Spiro compound as KRAS mutant inhibitor

Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof as a KRAS mutant inhibitor. The present invention also provides a pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and a use in treating cancer.

Description

Spirocyclic compounds as inhibitors of KRAS mutants Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to KRAS mutant inhibitors, more specifically compounds of formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers or stereoisomers thereof, and pharmaceutical compositions thereof, as well as their use in treating cancer. Background Art

[0002] The human RAS gene family includes three types of RAS genes, KRAS, NRAS, and HRAS, which encode four different RAS proteins (KRAS-4A, KRAS-4B, NRAS, and HRAS). RAS proteins belong to the GTPase protein family. When bound to GDP, they are in an inactive state, and when bound to GTP, they are in an active state, which can lead to the activation of downstream RAF-MAPK, PI3K-Akt and other signaling pathways, resulting in cell resistance to apoptosis and proliferation (Nat Rev Drug Discov, 2020; 19(8): 533-552.). Activating mutations of RAS genes are the most common oncogenic driver genes in human cancers, among which KRAS is the most common oncogenic activating mutation. For example, the mutation rate of KRAS in pancreatic cancer is 86-96%, in colorectal cancer is 40-54%, and in lung cancer is 27-39% (PNAS, 2019; 116(32): 15823-15829; Nature, 2014; 511, 543–550).

[0003] Oncogenic driver mutations can occur at multiple sites in the KRAS gene. The most common mutations occur at the G12 site, including G12C, G12D, G12V, etc. These mutations can reduce the GTPase activity of the KRAS protein, thereby causing the KRAS protein to be active for a long time, leading to malignant transformation of cells and the occurrence of cancer (Cell, 2017; 170(1): 17-33; Nat Rev Drug Discov, 2020; 19(8): 533-552). The types of KRAS mutations that frequently occur vary in different cancer types. For example, approximately 13% of lung cancer patients have G12C mutations (N Engl Med J, 2021; 384(25): 2382-2393); in pancreatic cancer, 33.8% of patients have G12D mutations and 40% of patients have G12V mutations, but only 1.7% of patients have G12C mutations; in colorectal cancer, approximately 10-12% of patients have G12D mutations, while the incidence of G12C mutations is less than 3% (Nat Rev Cancer 2018; 18(12): 767-777).

[0004] Unlike ATP-dependent protein kinases (proteins with micromolar affinity for ATP), KRAS proteins have picomolar affinity for GDP / GTP, making it difficult for compound molecules to effectively compete with GDP / GTP to inhibit the KRAS signaling pathway. This has seriously hindered the development of KRAS inhibitors (Nat Rev Drug Discov, 2020; 19(8): 533-552.). In recent years, non-GDP / GTP-competing "allosteric" binding cavities have been discovered on the KRAS protein that can effectively bind to small molecules. These findings have greatly promoted the development of targeted drugs targeting KRAS mutation-driven tumors. Currently, MRTX-849 (Adagrasib) and AMG510 (Sotorasib) targeting 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 been successfully approved by the FDA for marketing. Compared with the development of KRAS G12C drugs, the development of drugs targeting KRAS G12D, G13D, G12V, G12R and other mutations is still in the early stages, and only a few molecules have entered the clinic. The development of inhibitors targeting KRASG12V or pan-KRAS inhibitors will greatly meet clinical needs. Summary of the Invention

[0005] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0006] in,

[0007] Z is selected from O, S, NH or CH2;

[0008] X1 is selected from CH or N;

[0009] X2 is selected from CH or N;

[0010] R is selected from 4-12 membered heterocyclic groups,

[0011] R1 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl;

[0012] R2 is C 3-8 Cycloalkyl or 3-12 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4, 5 or 6 R xreplace;

[0013] Ring A is selected from 5-12 membered heterocyclyl or 5-14 membered heteroaryl, which is optionally substituted by 1-10 R b replace;

[0014] Ring B is absent or is selected from a 5-12 membered heterocyclyl or a 5-14 membered heteroaryl, which is optionally substituted by 1-10 R b replace;

[0015] R x Selected from H, D, halogen, -(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 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic group; and R x Optionally further substituted with 1, 2, 3, 4, 5 or 6 halogen, ═CH 2 , ═CHF or ═CF 2 ;

[0016] or two R on the same atom x Together they form =CH2, =CHF or =CF2;

