Boc] + .

[0295] 1 H NMR (400MHz, CDCl3) δ7.39-7.34(m,5H),5.18(s,2H),4.69-4.55(m,1H),3.74-3.71(m,3H) ,3.62-3.53(m,2H),3.20-3.12(m,1H),2.24-2.15(m,2H),1.47-1.46(m,3H),1.41(s,6H).

[0296] Step 3: Under hydrogen protection, intermediate b5-2 (5.76 g, 15.85 mmol) and Pd(OH)2 (580 mg, 20% purity) from the previous step were dissolved in 150 mL of methanol. The reaction was carried out at room temperature for 16 hours under hydrogen pressure of 45 psi. The mixture was filtered, and the filter cake was washed with methanol and dried. A yellow oily substance b5-3 (270 mg) was obtained, yield: 6%. LCMS ESI-MS m / z: 174.3 [M+H-Boc] + .

[0297] Step 4: Under nitrogen protection and in an ice bath, dissolve intermediate b5-3 (5.46 g, 19.98 mmol) from the previous step in 200 mL of anhydrous tetrahydrofuran. Slowly add LiBH4 (15 mL, 2 M). After the addition is complete, heat to 50 °C and react for 13 hours. Add 100 mL of ice water, adjust the pH to approximately 5 with dilute hydrochloric acid, extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate to obtain a yellow oily substance b5 (3.33 g, Purity: 90%), yield: 68%. LCMS ESI-MS m / z: 246.3 [M+H] + .

[0298] Preparation of intermediates b6-b7

[0299]

[0300] Step 1: In an ice bath, intermediate b5 (3.28 g, 13.37 mmol) and 2,6-lutidine (7.79 mL, 66.85 mmol) were dissolved in 45 mL of a mixed solution of acetonitrile and DMF (v / v, 8 / 1). HATU (7.63 g, 20.05 mmol) was added, and the mixture was stirred for 5 minutes. Then, the starting material L-valine benzyl ester hydrochloride b6-1 (4.16 g, 20.05 mmol) was added, and the reaction was carried out in an ice bath for 2 hours. The reaction was then stopped. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and washed with n-hexane. The crude product was separated by flash reversed column chromatography (column: C18; CH3CN / H2O, 1 / 1) to obtain an oily substance b6-2 (3.56 g, Purity: 99%), yield: 61%. LCMS ESI-MS m / z:335.3[M+H-Boc] + .

[0301] 1 H NMR (400MHz, CDCl3) δ7.43-7.32(m,4H),6.55-6.35(m,1H),5.25-5.18(m,1 H),5.17-5.11(m,1H),4.62(dd,J=4.6,8.8Hz,1H),4.14-3.95(m,1H),3.93 -3.81(m,1H),3.78-3.67(m,1H),3.66-3.56(m,1H),3.34-3.20(m,1H),3.1 3-2.68(m,1H),2.24-2.11(m,2H),2.08-2.00(m,1H),1.47(s,9H),0.93(br d,J=6.8Hz,3H),0.89-0.83(m,3H).

[0302] Step 2: Under nitrogen protection and in an ice bath, dissolve intermediate b6-2 (4.0 g, 9.21 mmol) and TEA (12.77 mL, 92.1 mmol) in 100 mL of dichloromethane. Add DMAP (230 mg, 1.84 mmol) and p-toluenesulfonyl chloride TsCl (7.02 g, 36.84 mmol). React at room temperature for 13 hours, then remove the solvent under reduced pressure. Add 100 mL of ice water, adjust the pH to approximately 6 with dilute hydrochloric acid, extract with dichloromethane, dry to anhydrous sodium sulfate, concentrate, and separate the crude product by flash column chromatography (nHex / EA, 2 / 5) to obtain a yellow oil b6-3 (4.6 g, Purity: 98%), yield: 85%. LCMS ESI-MS m / z: 489.3 [M+H-Boc] + .

[0303] 1 H NMR (400MHz, CDCl3) δ7.79 (d, J = 8.2Hz, 2H), 7.37 (s, 7H), 6.57-6.24 (m, 1H ),5.27-5.19(m,1H),5.18-5.12(m,1H),4.62-4.54(m,1H),4.46-4.37(m, 1H),4.30-4.16(m,1H),4.01(s,1H),3.81-3.59(m,1H),3.35-3.17(m,1H) ,3.01(s,1H),2.46(s,3H),2.30-2.00(m,3H),1.48-1.27(m,9H),0.93(br dd,J=6.6,16.9Hz,6H).

[0304] Step 3: Under hydrogen protection, intermediate b6-3 (160 mg, 0.27 mmol) and Pd / C (80 mg, 10% purity) from the previous step were dissolved in 5 mL of tetrahydrofuran. The reaction was carried out at room temperature for 16 hours under hydrogen pressure of 15 psi. The mixture was filtered, and the filter cake was washed with methanol and dried. A white solid b6 (90 mg, purity: 85%) was obtained, yield: 66%. LCMS ESI-MS m / z: 399.2 [M+H-Boc] + .

[0305] 1H NMR (400MHz, CD3OD) δ8.36-8.14(m,1H),7.78(d,J=8.3Hz,2H),7.49-7.41(m,2H),4.38-4.21(m,2H),4.17-4.08(m,2H) ,3.59-3.44(m,2H),3.24-3.07(m,2H),2.28-2.10(m,2H),1.98-1.82(m,3H),1.46-1.32(m,8H),0.97(d,J=6.7Hz,6H).

[0306] Following the synthetic route of intermediate b6, and using similar starting materials, the following intermediate was synthesized:

[0307]

[0308] Preparation of intermediate b8

[0309]

[0310] Step 1: Under nitrogen protection, starting material b8-1 (5.0 g, 49.94 mmol) was dissolved in 40 mL of dichloromethane. N,N-dicyclohexylcarbodiimide DCC (11.33 g, 54.93 mmol), 4-dimethylaminopyridine DMAP (0.61 g, 4.99 mmol), and tert-butanol (7.40 g, 99.88 mmol) were added sequentially. The reaction was carried out at room temperature for 16 hours, after which the reaction was stopped. The solvent was removed by vacuum distillation. The crude product was separated by flash column chromatography (nHex / EA, 9 / 1) to give a colorless oily substance b6-3 (5.7 g), yield: 73%. Note: This product is colorless at 254 nm and 220 nm, and MS was not detected in the product.

[0311] 1 H NMR (400MHz, CDCl3) δ3.10-2.96(m,1H),2.30-2.08(m,4H),1.99-1.82(m,2H),1.45(s,9H).

[0312] Step 2: Under nitrogen protection at -60℃, the intermediate b8-2 (2.0 g, 12.80 mmol) from the previous step was dissolved in 20 mL of anhydrous tetrahydrofuran. LDA (8.32 mL, 2 M) was added dropwise. After the addition was complete, the mixture was stirred for 40 minutes. Then, the starting material 3-bromopropene b8-3 (2.01 g, 16.64 mmol) was slowly added to the reaction solution. The mixture was slowly heated to room temperature and reacted for 5 hours, at which point the reaction was stopped. 10 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (nHex / EA, 9 / 1) to obtain a colorless oily substance b8-4 (2.0 g), yield: 80%.

[0313] 1 H NMR (400MHz, CDCl3) δ5.72 (tdd, J=7.1, 10.1, 17.1Hz, 1H), 5.11-5.00 (m, 2H ),2.47(d,J=7.0Hz,2H),2.41-2.32(m,2H),1.93-1.82(m,4H),1.45(s,9H).

[0314] Step 3: Under nitrogen protection, intermediate b8-4 (1.6 g, 8.15 mmol) was dissolved in 30 mL of a mixed solution of tetrahydrofuran and water (v / v, 2 / 1). K₂O₅O₄ (0.30 g, 0.82 mmol) and NaIO₄ (5.23 g, 24.45 mmol) were added, and the reaction was stopped at room temperature for 1 hour. 20 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and washed with n-hexane to give the oily compound b8-5 (1.0 g, Purity: 100%), yield: 62%.

[0315] Step 4: Under nitrogen protection in an ice bath, dissolve intermediate b8-5 (1.0 g, 5.04 mmol) from the previous step in 20 mL of anhydrous tetrahydrofuran. Slowly add sodium borohydride (0.38 g, 10.08 mmol), and slowly heat to room temperature for 2 hours. Stop the reaction. Add 30 mL of ice water, extract with ethyl acetate, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by flash column chromatography (nHex / EA, 1 / 1) to give a colorless oily substance b8 (210.0 mg), yield: 20%.

[0316] 1 H NMR (400MHz, CDCl3) δ3.58(t,J=6.6Hz,2H),2.39-2.31(m,2H),1.97-1.94(m,2H),1.90-1.81(m,4H),1.40(s,9H).

[0317] Preparation of intermediate b9

[0318]

[0319] Step 1: Triethyl orthoacetate (44.99 g, 277.35 mmol) and hexanoic acid (1.61 g, 13.87 mmol) were slowly added sequentially to raw material b9-1 (20.0 g, 277.35 mmol). The mixture was slowly heated to 150 °C and reacted for 12 hours. After cooling to room temperature, 100 mL of anhydrous ethanol and potassium hydroxide (23.34 g, 416.03 mmol) were added, and the mixture was heated again for 3 hours. The reaction was then stopped. After cooling to room temperature, 100 mL of methyl tert-butyl ether (MTBE) was added to dilute the reaction mixture. The pH was adjusted to 3-4 with dilute hydrochloric acid. The mixture was extracted with MTBE, dried over anhydrous sodium sulfate, and concentrated to obtain a colorless oily substance b9-2 (24.0 g, Purity: 85%), yield: 76%.

[0320] Step 2: Under nitrogen protection in an ice bath, dissolve the intermediate b9-2 (23.0 g, 201.51 mmol) from the previous step in 250 mL of acetonitrile, add iodine (115.08 g, 453.40 mmol), and react the mixture in the dark for 24 hours, then stop the reaction. Dilute the reaction solution with 100 mL of saturated sodium bicarbonate solution, extract with MTBE, dry over anhydrous sodium sulfate, and concentrate. Separate the crude product by flash column chromatography (nHex / EA, 7 / 3) to obtain a colorless oily substance b9-3 (30.0 g), yield: 62%.

[0321] 1 H NMR (400MHz, CDCl3) δ4.04 (q, J = 5.3Hz, 1H), 3.46-3.38 (m, 1H), 3.37-3.29 (m, 1H), 2.81 (dd, J=8.7,17.6Hz,1H),2.51-2.37(m,1H),2.26(dd,J=8.1,17.6Hz,1H),1.22(d,J=6.8Hz,3H).

[0322] Step 3: Under nitrogen protection in an ice bath, the intermediate b9-3 (28.0 g, 116.65 mmol) from the previous step was dissolved in 200 mL of anhydrous tetrahydrofuran, and lithium tert-butoxide (14.01 g, 174.98 mmol) was added. The reaction was carried out at room temperature for 18 hours, and then the reaction was stopped. The reaction solution was cooled to 0 °C, and 100 mL of saturated ammonium chloride solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give a colorless oily substance b9-4 (16.1 g), yield: 74%.

[0323] 1H NMR(400MHz,DMSO-d6)δ2.79(ddd,J=2.7,4.0,6.9Hz,1H),2.69-2.63(m,1H),2.53-2.51(m,1H),2.3 4(dd,J=5.5,14.8Hz,1H),2.17-2.08(m,1H),1.75-1.66(m,1H),1.40(s,9H),0.92(d,J=6.9Hz,3H).

[0324] Step 4: Under nitrogen protection at -78℃, dissolve intermediate b9-4 (16.1 g, 86.44 mmol) from the previous step in 250 mL of anhydrous tetrahydrofuran. Add LDA (10.19 g, 95.08 mmol, 2 M) dropwise. After the addition is complete, slowly raise the temperature to room temperature and react for 1 hour. Then lower the temperature to -30℃ and continue the reaction for 3 hours, then stop the reaction. Cool the reaction solution to 0℃, add 250 mL of saturated ammonium chloride solution, extract with ethyl acetate, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by flash column chromatography (nHex / EA, 1 / 1) to obtain a colorless oily substance b9-5 (7.50 g), yield: 47%.

[0325] 1 H NMR (400MHz, CDCl3) δ3.76 (dd, J=6.7, 11.5Hz, 1H), 3.59 (dd, J=8.3, 11.3Hz, 1 H),1.76-1.67(m,1H),1.57-1.48(m,2H),1.44(s,9H),1.17(d,J=6.4Hz,3H).

[0326] Step 5: Ice bath. Dissolve intermediate b9-5 (2.0 g, 10.74 mmol) from the previous step in 50 mL of dichloromethane, add rhodium acetate dimer (0.24 g, 0.54 mmol), and slowly add ethyl diazonium acetate b9-6 (2.45 g, 21.48 mmol). Heat to room temperature and react for 18 hours, then stop the reaction. Filter the reaction solution, evaporate to dryness, and concentrate. Separate the crude product by flash column chromatography (nHex / EA, 7 / 3) to obtain a colorless oily substance b9-7 (1.27 g), yield: 43%.

[0327] 1H NMR (400MHz, CDCl3) δ4.22(q,J=7.1Hz,2H),4.10(d,J=4.5Hz,2H),3.70(dd,J=6.2,10.5Hz,1H),3.52(dd,J=8 .5,10.4Hz,1H),1.79-1.69(m,1H),1.56-1.48(m,1H),1.44(s,9H),1.35-1.23(m,4H),1.17(d,J=6.4Hz,3H).

[0328] Step 6: Dissolve intermediate b9-7 (1.20 g, 4.41 mmol) from the previous step in 5 mL of tetrahydrofuran aqueous solution (v / v, 4 / 1), add lithium hydroxide (0.16 g, 6.62 mmol), and react at room temperature for 2 hours. Then stop the reaction. Cool to 0 °C, adjust the pH to 4-5 with dilute hydrochloric acid, extract with ethyl acetate, dry to anhydrous sodium sulfate, and concentrate to give a colorless oily substance b9-8 (1.0 g), yield: 93%.

[0329] 1 H NMR (400MHz, CDCl3) δ4.15(d,J=3.1Hz,2H),3.74(dd,J=6.4,10.6Hz,1H),3.56(dd,J=8.5,10.5Hz,1H),2. 12(s,1H),1.80-1.68(m,1H),1.61-1.51(m,1H),1.45(s,9H),1.21(t,J=4.6Hz,1H),1.17(d,J=6.4Hz,3H).

[0330] Step 7: Under nitrogen protection in an ice bath, dissolve intermediate b9-8 (1.0 g, 4.09 mmol) from the previous step in 40 mL of anhydrous tetrahydrofuran. Add boron dimethyl sulfide complex (BMS, 0.93 g, 12.27 mmol) dropwise. Slowly heat to room temperature and react for 18 hours, then stop the reaction. Cool the reaction solution to 0 °C, add 5 mL of methanol, filter, evaporate to dryness, concentrate, and separate the crude product by flash column chromatography (nHex / EA, 7 / 3) to obtain a colorless oil b9-9 (0.86 g), yield: 91%.

[0331] 1H NMR (400MHz, CDCl3) δ3.78-3.71(m,2H),3.66(dd,J=6.1,10.7Hz,1H),3.62-3.52(m,2H),3.43(dd,J=8.3,10 .6Hz,1H),1.76-1.66(m,1H),1.58-1.49(m,1H),1.47-1.42(m,9H),1.20-1.18(m,1H),1.16(d,J=6.4Hz,3H).

[0332] Step 8: Under nitrogen protection at -78℃, oxalyl chloride (946.90 mg, 7.46 mmol) was dissolved in 30 mL of dichloromethane. A 2 mL solution of dimethyl sulfoxide (1165.70 mg, 14.92 mmol) in dichloromethane was slowly added dropwise. Then, a 5 mL solution of intermediate b9-9 (860 mg, 3.73 mmol) from the previous step was slowly added dropwise. The mixture was stirred for 15 minutes, followed by the slow addition of triethylamine (2264.63 mg, 22.38 mmol). The mixture was slowly heated to room temperature and reacted for 1 hour, at which point the reaction was stopped. 10 mL of ice water was added to the reaction mixture, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (nHex / EA, 7 / 3) to obtain a colorless oily substance b9 (0.80 g), yield: 94%.

[0333] 1 H NMR(400MHz, CDCl3)δ9.75(s,1H),3.77-3.64(m,1H),3.61-3.43(m,2H),1.8 0-1.63(m,2H),1.57-1.49(m,1H),1.44(d,J=3.1Hz,9H),1.22-1.12(m,4H).

[0334] Preparation of intermediate c1

[0335]

[0336] Step 1: Under nitrogen protection, intermediates a22 (4.04 g, 6.0 mmol) and b1 (4.8 g, 7.0 mmol) were dissolved in 60 mL of a mixed solution of 1,4-dioxane and water (v / v, 5 / 1). Na2CO3 (1.48 g, 14 mmol) and catalyst Pd(dtBPF)Cl2 (388 mg, 0.6 mmol) were added. The mixture was heated to 90 °C and reacted for 6 hours, then the reaction was stopped. 100 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (column: C18; CH3CN / H2O, 1 / 1) to give a yellow solid c1-1 (3.6 g), yield: 52%. LCMS ESI-MS m / z: 1158 [M+H] + .

[0337] Step 2: Under nitrogen protection in an ice bath, intermediate c1-1 (3.6 g, 3.1 mmol) from the previous step was dissolved in 30 mL of anhydrous dichloroethane. Trimethyltin hydroxide (Me3SnOH) (2.8 g, 15.5 mmol) was added, and the mixture was slowly heated to 60 °C and reacted for 16 hours. The reaction was then stopped. 500 mL of saturated brine was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. A yellow solid c1-2 (3.1 g) was obtained, yield: 87%. LCMS ESI-MS m / z: 1142 [MH] - .

[0338] Step 3: In an ice bath, dissolve intermediate C1-2 (3.1 g, 2.7 mmol) and DIEA (698 mg, 5.4 mmol) from the previous step in 15 mL of dichloromethane. Add EDCI (518 mg, 2.7 mmol) and HOBT (176 mg, 1.3 mmol). Heat to room temperature and react for 12 hours, then stop the reaction. Add 40 mL of ice water to the reaction solution, extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by flash reversed column chromatography (column: C18; CH3CN / H2O, 2 / 1) to obtain a white solid C1 (941 mg), yield: 31%. LCMS ESI-MS m / z: 1126 [M+H] + .

[0339] Preparation of intermediate C2

[0340]

[0341] Step 1: Under nitrogen protection, intermediates a34 (0.15 g, 0.27 mmol) and b1 (0.19 g, 0.27 mmol) were dissolved in 8 mL of a mixed solution of toluene / 1,4-dioxane and water (v / v / v, 3 / 1 / 1). K3PO4 (0.11 g, 0.54 mmol) and catalyst Pd(dppf)Cl2 (22 mg, 0.027 mmol) were added, and the mixture was heated to 70 °C and reacted for 16 hours. The reaction was then stopped. 10 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reversed column chromatography (column: C18; CH3CN / H2O, 1 / 1) to give a yellow solid c2-1 (0.27 g), yield: 96%. LCMSESI-MS m / z: 1038.5 [M+H] + .

[0342] Step 2: Under nitrogen protection in an ice bath, dissolve intermediate C2-1 (0.27 g, 0.26 mmol) from the previous step in 8 mL of a mixed solution of tetrahydrofuran and water (v / v, 3 / 1). Add LiOH (32 mg, 0.78 mmol). React in an ice bath for 2 hours, then stop the reaction. Add 10 mL of saturated saline solution to the reaction mixture, adjust the pH to approximately 5 with dilute hydrochloric acid, extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate. Obtain yellow solid C2-2 (0.23 g), yield: 87%. LCMS ESI-MS m / z: 1024.5 [M+H] + .