[0017] R b Selected from H, -(CH2) p -halogen, -(CH2)p -CN, -(CH2) p -OH, -(CH2) p -NH2、-LC(O)R a 、-LC(O)OR a 、-LC(O)N(R a )(R a '),-NHC(O)OR a 、-(CH2) p -OR a 、-(CH2) p -SR a 、-LS(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10 aryl or -L-5-10 membered heteroaryl; and R b Optionally further 1, 2, 3, 4, 5 or 6 R c replace;

[0018] or two R on the same atom b Together they form =O, =S, =NH, =CH2, =CHF or =CF2;

[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 Haloalkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10 aryl or -L-5-10 membered heteroaryl; and R a and R a 'optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, CN, -(CH2) p -OH, -(CH2) p -NH2, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution;

[0020] p is selected from 0, 1, 2, 3, 4, 5 or 6;

[0021] R c Selected from H, D, halogen, OH, NH2, -L-CN, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2N(R a )(R a '), C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; and R c Optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, -L-CN, OH, NH2, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution;

[0022] or two R on the same atom c Together they form =O, =S or =NH;

[0023] L is selected from a bond, -C(O)-, -C(S)-, C 1-6 Alkylene or C 1-6 haloalkylene;

[0024] Each of the radical definitions recited is optionally substituted with 1, 2, 3, 4, 5 or more D, up to full deuteration.

[0025] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, and optionally a pharmaceutically acceptable excipient.

[0026] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, and further comprising another therapeutic agent.

[0027] In another aspect, the present invention provides use of the compound of the present invention in the preparation of a medicament for treating and / or preventing diseases mediated by KRAS or a mutant thereof.

[0028] In another aspect, the present invention provides a method for treating and / or preventing a disease mediated by KRAS or a mutant thereof in a subject, comprising administering to the subject a compound or composition of the present invention.

[0029] In another aspect, the present invention provides a compound of the present invention or a composition of the present invention for use in treating and / or preventing diseases mediated by KRAS or a mutant thereof.

[0030] In a specific embodiment, the disease treated by the present invention is cancer, for example, a cancer selected from the group consisting of colorectal cancer (eg, colon cancer, rectal cancer, large intestine adenocarcinoma), non-small cell lung cancer (NSCLC), or pancreatic cancer.

[0031] Other objects and advantages of the present invention will be apparent to those skilled in the art from the following detailed description, examples and claims.

[0032] definition

[0033] Chemical definition

[0034] Definitions of specific functional groups and chemical terms are described in more detail below.

[0035] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" includes C1, C2, C3, C4, C5, C6, C 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.

[0036] “C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl and C 1-2 Alkyl groups are preferred. 1-6 Examples 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 1-6"Alkyl" also includes heteroalkyl groups in which 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 with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0037] “C 2-6 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl is preferred. 2-6 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. The term "C 2-6 "Alkenyl" also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). An alkenyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0038] “C 2-6 "Alkynyl" refers to a straight or branched chain 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 Alkynyl is preferred. 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), pentynyl (C5), hexynyl (C6), and the like. The term "C 2-6 "Alkynyl" also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups can be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0039] “C 1-6 "Alkylene" refers to the removal of C 1-6 In some embodiments, C 1-4 Alkylene, C 2-4Alkylene and C 1-3 Alkylene is preferred. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylenes, for example, alkylenes 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 propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0040] “C 1-6 "Haloalkylene" refers to the removal of C 1-6 The other hydrogen of the haloalkyl group is replaced to form a divalent group, and the group may be substituted or unsubstituted.

[0041] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0042] Therefore, “C 1-6 "Haloalkyl" refers to the above-mentioned "C 1-6 Alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-4 Halogenated alkyl is particularly preferred, more preferably C 1-2 Haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. The haloalkyl group can be substituted at any available point of attachment, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0043] "Deuterated" or "D-substituted" refers to a compound or group in which one or more hydrogen atoms are replaced by deuterium; deuterated groups may be monosubstituted, disubstituted, polysubstituted, or fully substituted.

[0044] Therefore, “C 1-6 Deuterated alkyl" refers to the above-mentioned "C 1-6alkyl" which is substituted with one or more deuteriums.

[0045] “C 1-6 "Alkoxy" refers to an -OR group, wherein R is a C 1-6 Alkyl. C 1-4 Alkoxy groups are preferred.