[0343] Step 3: Dissolve intermediate C2-2 (0.23 g, 0.22 mmol) and NMI (180 mg, 2.2 mmol) from the previous step in 8 mL of acetonitrile. Add N,N,N,N-Tetramethylchlorourea hexafluorophosphate (TCFH) (93 mg, 0.33 mmol). React in an ice bath for 2 hours, then stop the reaction. Add 40 mL of ice water to the reaction solution, extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by flash column chromatography (DCM / MeOH, 10 / 1) to obtain an oily substance C2 (570 mg), yield: 25%. LCMS ESI-MS m / z: 1006.4 [M+H] + .

[0344] Preparation of intermediate d1

[0345]

[0346] Step 1: Dissolve raw material b1-1 (13.4 g, 0.023 mmol) in 210 mL of a mixed solution of acetonitrile and water (v / v, 6 / 1). Add N-iodosuccinimide (NIS, 6.86 g, 30.47 mmol) dropwise, followed by catalyst CuI (15.83 g, 83.1 mmol). Heat the mixture to 75 °C and react for 3 hours, then stop the reaction. Filter off the catalyst, extract with ethyl acetate, dry to anhydrous sodium sulfate, and concentrate to obtain a brownish-yellow oil d1-1 (6.7 g, Purity: 95%), yield: 51%. LCMS ESI-MS m / z: 478.0 [M+H-Boc] + .

[0347] Step 2: Under nitrogen protection in an ice bath, intermediate d1-1 (1.53 g, 2.7 mmol) from the previous step was dissolved in 2 mL of anhydrous DMF. Cesium fluoride catalyst (240 mg, 1.6 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was then stopped. Extraction was performed with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give a colorless oily substance d1-2 (133.0 mg, Purity: 90%), yield: 90%. LCM SESI-MS m / z: 421.9 [M+H] + .

[0348] Step 3: In an ice bath, dissolve intermediate d1-2 (2.0 g, 4.75 mmol) from the previous step in 20 mL of anhydrous dichloromethane. Slowly add 4 mL of trifluoroacetic acid (TFA) and react for 1 hour. Then stop the reaction. Rotate the reaction solution to dryness to obtain compound d1-3 (1.52 g), yield: 99%. LCMS ESI-MS m / z: 322.1 [M+H] + .

[0349] Step 4: Under nitrogen protection and in an ice bath, dissolve intermediate d1-3 (1002.71 mg, 2.01 mmol) and DIEA (3.65 mg, 22.1 mmol) in 25 mL of DMF. Add intermediate b6 (1046 mg, 2.1 mmol) and condensation reagent COMU (946.48 mg, 2.21 mmol) to the reaction solution. React at room temperature for 16 hours, then stop the reaction. Add 15 mL of ice water to the reaction solution, adjust the pH to approximately 7 with dilute hydrochloric acid, extract with ethyl acetate, dry to anhydrous sodium sulfate, and concentrate to obtain a pale yellow solid compound d1-4 (1.99 g), yield: 99%. LCMS ESI-MS m / z: 802.1 [M+H] + .

[0350] Step 5: Under nitrogen protection, the intermediate d1-4 (1767 mg, 0.99 mmol, Purity: 44.7%) from the previous step was dissolved in 10 mL of DMF. K2CO3 (1368.28 mg, 9.9 mmol) and potassium iodide (164.34 mg, 0.99 mmol) were added, and the mixture was heated to 80 °C and reacted for 2 hours. The mixture was then filtered. 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated by flash column chromatography (nHex / EA, 1 / 1) to give a pale yellow solid compound d1-5 (415.0 mg), yield: 67%. LCMS ESI-MS m / z: 630.1 [M+H] + .

[0351] 1 H NMR (400MHz, DMSO-d6) δ7.18 (d, J = 2.1Hz, 1H), 7.14-7.12 (m, 1H), 3.67 (s, 3H), 2.67 (br d,J=1.9Hz,6H),2.33(s,5H),1.53-1.41(m,9H),0.80(dd,J=6.4,12.5Hz,6H).

[0352] Step 6: Dissolve intermediate d1-5 (256.0 mg, 0.407 mmol) from the previous step in 5 mL of anhydrous tetrahydrofuran. Slowly add lithium hydroxide monohydrate (55.39 mg, 1.32 mmol) dissolved in 1 mL of water. React the mixture at 0 °C for 3 hours, then stop the reaction. Adjust the pH of the reaction solution to approximately 5 with dilute hydrochloric acid. Extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate to obtain a pale yellow solid compound d1-6 (250.0 mg), yield: 100%. LCMS ESI-MS m / z: 616.1 [M+H] + .

[0353] Step 7: Under nitrogen protection at -30℃, dissolve intermediate d1-6 (234.6 mg, 0.381 mmol) and starting material b1-3 (137.28 mg, 0.76 mmol) from the previous step in 4 mL of DMF. Add HATU (288.97 mg, 0.76 mmol) and DIEA (491.11 mg, 3.8 mmol) sequentially. Stir the reaction mixture at -30℃ for 2 hours, then stop the reaction. Extract with ethyl acetate, dry to anhydrous sodium sulfate, and remove the solvent under reduced pressure. Separate the crude product by TLC (DCM / MeOH, 19 / 1) to obtain compound d1 (65.0 mg), yield: 23%. LCMS ESI-MS m / z: 742.2 [M+H] + .

[0354] 1 H NMR(400MHz, CDCl3)δ7.10(s,1H),7.03-6.99(m,1H),6.68-6.63(m,1H),6.54(s,1H), 6.23(s,1H),5.47(s,1H),4.46-4.29(m,2H),4.11-4.00(m,1H),3.83(s,3H),3.60(br d,J=2.6Hz,2H),3.33-3.07(m,2H),3.01-2.84(m,1H),2.76-2.60(m,1H),2.56-2.44 (m,1H),2.17-1.96(m,6H),1.57-1.49(m,9H),1.32-1.22(m,1H),0.91-0.86(m,6H).

[0355] Example 2: Molecular Synthesis of the Invention

[0356] Synthesis of target molecule P1

[0357]

[0358] Step 1: Under hydrogen (10 atm), intermediate C1 (225 mg, 0.2 mmol) and formaldehyde aqueous solution (95 mg, 1 mmol, 30%) were dissolved in 9 mL of methanol. Carbon-activated Pd(OH)₂ (100 mg) was added, and the mixture was reacted at room temperature under a hydrogen atmosphere for 12 hours. 50 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow solid C2 (138 mg), yield: 69%. LCMS ESI-MS m / z: 1006.4 [M+H] + .

[0359] Step 2: Dissolve intermediate C2 (138 mg, 0.137 mmol) in 4 mL of tetrahydrofuran in an ice bath. Add 0.2 mL of TBAF in tetrahydrofuran solution (1 M) to the reaction mixture. React in an ice bath for 1 hour, then stop the reaction. Add 20 mL of ice water to the reaction mixture, extract with ethyl acetate, dry to anhydrous sodium sulfate, concentrate, and separate the crude product by column chromatography (PE / EA, 1 / 1) to give compound P1-2 (45 mg), yield: 39%. LCMS ESI-MS m / z: 850 [M+H] + .

[0360] Step 3: Ice bath. Dissolve compound P1-2 (45 mg, 0.053 mmol) and Cs2CO3 (52 mg, 0.16 mmol) from the previous step in 2 mL of DMF. Add intermediate b2 (34 mg, 0.1 mmol) to the reaction solution. Heat to 60 °C and react for 3 hours, then stop the reaction. Add 10 mL of ice water to the reaction solution, extract with ethyl acetate, dry to anhydrous sodium sulfate, concentrate, and separate the crude product by flash reversed column chromatography (column: C18; CH3CN / H2O, 1 / 1) to obtain compound P1-3 (29 mg), yield: 50%. LCMSESI-MS m / z: 1098 [M+H] + .

[0361] Step 4: Hydrogen gas (10 atm). Dissolve compound P1-3 (29 mg, 0.026 mmol) from the previous step in 2 mL of methanol, add carbon-activated Pd(OH)2 (29 mg), and react the mixture at room temperature under a hydrogen atmosphere for 4 hours. Filter. Remove the solvent under reduced pressure to give a pale yellow solid P1-4 (23 mg), yield: 88%. LCMS ESI-MS m / z: 1008 [M+H] + .

[0362] Step 5: Dissolve compound P1-4 (23 mg, 0.023 mmol) from the previous step in 1 mL of a 1,4-dioxane solution of hydrogen chloride (4 M) in an ice bath. React at room temperature for 1 hour, then stop the reaction. Remove the solvent under reduced pressure to obtain the crude compound P1-5 (23 mg). LCMS ESI-MS m / z: 908 [M+H] + .

[0363] Step 6: Dissolve compound P1-5 (23 mg, 0.023 mmol) and DIEA (6.5 mg, 0.05 mmol) from the previous step in 1 mL of LDM. Add HATU (19 mg, 0.05 mmol) to the reaction solution and react at room temperature for 3 hours. Then stop the reaction. Add 10 mL of ice water to the reaction solution, extract with ethyl acetate, dry to anhydrous sodium sulfate, concentrate, and separate the crude product by preparative HPLC to obtain the target compound P1 (5.3 mg), yield: 26%. LCMS ESI-MS m / z: 890 [M+H] + .

[0364] 1H NMR (400MHz, CD3OD) δ8.39(d,J=2.6Hz,1H),7.92(s,1H),7.46-7.42(m,1H),7.37-7.30(m,2H),7.25( d,J=2.6Hz,1H),7.14-7.10(m,1H),5.70-5.64(m,1H),4.63-4.57(m,1H),4.50-4.42(m,2H),4.37(br d,J=6.2Hz,1H),4.29-4.17(m,3H),3.92(br d,J=11.1Hz,1H),3.83-3.75(m,2H),3.66-3.61(m,2H),3.60-3.55(m,1H),3.49-3.43(m, 1H),3.14-3.04(m,2H),3.02-2.94(m,1H),2.89-2.84(m,2H),2.83-2.75(m,1H),2.64(br d,J=5.2Hz,4H),2.50-2.41(m,2H),2.36(s,3H),2.31-2.26(m,1H),2.23-2.17(m,2H),2.06-1.95(m,2H),1.91-1.83(m,1H),1.72(br d,J=7.0Hz,3H),1.61-1.50(m,3H),1.43(d,J=6.2Hz,3H),1.32-1.26(m,3H),1.18-1.11(m,1H),0.96(br d,J=2.6Hz,3H),0.88(d,J=6.6Hz,3H),0.57(s,3H).

[0365] Example 3:

[0366] Synthesis of target molecule P2-P5

[0367]

[0368] Step 1: Dissolve compound P1-2 (120 mg, 0.14 mmol) in 2 mL of 1,4-dioxane in an ice bath. Add 4 mL of a 2 M solution of 1,4-dioxane containing hydrogen chloride to the reaction solution. React at room temperature for 2 hours, then stop the reaction. Remove the solvent under reduced pressure to obtain compound P2-1 (105 mg), yield: 99%. LCMS ESI-MS m / z: 750.4 [M+H] + .

[0369] Step 2: Dissolve compound P2-1 (120 mg, 0.16 mmol) and DIEA (410 mg, 3.2 mmol) in 15 mL of DMF in an ice bath. Add intermediate b7 (98 mg, 0.19 mmol) and condensation reagent COMU (100 mg, 0.24 mmol) to the reaction solution. React in an ice bath for 1 hour, then stop the reaction. Add 20 mL of ice water to the reaction solution, extract with ethyl acetate, dry to anhydrous sodium sulfate, concentrate, and separate the crude product by TLC (DCM / MeOH, 10 / 1) to obtain compound P2-2 (87 mg, Purity: 99%), yield: 43%. LCMS ESI-MS m / z: 623.2 [M / 2+H] + .

[0370] Step 3: Using hydrogen gas (10 atm), dissolve compound P2-2 (87 mg, 0.07 mmol) from the previous step in 5 mL of anhydrous DMF, add K2CO3 (97 mg, 0.7 mmol), and heat the mixture to 80 °C for 4 hours. Filter. Add 30 mL of water to the reaction solution, extract with ethyl acetate, dry to anhydrous sodium sulfate, and remove the solvent under reduced pressure. Separate the crude product by TLC (DCM / MeOH, 10 / 1) to give a pale yellow solid P2-3 (50 mg), yield: 67%. LCMS ESI-MS m / z: 1072.6 [M+H] + .

[0371] Step 4: Ice bath. Dissolve compound P2-3 (50 mg, 0.047 mmol) from the previous step in 3 mL of dichloromethane, add 1 mL of trifluoroacetic acid dropwise, and react at room temperature for 1 hour. Stop the reaction. Remove the solvent under reduced pressure to obtain crude compound P2 (44 mg). Compound P2 was separated by high-performance preparative HPLC (column: Boston Prime C18 150*30 mm*5 μm; mobile phase A: H2O (0.04% HCl); mobile phase B: CH3CN; flow rate: 25.00 mL / min) to obtain target molecules P2a (2.44 mg) and P2b (8.89 mg). LCMS ESI-MS m / z: 486.8 [M / 2+H] + .

[0372] P2a 1H NMR(400MHz,CD3OD)δ8.44-8.38(m,1H),7.85(s,1H),7.44(d,J=2.7Hz,1H),7.34(br d,J=9.2Hz,2H),7.18(s,1H),6.60(s,1H),5.50-5.43(m,1H),4.67-4.56(m,3H),4.42(br dd,J=7.0,12.8Hz,3H),4.32-4.12(m,4H),3.89-3.82(m,2H),3.82-3.77(m,1H),3.98-3.76(m,2H),3.66-3.55(m,3H),3.26(s,3H),3.22-3.12(m,3H),3.09-2.97(m,6H),2.92(s,3H),2.64(br d,J=4.6Hz,4H),2.36(s,4H),2.29-2.21(m,4H),2.19-2.05(m,2H),1.98(br dd,J=3.8,8.5Hz,2H),1.89-1.79(m,1H),1.70-1.59(m,1H),1.16(br d,J=6.3Hz,3H),1.01-0.96(m,6H),0.87(br d,J=6.4Hz,3H).

[0373] P2b 1 H NMR(400MHz,CD3OD)δ8.40(d,J=2.9Hz,1H),7.86(s,1H),7.58-7.46(m,1H),7.39-7.28(m,2H),7.27-7.18(m,1H),6.78-6.63(m,1H),5.45(br d,J=9.9Hz,1H),5.08(br s,1H),4.66-4.44(m,3H),4.37-4.05(m,4H),3.95-3.42(m,6H),3.34(br d,J=4.1Hz,4H),3.19-2.90(m,9H),2.89-2.77(m,4H),2.68-2.61(m,6H),2.41-2.34(m,3H),2.28-2.17(m,4H),2.02-1.95(m,1H),1.92-1.76(m,2H),1.73-1.61(m,1H),1.51-1.41(m,3H),0.98-0.92(m,3H),0.89-0.75(m,6H),0.74-0.54(m,3H).

[0374]

[0375] Procedure: Compound P2 (23 mg, 0.023 mmol) and DIEA (59 mg, 0.46 mmol) were dissolved in 3 mL of dichloromethane. 2-fluoroisobutyric acid P3-1 (5 mg, 0.046 mmol) and condensation reagent COMU (15 mg, 0.035 mmol) were added to the reaction solution. The reaction was carried out at room temperature for 1 hour, then stopped. 10 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude P3 was separated by preparative HPLC (column: Boston Prime C18 150*30 mm*5 μm; mobile phase A: H2O (0.04% HCl); mobile phase B: CH3CN; flow rate: 25.00 mL / min), yielding target compounds P3a (4.23 mg) and P3b (14.88 mg), yield: 26%. LCMS ESI-MS m / z: 531.1 [M / 2+H] + .

[0376] P3a 1H NMR(400MHz,CD3OD)δ8.39(d,J=2.6Hz,1H),7.90(s,1H),7.45(br d,J=2.1Hz,2H),7.40(s,1H),7.27(s,1H),6.62(br s,1H),5.61(br d,J=10.5Hz,1H),4.64-4.57(m,2H),4.53-4.41(m,3H),4.30-4.23(m,2H),4.21-4.15(m,1H),4.00-3.93(m,1H),3.90(br d,J=10.3Hz,1H),3.78(br d,J=10.8Hz,1H),3.68-3.54(m,3H),3.49-3.40(m,4H),3.19(br d,J=14.8Hz,1H),3.10-2.94(m,4H),2.90-2.79(m,3H),2.75(s,3H),2.71-2.59(m,5H),2.36(s,5H),2.31-2.25(m,1H),2.23-2.17(m,2H),2.23-2.08(m,2H),2.04-1.95(m,2H),1.90-1.76(m,3H),1.70(br dd,J=1.5,11.0Hz,1H),1.65(br d,J=8.9Hz,3H),1.60(br d,J=7.6Hz,3H),1.32(br s,1H),1.13(br d,J=6.2Hz,3H),1.00(s,3H),0.93(br d,J=6.3Hz,3H),0.81(br d,J=6.4Hz,3H),0.61(s,3H).

[0377] P3b 1H NMR(400MHz,CD3OD)δ8.40(d,J=2.6Hz,1H),7.91(s,1H),7.65-7.56(m,1H),7 .54-7.34(m,2H),7.30-7.19(m,1H),6.79-6.61(m,1H),6.21(s,1H),5.54(br d,J=10.8Hz,1H),5.20-5.16(m,1H),4.75(br d,J=11.1Hz,1H),4.63-4.43(m,3H),4.34-4.20(m,2H),4.13-3.96(m,2H),3.90-3.81(m,1H),3.74-3.55(m,4H),3.39-3.33 (m,5H),3.17-2.96(m,6H),2.94-2.82(m,3H),2.75-2.56(m,6H),2.36(d,J=2.9Hz,3H),2.30(td,J=4.2,8.7Hz,2H),2.18(br d,J=12.5Hz,2H),2.10-1.93(m,3H),1.87-1.72(m,3H),1.67-1.44(m,10H),0.96-0.56(m,12H).

[0378] Following the synthetic routes of compounds P2 or P3, and using similar starting materials / intermediates, the following target molecules were synthesized:

[0379]

[0380] Synthesis of target molecule P6

[0381]

[0382] Step 1: Under nitrogen protection in an ice bath, the starting material P6-1 (54.0 mg, 0.23 mmol) and the condensation reagent COMU (100.0 mg, 0.24 mmol) were dissolved in 3 mL of DMF. DIEA (700.0 mg, 5.4 mmol) was slowly added dropwise, and the mixture was stirred for 10 minutes. Then, a 2 mL solution of DMF containing compound P2-1 (135.0 mg, 0.18 mmol) was slowly added dropwise. The mixture was reacted at room temperature for 1 hour, and then the reaction was stopped. 20 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by TLC (DCM / MeOH, 10 / 1) to obtain compound P6-2 (114.0 mg), yield: 66%. LCMSESI-MS m / z: 963.5 [M+H] + .

[0383] 1H NMR (400MHz, CDCl3) δ8.47(d,J=2.7Hz,1H),7.91(s,1H),7.40(s,1H),7.25-7.22(m,2H),7.17-7.14(m,1H),7.02(br s,1H),6.26(s,1H),6.01(br d,J=9.4Hz,1H),5.80-5.71(m,1H),4.66-4.57(m,1H),4.43-4.39(m,1H),4.32-4.24(m,1H),4.11-4.03(m,3H),3.95-3.87(m ,1H),3.84-3.78(m,1H),3.75-3.70(m,2H),3.60-3.52(m,1H),3.50(s,1H),3.42-3.38(m,3H),3.17(q,J=7.4Hz,3H),3.04(br d,J=6.8Hz,3H),2.98-2.94(m,3H),2.89(s,1H),2.79(br s,8H),2.66(s,3H),2.50(s,3H),2.36(s,1H),1.64(s,9H),1.55(br d,J=7.0Hz,3H),1.45(br d,J=6.0Hz,6H),0.93(s,3H).

[0384] Step 2: Under nitrogen protection, compound P6-2 (30.0 mg, 0.031 mmol) and intermediate b8 (50.0 mg, 0.25 mmol) from the previous step were dissolved in 1.5 mL of toluene. Tributyl cyanomethylene phosphate (CMBP, 60.0 mg, 0.25 mmol) was added. The mixture was heated to 90 °C using microwave for 1.5 hours, and then the reaction was stopped. The mixture was filtered, and the solvent was removed by vacuum distillation. The crude product was separated by TLC (DCM / MeOH, 10 / 1) to give a yellow solid P6-3 (30.0 mg), yield: 84%. LCMSESI-MS m / z: 1146.0 [M+H] + .

[0385] Step 3: The compound P6-3 (35.0 mg, 0.031 mmol) from the previous step was dissolved in 2 mL of dichloromethane in an ice bath. 1 mL of trifluoroacetic acid (TFA) was added dropwise, and the reaction was carried out at room temperature for 2 hours. The reaction was then stopped. The solvent was removed by vacuum distillation to obtain the crude compound P6-4 (30.0 mg), yield: 99%. LCMS ESI-MS m / z: 989.5 [M+H] + .

[0386] Step 4: Under nitrogen protection in an ice bath, dissolve compounds P6-4 (47.2 mg, 0.047 mmol) and COMU (35.5 mg, 0.088 mmol) from the previous step in 6 mL of DMF. Add DIEA (122.0 mg, 0.95 mmol) to the reaction solution. React the mixture at room temperature for 16 hours, then stop the reaction. Add 10 mL of ice water to the reaction solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, concentrate, and separate the crude P6 by HPLC preparative chromatography (column: Boston Prime C18 150*30 mm*5 μm; mobile phase A: H2O (0.065% TFA); mobile phase B: CH3CN; flow rate: 25.00 mL / min) to obtain target compounds P6a (1.26 mg, Purity: 87.80%) and P6b (4.5 mg, Purity: 99.6%), yield: 12%. LCMS ESI-MS m / z: 971.6 [M+H] + .

[0387] P6a 1 H NMR (400MHz, CD3OD) δ8.42(d,1H,J=2.7Hz),7.95(s,1H),7.46(d,1H,J=2.7Hz),7.38(d,2H,J=10.3Hz),7.19(s,1H),6.6 5(s,1H),5.4-5.5(m,1H),4.1-4.6(m,6H),3.8-4.1(m,3H),3.5-3.6(m,1H),3.3-3.4(m,3H),3.28(s,3H),2.9-3.2(m,5H) ,2.8-2.9(m,5H),2.6-2.7(m,4H),2.4-2.6(m,3H),2.39(s,4H),2.2-2.4(m,4H),2.1-2.2(m,4H),1.8-2.1(m,4H),1.6-1 .7(m,1H),1.2-1.6(m,1H),1.17(d,3H,J=6.2Hz),1.02(s,3H),0.97(d,3H,J=6.4Hz),0.93(d,3H,J=6.7Hz),0.64(s,3H).

[0388] P6b 1H NMR (400MHz, CD3OD) δ8.39 (d, J=2.9Hz, 1H), 7.89 (s, 1H), 7.37 (br d,J=13.4Hz,2H),7.27(d,J=2.9Hz,1H),7.16(s,1H),6.65(s,1H),5.41-5.34(m,1H),4.96(brd,J=12.5Hz,1H ),4.51-4.42(m,1H),4.40-4.15(m,5H),3.88(d,J=11.1Hz,1H),3.81-3.75(m,1H),3.67-3.56(m,1H),3.34(br s,4H),3.28(s,3H),3.12-3.05(m,1H),3.04-2.78(m,5H),2.76(s,3H),2.70-2.59(m,5H),2.54-2.40(m,3H),2.36(s,3H),2.32-2.16(m ,4H),2.14-2.02(m,3H),2.00-1.80(m,3H),1.79-1.70(m,1H),1.43(d,J=6.2Hz,3H),1.37-1.29(m,1H),0.96-0.86(m,9H),0.60(s,3H).

[0389] Synthesis of target molecule P7

[0390]

[0391] Step 1: The above compound P1-2 (240.0 mg, 0.28 mmol) was dissolved in 4 mL of dichloromethane in an ice bath. TEA (85.0 mg, 0.84 mmol) and trifluoromethanesulfonic anhydride (Tf₂O, 237.0 mg, 0.84 mmol) were added sequentially. The mixture was reacted at 0-20 °C for 15 hours, then the reaction was stopped. 10 mL of ice water was added to the reaction solution, followed by extraction with dichloromethane, drying over anhydrous sodium sulfate, and concentration. The crude product was separated by TLC (DCM / MeOH, 7 / 1) to obtain compound P7-1 (90.0 mg), yield: 32%. LCMS ESI-MS m / z: 982.4 [M+H] + .

[0392] Step 2: Under nitrogen protection, compound P7-1 (179.0 mg, 0.18 mmol) and starting material P7-2 (71.77 mg, 0.40 mmol) from the previous step were dissolved in 4 mL of toluene. Then, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (Xantphos, 20.83 mg, 0.036 mmol), palladium acetate (4.04 mg, 0.018 mmol), and cesium carbonate (129.02 mg, 0.40 mmol) were added sequentially. The mixture was reacted at 80 °C for 15 hours, and then the reaction was stopped. The mixture was filtered and concentrated to obtain crude compound P7-3 (180.0 mg), yield: 97%. LCMS ESI-MS m / z: 507.5 [M / 2+H] + .

[0393] Step 3: Dissolve compound P7-3 (100.0 mg, 0.099 mmol) from the previous step in 4 mL of THF aqueous solution (v / v, 1 / 1), add citric acid monohydrate (208.04 mg, 0.99 mmol), and react the mixture at 20 °C for 15 hours, then stop the reaction. Filter and concentrate the solution. The crude product is then separated by reversed-phase HPLC preparative chromatography (column: Boston Prime C18 150*30 mm*5 μm; mobile phase A: H2O (0.075% TFA); mobile phase B: CH3CN; flow rate: 25.00 mL / min) to obtain compound P7-4 (50.0 mg), yield: 60%. LCMS ESI-MS m / z: 849.5 [M+H] + .

[0394] Step 4: Ice bath. Compound P7-4 (50.0 mg, 0.059 mmol) and intermediate b9 (26.94 mg, 0.12 mmol) from the previous step were dissolved in 1 mL of methanol. Zinc chloride (6.84 mg, 0.059 mmol) and sodium cyanoborohydride (18.54 mg, 0.29 mmol) were added as catalysts. The mixture was reacted at room temperature for 1 hour, then the reaction was stopped. 1 mL of ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by thin-layer chromatography (TLC) (DCM / MeOH, 9 / 1) to remove most impurities, followed by preparative chromatographic separation by reversed-phase HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase A: H2O (0.075% TFA); mobile phase B: CH3CN; flow rate: 25.00 mL / min) to obtain compound P7-5 (10.8 mg), yield: 17%. LCMS ESI-MS m / z: 1062.2 [M+H] + .

[0395] Step 5: Dissolve compound P7-5 (10.8 mg, 0.010 mmol) from the previous step in 2 mL of dichloromethane in an ice bath. Add 1 mL of TFA dropwise and react at room temperature for 2 hours. Stop the reaction. Remove the solvent under reduced pressure to obtain crude compound P7-6 (8.0 mg), yield: 114%. LCMS ESI-MS m / z: 905.9 [M+H] + .

[0396] Step 6: Dissolve compound P7-6 (10.0 mg, 0.011 mmol) from the previous step in 1 mL of acetonitrile, and slowly add it dropwise to a 2 mL solution of acetonitrile containing COMU (7.72 mg, 0.027 mmol) and DIEA (9.03 mg, 0.11 mmol). React the mixture at room temperature for 10 minutes, then stop the reaction. Add 2 mL of ice water to the reaction solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, concentrate, and separate the crude P7 by HPLC preparative chromatography (column: Boston Prime C18 150*30 mm*5 μm; mobile phase A: H2O (0.075% TFA); mobile phase B: CH3CN; flow rate: 25.00 mL / min), yielding target compounds P7a (1.36 mg) and P7b (2.25 mg), yield: 37%. LCMS ESI-MS m / z: 888.0 [M+H] + .

[0397] P7a 1H NMR(400MHz,CD3OD)δ8.40(br d,J=2.3Hz,1H),7.87(s,1H),7.34(s,2H),7.31(s,1H),6.98(s,1H),6.44(s,1H),5.48(br d,J=11.0Hz,1H),5.36-5.33(m,1H),4.49(br dd,J=5.3,9.4Hz,1H),4.33-4.30(m,1H),4.16(br d,J=11.7Hz,1H),4.08-4.01(m,2H),4.01-3.95(m,2H),3.91-3.84(m,2H),3.81-3.75(m,3H),3.63-3.54(m,4H),3.14-3.11(m,3H),2.86(s,1H),2.64(br t,J=4.7Hz,5H),2.36(s,3H),2.24-2.17(m,4H),2.04(s,3H),1.46(br d,J=6.2Hz,3H),1.34(br s,3H),1.31-1.29(m,3H),1.09(d,J=6.1Hz,3H),0.96-0.90(m,3H),0.82-0.73(m,6H).

[0398] P7b 1 H NMR(400MHz,CD3OD)δ8.39(br d,J=2.7Hz,1H),7.89(s,1H),7.35(s,1H),7.28(br d,J=2.6Hz,1H),7.16(s,1H),6.97(s,1H),6.60(s,1H),5.55(br d,J=9.8Hz,1H),5.02-4.98(m,1H),4.51-4.46(m,1H),4.34(br d,J=6.3Hz,1H),4.19-4.10(m,3H),3.93-3.85(m,3H),3.77(br d,J=10.8Hz,2H),3.74-3.60(m,4H),3.46-3.41(m,3H),3.24(s,3H),2.92-2.85(m,3H),2.83-2.77(m,2H),2.66-2.60(m,5H),2.36(s,3H),2.22-2.16(m,3H),2.05-2.01(m,3H),1.56(br s,2H),1.44(br d,J=6.2Hz,3H),1.35-1.28(m,3H),1.13(br d,J=5.4Hz,3H),0.88(s,3H),0.64(s,3H).

[0399] Synthesis of target molecule P8

[0400]

[0401]

[0402] Step 1: Under nitrogen protection, the intermediate a36 (1.5 g, 3.05 mmol) and the starting material pinacol diborate (1.16 g, 4.57 mmol) were dissolved in 30 mL of toluene. Pd(dppf)Cl2 catalyst (330 mg, 0.46 mmol) was added. The mixture was reacted at 90 °C for 6 hours, and then the reaction was stopped. The reaction solution was cooled to room temperature and concentrated. The crude product was separated by flash column chromatography (nHex / EA, 3 / 2) to give compound P8-1 (1.5 g), yield: 91%. LCMS ESI-MS m / z: 539.3 [M+H] + .

[0403] 1 H NMR(400MHz,CD3OD)δ8.70(d,1H,J=2.4Hz),7.9-8.0(m,2H),7.32(s,1H),4.24(q,1H,J =6.2Hz),3.90(ddd,1H,J=3.7,8.5,12.2Hz),3.7-3.8(m,1H),3.26(s,1H),3.1-3.2(m,1 H),3.0-3.0(m,2H),2.92(s,3H),2.79(d,1H,J=14.1Hz),2.2-2.4(m,2H),2.1-2.2(m,1H ), 2.00 (d, 1H, J = 9.9Hz), 1.48 (d, 3H, J = 6.3Hz), 1.37 (s, 12H), 0.81 (s, 3H), 0.70 (s, 3H).

[0404] Step 2: Under nitrogen protection, compound P8-1 (75 mg, 0.10 mmol) and intermediate d1 (59.28 mg, 0.11 mmol) from the previous step were dissolved in 5 mL of a mixed solution of toluene, 1,4-dioxane, and water (v / v / v, 3 / 1 / 1). Potassium phosphate (42.45 mg, 0.20 mmol) and catalyst Pd(dtBPF)Cl2 (6.52 mg, 0.010 mmol) were added. The mixture was heated to 70 °C and reacted for 4 hours, after which the reaction was stopped. 10 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by TLC (DCM / MeOH, 19 / 1) to give compound P8-2 (65.0 mg), yield: 63%. LCMS ESI-MS m / z: 1026.5 [M+H] + .

[0405] Step 3: Ice bath. Dissolve intermediate P8-2 (65.0 mg, 0.063 mmol) from the previous step in 4 mL of tetrahydrofuran aqueous solution (v / v, 3 / 1). Add lithium hydroxide (8.0 mg, 0.19 mmol). React the mixture at 0 °C for 1.5 hours, then stop the reaction. Adjust the pH of the reaction solution to approximately 4 with dilute hydrochloric acid. Extract with a dichloromethane / methanol mixture (v / v, 10 / 1), dry over anhydrous sodium sulfate, and concentrate to obtain compound P8-3 (60.0 mg), yield: 94%. LCMS ESI-MS m / z: 507.3 [M / 2+H] + .

[0406] Step 4: Under nitrogen protection, in an ice bath, dissolve compound P8-3 (60.0 mg, 0.059 mmol) and DIEA (0.046 g, 0.35 mmol) from the previous step in 12 mL of dichloromethane. Add EDCI (51.0 mg, 0.27 mmol) and HOBT (16.0 mg, 0.12 mmol). Slowly heat to room temperature and react for 16 hours, then stop the reaction. Add 20 mL of ice water to the reaction solution, extract with dichloromethane, dry to anhydrous sodium sulfate, and concentrate. Separate the crude product by TLC (DCM / MeOH, 10 / 1) to obtain compound P8-4 (44.0 mg), yield: 75%. LCMS ESI-MS m / z: 994.4 [M+H] + .

[0407] Step 5: Under nitrogen protection in an ice bath, compound P8-4 (44.0 mg, 0.044 mmol) and starting material P8-5 (27.54 mg, 0.22 mmol) from the previous step were dissolved in 5 mL of anhydrous tetrahydrofuran. Cesium carbonate (57.34 mg, 0.18 mmol) as a catalyst, 2-dicyclohexylphospho-2,4,6-triisopropylbiphenyl (X-Phos, 20.98 mg, 0.044 mmol) and palladium acetate (1.98 mg, 0.0088 mmol) were added. The mixture was heated to 65 °C and reacted for 4 hours, then the reaction was stopped. 15 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by TLC (DCM / MeOH, 10 / 1) to obtain compound P8-6 (32.0 mg), yield: 67%. LCMS ESI-MS m / z: 1084.1 [M+H] + .

[0408] Step 6: Dissolve compound P8-6 (32.0 mg, 0.030 mmol) from the previous step in 3 mL of dichloromethane in an ice bath. Add 1 mL of trifluoroacetic acid and react the mixture for 1 hour. Then stop the reaction. Remove the solvent under reduced pressure to obtain crude compound P8-7 (29.0 mg), yield: 99%. LCMS ESI-MS m / z: 983.7 [M+H] + .

[0409] Step 7: Under nitrogen protection, in an ice bath, dissolve compound P8-7 (42.0 mg, 0.042 mmol) and DIEA (93.0 mg, 0.72 mmol) from the previous step in 4 mL of dichloromethane. Add 2-fluoroisobutyric acid P3-1 (7.80 mg, 0.074 mmol) and condensation reagent COMU (27.64 mg, 0.064 mmol) to the reaction solution. React at 0 °C for 1 hour, then stop the reaction. Add 10 mL of ice water to the reaction solution, extract with dichloromethane, dry with anhydrous sodium sulfate, concentrate, and separate the crude P8 by HPLC preparative chromatography (column: Boston Prime C18 150*30 mm*5 μm; mobile phase A: H2O (0.04% HCl); mobile phase B: CH3CN; flow rate: 25.00 mL / min) to obtain target compounds P8a (2.1 mg) and P8b (8.26 mg), yield: 22%. LCMS ESI-MS m / z: 1071.7 [M+H] + .

[0410] P8a 11H NMR (400 MHz, CD3OD) δ 8.76 (d, J = 2.0 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.92 (s, 1H), 7.41 (br d, J = 4.6 Hz, 2H), 7.16 (s, 1H), 6.60 (s, 1H), 5.73 (br d, J = 9.5 Hz, 1H), 4.73 - 4.64 (m, 1H), 4.60 (s, 1H), 4.59 - 4.53 (m, 1H), 4.44 (br dd, J = 1.6, 12.5 Hz, 1H), 4.34 - 4.29 (m, 2H), 4.29 - 4.21 (m, 2H), 4.16 (dd, J = 5.5, 11.1 Hz, 1H), 3.99 - 3.93 (m, 1H), 3.90 (brd, J = 10.7 Hz, 1H), 3.74 (br t, J = 4.6 Hz, 5H), 3.60 (s, 3H), 3.22 (s, 1H), 3.10 - 3.01 (m, 2H), 2.97 - 2.76 (m, 4H), 2.71 - 2.63 (m, 4H), 2.37 - 2.25 (m, 2H), 2.23 - 2.17 (m, 2H), 2.01 - 1.92 (m, 3H), 1.67 - 1.58 (m, 7H), 1.35 - 1.26 (m, 8H), 1.15 (d, J = 6.4 Hz, 3H), 1.00 (s, 3H), 0.95 - 0.88 (m, 6H), 0.57 (s, 3H).

[0411] P8b 1 1H NMR (400 MHz, CD3OD) δ 8.7 - 8.8 (m, 1H), 7.6 - 8.1 (m, 2H), 7.2 - 7.5 (m, 2H), 6.8 - 7.2 (m, 1H), 6.4 - 6.7 (m, 1H), 5.65 (d, 1H, J = 10.6 Hz), 5.0 - 5.2 (m, 1H), 4.6 - 4.8 (m, 2H), 4.1 - 4.5 (m, 6H), 3.8 - 4.1 (m, 2H), 3.7 - 3.8 (m, 4H), 3.5 - 3.7 (m, 5H), 3.17 (s, 3H), 3.0 - 3.1 (m, 2H), 2.6 - 2.9 (m, 8H), 2.1 - 2.4 (m, 4H), 1.8 - 2.4 (m, 5H), 1.6 - 1.8 (m, 6H), 1.4 - 1.5 (m, 4H), 1.2 - 1.4 (m, 1H), 0.8 - 1.0 (m, 9H), 0.69 (s, 2H), 0.52 (s, 1H).

[0412] Example 4:

[0413] The compound for KRAS G12DThe p-ERK-mediated inhibition assay (directly reflects the cellular-level inhibitory effect of the test compound). Details are as follows:

[0414] AGS cells cultured in F-12K medium (Gibco, Cat. No. 30-2004) containing 10% fetal bovine serum and 1% penicillin and streptomycin were seeded into 384-well microplates and incubated overnight at 37°C with 5% carbon dioxide. 200 nL of different concentrations of the compound (1000 nM starting concentration, 4-fold dilution) were added to each well and incubated at 37°C for 3 hours. The cells were then fixed in 8% fixative (Solarbio, Cat. No. P1112) and washed once with phosphate-buffered saline (PBS). After washing, blocking solution (LI-COR, Cat. No. 927-40000) was added to each well and the cells were blocked at room temperature for 1 hour. After removing the blocking solution, add phospho-p44 / 42MAPK(T202 / Y204) Rabbit mAb (CST, Cat. No. 4370S) and GAPDH(D4C6R) MousemAb (CST, Cat. No. 97166S) antibody working solutions to each well and incubate overnight at 4°C. Wash the microplate three times with PBS solution containing 0.1% Tween-80 (PBST), add IRDye 800CW Goat anti-Rabbit IgG (H+L) (LI-COR, Cat. No. 926-32211) and IRDye 680RD Goat anti-Mouse IgG (H+L) (LI-COR, Cat. No. 926-68070) antibody working solutions, and incubate the microplate at room temperature in the dark. After washing the microplate three times with PBST, the microplate was centrifuged at 1000 rpm for 1 minute, and the plate was scanned and the signal value was recorded using an Odyssey CLx (LI-COR) instrument.

[0415] IC 50 Calculation formula

[0416] Calculation of compound IC using nonlinear regression equations 50 Value: Y = Lower platform signal + (Upper platform signal - Lower platform signal) / (1 + 10^(LogIC)) 50 -X)*Hill slope)); X = logarithm of compound concentration.

[0417] Table 4.1 Target molecule for AGS (KRAS) G12D pERK inhibition effect in cells

[0418] Molecular numbering <![CDATA[pERK / IC 50 / nM]]> P1 <1000 P3b ～2000

[0419] ND = Untested

[0420] # = The absolute axial chiral configuration has not yet been determined; it is a mixture.

[0421] After testing, the molecules of this invention are effective against KRAS. G12D Mutated tumor cells have a good inhibitory effect and hold promise for inhibiting KRAS. G12D To achieve a better tumor suppression effect.

[0422] Example 5: Compounds for KRAS G12V Inhibition assay of p-ERK in mutant cells (directly reflects the cellular-level inhibitory effect of the test compound). Details are as follows:

[0423] SW620 cells cultured in DMEM medium (Gibco, Cat. No. 11995065) containing 10% fetal bovine serum and 1% penicillin were seeded into 384-well microplates and incubated overnight at 37°C with 5% carbon dioxide. 200 nL of different concentrations of the compound (1000 nM starting concentration, 4-fold dilution) were added to each well and incubated at 37°C for 3 hours. The cells were then fixed in 8% fixative (Solarbio, Cat. No. P1112) and washed once with phosphate-buffered saline (PBS). After washing, blocking solution (LI-COR, Cat. No. 927-40000) was added to each well and the cells were blocked at room temperature for 1 hour. After removing the blocking solution, add phospho-p44 / 42MAPK(T202 / Y204) Rabbit mAb (CST, Cat. No. 4370S) and GAPDH(D4C6R) Mouse mAb (CST, Cat. No. 97166S) antibody working solutions to each well and incubate overnight at 4°C. Wash the microplate three times with PBS solution containing 0.1% Tween-80 (PBST), add IRDye 800CW Goat anti-Rabbit IgG (H+L) (LI-COR, Cat. No. 926-32211) and IRDye 680RD Goat anti-Mouse IgG (H+L) (LI-COR, Cat. No. 926-68070) antibody working solutions, and incubate the microplate at room temperature in the dark. After washing the microplate three times with PBST, the microplate was centrifuged at 1000 rpm for 1 minute, and the plate was scanned and the signal value was recorded using an Odyssey CLx (LI-COR) instrument.

[0424] IC 50 Calculation formula

[0425] Calculation of compound IC using nonlinear regression equations 50 Value: Y = Lower platform signal + (Upper platform signal - Lower platform signal) / (1 + 10^(LogIC)) 50-X)*Hill slope)); X = logarithm of compound concentration.

[0426] Table 5.1 Target molecule for SW620 (KRAS) G12V pERK inhibition effect in cells

[0427] Molecular numbering <![CDATA[pERK / IC 50 / nM]]> P1 <50 P3b ～1500

[0428] ND = Untested

[0429] # = The absolute axial chiral configuration has not yet been determined; it is a mixture.

[0430] After testing, the molecules of this invention are effective against KRAS. G12v Mutated tumor cells have a good inhibitory effect and hold promise for inhibiting KRAS. G12v To achieve a better tumor suppression effect.

[0431] Example 6: Antiproliferative effect of the compound on KRAS mutant cell lines

[0432] Basic information:

[0433] The compound exhibits a 3D antiproliferative effect against the KRAS G12D-mutant pancreatic cancer HPAC cell line. Details are as follows:

[0434] Cell culture: HPAC pancreatic cancer cells were cultured in T75 culture flasks in RPMI 1640 medium containing 10% fetal bovine serum and 1% penicillin / streptomycin.

[0435] Cell culture: SW620 colorectal cancer cells were cultured in T75 culture flasks in RPMI 1640 medium containing 10% fetal bovine serum and 1% penicillin / streptomycin.

[0436] Experimental Procedure: Using a nanoliter pipetting system, 200 nL (1000 nM, 4-fold dilution) of the diluted test compound was added to a 384-well low-adsorption cell culture plate. After seeding the cells, the plate was incubated at 37°C in a 5% CO2 incubator for 3D. After co-incubating the test compound with the cells for 5 days, the solution was added to each well. The 3D reagent was used, and the luminescence value was read using an Envision multi-functional microplate reader (Perkin Elmer, catalog number Envision 2104). The light signal was directly proportional to the amount of ATP in the system, and the ATP content directly represented the number of viable cells in the system. Finally, the IC50 of the compound was obtained using a non-linear fitting formula with XLFIT software. 50 (Half-maximal inhibitory concentration).

[0437] Inhibition rate (%) = 100 × (Negative control average value - Compound reading) / (Negative control average value - Positive control average value)

[0438] Negative control: DMSO. Positive control: Culture medium.

[0439] Example 7: Liver microsomal stability experiment of the compound

[0440]

[0441] The liver microsomal stability of the compounds of this invention was studied. The test compounds were co-incubated with liver microsomes of different species with or without the addition of NADPH. The final concentrations of the test compounds, NADPH, and liver microsomes in the experimental system were 1 μM, 1 mM, and 0.5 mg / mL, respectively. The concentrations of the compounds in the supernatant at different time points (15, 30, 45, and 60 minutes) were measured, and pharmacokinetic parameters (e.g., clearance rate Cl) were calculated. int ).

[0442] Plot the logarithmic percentage of the test compound remaining relative to the reaction time, T 1 / 2 =0.693 / k, which is used as the half-life of the compound.

[0443] Some molecules of this invention exhibit good metabolic stability in human liver microsomes.

[0444] The above description, in conjunction with specific preferred embodiments, provides a further detailed explanation of the present invention. It should not be construed that the specific implementation of the present invention is limited to these descriptions. For those skilled in the art, various simple deductions or substitutions can be made without departing from the concept of the present invention, and all such modifications and substitutions should be considered within the scope of protection of the present invention.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof: in, X1 is selected from CH2, -CH(=C)H-, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe; X2 is selected from CH2, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -N(R) a )-C(O), -NHC(O)-N(Me)-, NMe, C 3-6 Cycloalkyl or C 4-7 Metacyclic group; wherein C 3-6 Cycloalkyl or C 4-7 The heterocyclic group can be optionally C 1-6 Alkyl, halogen, C 1-6 Further substitution with haloalkyl groups and 5-6-membered heteroaryl groups; X3 is selected from CH2, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe; X3 may optionally be further reacted with halogen or C 1-6 Alkyl substitution; Ring A1 is selected from phenyl or 5-6-membered heteroaryl groups; Ring A2 is selected from phenyl or 5-6-membered heteroaryl groups; R1 is selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups; L1 is selected from the following: -C(O)-, -C(S)-, O, S, NH, -NMe-, -C(O)NH, -NHC(O), -NHC(O)-N(Me)-C 1-6 Alkylene, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups; L2 is selected from the following groups: -C(O)-, -C(S)-, O, S, NH, -NMe-, -C(O)NH, -NHC(O), -NHC(O)-N(Me)-C 1-6 Alkylene, -CH2O-, -CH2S-, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 4-6 membered heterocyclic; L1 and L2 can form 3-6 membered cycloalkyl groups or 4-10 membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group may optionally be surrounded by one, two or three R groups. x replace; R x Selected from H, D, halogens, and -(CH2). p CN, -(CH2) p -OR a -(CH2) p -NH2、-C(O)R a -SR a -S(O)2R a -S(O)R a -S(O)2N(R) a (R) a '), -(CH2) p -C(O)OR a -(CH2) p -C(O)N(R a (R) a '), -(CH2) p -NHC(O)OR a -(CH2) p -OC(O)N(R a (R) a '), -O-phenyl-, -(CH2) p -Phenyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups; R a and R a 'Independently selected from H, -L-CN, -(CH2)' p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic groups, -LC 6-10 Aryl or -L-5-10 heteroaryl; R b Selected from H, D, halogen, -L-CN, -L-OR a or -LC(O)OR a ; R c Selected from H, D, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy or -LC 3-8 cycloalkyl; R d Selected from H, D, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl; or two R d Their atoms connect to form 4-6 membered rings; R e Selected from H, D, halogens, C 2-6 alkenyl, C 2-6 alkynyl group, -C 2-6 alkynyl-L-4-8-membered heterocyclic group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 cycloalkyl or -L-4-8 membered heterocyclic group; R e It can be further divided into 1 or 2 Rs x replace; R f Selected from H or C 1-6 alkyl; R g Selected from H or C 1-6 Alkyl; R f and R g Connecting the carbon atom to it can form a 3-6 membered cycloalkyl group; n is selected from 0, 1, 2, 3, 4, 5, or 6; p is selected from 0, 1, 2, 3, 4, 5, or 6; L is selected from bond, -C(O)-, -C(S)-, C 1-6 Alkylene or C 1-6 Halogenated alkyl groups.

2. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, having a structure of formula (II) or (III): in, X1 is selected from CH2, -CH(=C)H-, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe; X3 is selected from CH2, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe; X3 may optionally be further reacted with halogen or C 1-6 Alkyl substitution; Ring A1 is selected from phenyl or 5-6-membered heteroaryl groups; Ring A2 is selected from phenyl or 5-6-membered heteroaryl groups; R1 is selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups; L2 is selected from the following groups: -C(O)-, -C(S)-, O, S, NH, -NMe-, -C(O)NH, -NHC(O), -NHC(O)-N(Me)-C 1-6 Alkylene, -CH2O-, -CH2S-, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 4-6 membered heterocyclic; Ring B1 is absent or ring B1 is selected from 4-10 member heterocyclic groups, wherein the heterocyclic group is optionally surrounded by 1, 2 or 3 R groups. x replace; R x Selected from H, D, halogens, and -(CH2). p CN, -(CH2) p -OR a -(CH2) p -NH2、-C(O)R a -SR a -S(O)2R a -S(O)R a -S(O)2N(R) a (R) a '), -(CH2) p -C(O)OR a -(CH2) p -C(O)N(R a (R) a '), -(CH2) p -NHC(O)OR a -(CH2) p -OC(O)N(R a (R) a '), -O-phenyl-, -(CH2) p -Phenyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups; R a and R a 'Independently selected from H, -L-CN, -(CH2)' p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic groups, -LC 6-10 Aryl or -L-5-10 heteroaryl; R b Selected from H, D, halogen, -L-CN, -L-OR a or -LC(O)OR a ; R c Selected from H, D, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy or -LC 3-8 cycloalkyl; R d Selected from H, D, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl; or two R d Their atoms connect to form 4-6 membered rings; R e Selected from H, D, halogens, C 2-6 alkenyl, C 2-6 alkynyl group, -C 2-6 alkynyl-L-4-8-membered heterocyclic group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 cycloalkyl or -L-4-8 membered heterocyclic group; R e It can be further divided into 1 or 2 Rs x replace; n is selected from 0, 1, 2, 3, 4, 5, or 6; p is selected from 0, 1, 2, 3, 4, 5, or 6; L is selected from bond, -C(O)-, -C(S)-, C 1-6 Alkylene or C 1-6 Halogenated alkyl groups.

3. The compound of claim 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, having a structure of formula (II-1) or (III-1): in, X1 is selected from CH2, -CH(=C)H-, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe; X3 is selected from CH2, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe; X3 may optionally be further reacted with halogen or C 1-6 Alkyl substitution; Ring A1 is selected from phenyl or 5-6-membered heteroaryl groups; R1 is selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups; L2 is selected from the following groups: -C(O)-, -C(S)-, O, S, NH, -NMe-, -C(O)NH, -NHC(O), -NHC(O)-N(Me)-C 1-6 Alkylene, -CH2O-, -CH2S-, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 4-6 membered heterocyclic; Ring B1 is absent or ring B1 is selected from 4-10 member heterocyclic groups, wherein the heterocyclic group is optionally surrounded by one, two or three R groups. x replace; R x Selected from H, D, halogens, and -(CH2). p CN, -(CH2) p -OR a -(CH2) p -NH2、-C(O)R a -SR a -S(O)2R a -S(O)R a -S(O)2N(R) a (R) a '), -(CH2) p -C(O)OR a -(CH2) p -C(O)N(R a (R) a '), -(CH2) p -NHC(O)OR a -(CH2) p -OC(O)N(R a (R) a '), -O-phenyl-, -(CH2) p -Phenyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups; R a and R a 'Independently selected from H, -L-CN, -(CH2)' p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic groups, -LC 6-10 Aryl or -L-5-10 heteroaryl; R c Selected from H, D, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy or -LC 3-8 cycloalkyl; R e Selected from H, D, halogens, C 2-6 alkenyl, C 2-6 alkynyl group, -C 2-6 alkynyl-L-4-8-membered heterocyclic group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 cycloalkyl or -L-4-8 membered heterocyclic group; R e It can be further divided into 1 or 2 Rs x replace; p is selected from 0, 1, 2, 3, 4, 5, or 6; L is selected from bond, -C(O)-, -C(S)-, C 1-6 Alkylene or C 1-6 Halogenated alkyl groups.

4. The compound of claim 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, having a structure of formula (II-2) or (II-3): in, X1 is selected from CH2, -CH(=C)H-, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe; X3 is selected from CH2, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe; X3 may optionally be further reacted with halogen or C 1-6 Alkyl substitution; R1 is selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups; L2 is selected from the following groups: -C(O)-, -C(S)-, O, S, NH, -NMe-, -C(O)NH, -NHC(O), -NHC(O)-N(Me)-C 1-6 Alkylene, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 4-6 membered heterocyclic; R x Selected from H, D, halogens, and -(CH2). p CN, -(CH2) p -OR a -(CH2) p -NH2、-C(O)R a -SR a -S(O)2R a -S(O)R a -S(O)2N(R) a (R) a '), -(CH2) p -C(O)OR a -(CH2) p -C(O)N(R a (R) a '), -(CH2) p -NHC(O)OR a -(CH2) p -OC(O)N(R a (R) a '), -O-phenyl-, -(CH2) p -Phenyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups; R a and R a 'Independently selected from H, -L-CN, -(CH2)' p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic groups, -LC 6-10 Aryl or -L-5-10 heteroaryl; R e Selected from H, D, halogens, C 2-6 alkenyl, C 2-6 alkynyl group, -C 2-6 alkynyl-L-4-8-membered heterocyclic group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 cycloalkyl or -L-4-8 membered heterocyclic group; R e It can be further divided into 1 or 2 Rs x replace; p is selected from 0, 1, 2, 3, 4, 5, or 6; L is selected from bond, -C(O)-, -C(S)-, C 1-6 Alkylene or C 1-6 Halogenated alkyl groups.

5. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, having the structure of formula (IV): in, X1 is selected from CH2, -CH(=C)H-, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe; X3 is selected from CH2, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe; X3 may optionally be further reacted with halogen or C 1-6 Alkyl substitution; Ring A1 is selected from phenyl or 5-6-membered heteroaryl groups; Ring A2 is selected from phenyl or 5-6-membered heteroaryl groups; L1 is selected from the following: -C(O)-, -C(S)-, O, S, NH, -NMe-, -C(O)NH, -NHC(O), -NHC(O)-N(Me)-C 1-6 Alkylene, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Halogenated alkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclic groups; L2 is selected from the following groups: -C(O)-, -C(S)-, O, S, NH, -NMe-, -C(O)NH, -NHC(O), -NHC(O)-N(Me)-C 1-6 Alkylene, -CH2O-, -CH2S-, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 4-6 membered heterocyclic; L1 and L2 can form 3-6 membered cycloalkyl groups or 4-10 membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group may optionally be surrounded by one, two or three R groups. x replace; R x Selected from H, D, halogens, and -(CH2). p CN, -(CH2) p -OR a -(CH2) p -NH2、-C(O)R a -SR a -S(O)2R a -S(O)R a -S(O)2N(R) a (R) a '), -(CH2) p -C(O)OR a -(CH2) p -C(O)N(R a (R) a '), -(CH2) p -NHC(O)OR a -(CH2) p -OC(O)N(R a (R) a '), -O-phenyl-, -(CH2) p -Phenyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups; R a and R a 'Independently selected from H, -L-CN, -(CH2)' p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic groups, -LC 6-10 Aryl or -L-5-10 heteroaryl; R b Selected from H, D, halogen, -L-CN, -L-OR a or -LC(O)OR a ; R c Selected from H, D, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy or -LC 3-8 cycloalkyl; R d Selected from H, D, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl; or two R d Their atoms connect to form 4-6 membered rings; R e Selected from H, D, halogens, C 2-6 alkenyl, C 2-6 alkynyl group, -C 2-6 alkynyl-L-4-8-membered heterocyclic group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 cycloalkyl or -L-4-8 membered heterocyclic group; R e It can be further divided into 1 or 2 Rs x replace; n is selected from 0, 1, 2, 3, 4, 5, or 6; p is selected from 0, 1, 2, 3, 4, 5, or 6; L is selected from bond, -C(O)-, -C(S)-, C 1-6 Alkylene or C 1-6 Halogenated alkyl groups.

6. The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, having the structure of formula (IV-1): in, X1 is selected from CH2, -CH(=C)H-, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe; X3 is selected from CH2, O, S, SO2, S(O), NH, -C(O)NH, -NHC(O), -NHC(O)-N(Me)- or NMe; X3 may optionally be further reacted with halogen or C 1-6 Alkyl substitution; L1 is selected from the following: -C(O)-, -C(S)-, O, S, NH, -NMe-, -C(O)NH, -NHC(O), -NHC(O)-N(Me)-C 1-6 Alkylene, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Halogenated alkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclic groups; L2 is selected from the following groups: -C(O)-, -C(S)-, O, S, NH, -NMe-, -C(O)NH, -NHC(O), -NHC(O)-N(Me)-C 1-6 Alkylene, -CH2O-, -CH2S-, C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 4-6 membered heterocyclic; L1 and L2 can form 3-6 membered cycloalkyl groups or 4-10 membered heterocyclic groups, wherein the cycloalkyl or heterocyclic group may optionally be surrounded by one, two or three R groups. x replace; R x Selected from H, D, halogens, and -(CH2). p CN, -(CH2) p -OR a -(CH2) p -NH2、-C(O)R a -SR a -S(O)2R a -S(O)R a -S(O)2N(R) a (R) a '), -(CH2) p -C(O)OR a -(CH2) p -C(O)N(R a (R) a '), -(CH2) p -NHC(O)OR a -(CH2) p -OC(O)N(R a (R) a '), -O-phenyl-, -(CH2) p -Phenyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic groups; R a and R a 'Independently selected from H, -L-CN, -(CH2)' p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic groups, -LC 6-10 Aryl or -L-5-10 heteroaryl; R b Selected from H, D, halogen, -L-CN, -L-OR a or -LC(O)OR a ; R d Selected from H, D, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl; or two R d Their atoms connect to form 4-6 membered rings; R e Selected from H, D, halogens, C 2-6 alkenyl, C 2-6 alkynyl group, -C 2-6 alkynyl-L-4-8-membered heterocyclic group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -LC 3-8 cycloalkyl or -L-4-8 membered heterocyclic group; R e It can be further divided into 1 or 2 Rs x replace; n is selected from 0, 1, 2, 3, 4, 5, or 6; p is selected from 0, 1, 2, 3, 4, 5, or 6; L is selected from bond, -C(O)-, -C(S)-, C 1-6 Alkylene or C 1-6 Halogenated alkyl groups.

7. A compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein the compound is selected from:

8. Use of any compound of claims 5-7 or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof in the preparation of a medicament for the treatment and / or prevention of RAS-mediated diseases.

9. The use of claim 8 or the compounds of claims 5-7, wherein the RAS-mediated disease is cancer, preferably, the cancer is selected from: colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), non-small cell lung cancer (NSCLC), or pancreatic cancer, etc.

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