[0046] “C 1-6 "Haloalkoxy" refers to "C 1-6 Alkoxy", which is substituted by one or more halogen groups. In some embodiments, C 1-4 Halogenated alkoxyalkyl is particularly preferred, more preferably C 1-2 Halogenated alkoxyalkyl.

[0047] “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 is particularly preferred, more preferably C 5-6 Cycloalkyl. Cycloalkyl also includes a ring system in which the above-mentioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such a case, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyls 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), cycloheptatrienyl (C7), and the like. The cycloalkyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0048] "3-12 membered heterocyclyl" refers to a group of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. In some embodiments, 4-12 membered heterocyclyl is preferred, which is a 4-12 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 5-12 membered heterocyclyl is preferred, which is a 5-12 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 3-10 membered heterocyclyl is preferred, which is a 3-10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 4-10 membered heterocyclyl is preferred, which is a 4-10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 5-8 membered heterocyclyl is preferred, which is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; in some embodiments, 5-7 membered heterocyclyl is preferred, which is a 5-7 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms system; in some embodiments, a 4-8 membered heterocyclyl is preferably a 4-8 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; in some embodiments, a 3-7 membered heterocyclyl is preferably a 3-7 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; a 3-6 membered heterocyclyl is preferably a 3-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 4-7 membered heterocyclyl is preferably a 4-7 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; a 4-6 membered heterocyclyl is preferably a 4-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 5-6 membered heterocyclyl is more preferably a 5-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 3-5 membered heterocyclyl is more preferably a 3-5 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes a ring system in which the above-mentioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or a ring system in which the above-mentioned heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such a case, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiorenyl. Exemplary 4-membered heterocyclyls containing one heteroatom include, but are not limited to, azetidinyl, oxetane, and thiidine. Exemplary 5-membered heterocyclyls containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, 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, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thienyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyl groups) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrobenzopyranyl, tetrahydropyranopyridinyl, and the like. The heterocyclyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0049] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 Aryl also includes ring systems in which an aryl ring as described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Aryl groups can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0050] "5-14 membered heteroaryl" refers to a group of a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment 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 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5-10 membered heteroaryls are preferred, which are 6-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5-9 membered heteroaryls are preferred, which are 5-9 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryls are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryls 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 tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azacycloheptatrienyl, oxacycloheptatrienyl, and thiacycloheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.A heteroaryl group can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0051] "Cycloalkylene", "heterocyclylene", "arylene" or "heteroarylene" is a divalent group formed by removing another hydrogen from the above-defined "cycloalkyl", "heterocyclyl", "aryl" or "heteroaryl", and may be substituted or unsubstituted. For example, "C 5-7 "Cycloalkylene" refers to the removal of C 5-7 The "5-8 membered heterocyclylene" refers to a divalent group formed by removing another hydrogen atom of a 5-8 membered heterocyclyl. The "C 6-10 "Arylene" refers to the removal of C 6-10 The "5- to 6-membered heteroarylene group" refers to a divalent group formed by removing another hydrogen atom of a 5- to 6-membered heteroaryl group.

[0052] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like are defined herein as optionally substituted groups.

[0053] 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, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0054] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =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;

[0055] R aa Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R aa The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0056] R bb Each of the following 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, heterocyclyl, aryl and heteroaryl, or two R bb The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0057] R cc Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R cc The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0058] R dd Each of the 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, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0059] R ee Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0060] R ff Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ff The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0061] R ggEach of the independently: 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), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -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), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1- 6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 alkyl), -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), -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, -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 Halogenated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; wherein X - For the counter ion.

[0062] Exemplary substituents on nitrogen atoms 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, heterocyclyl, aryl and heteroaryl, or two R attached to the nitrogen atom cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd Group substituted, and wherein R aa 、R bb 、R cc and R dd As mentioned above.

[0063] Other definitions

[0064] As used herein, the term "pharmaceutically acceptable salt" refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention that are suitable for use in contact with patient tissues within the scope of sound medical judgment, do not produce undue toxicity, irritation, allergic response, etc., are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the present invention.

[0065] "Subjects" to be administered include, but are not limited to, humans (i.e., males or females 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, e.g., 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.

[0066] "Disease," "disorder," and "condition" are used interchangeably herein.

[0067] Generally, an "effective amount" of a compound is an amount sufficient to elicit the desired biological response. As will be appreciated by those skilled in the art, the effective amount of a compound of the invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount includes both a therapeutically effective amount and a prophylactically effective amount.

[0068] "Combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and other therapeutic agents. For example, a compound of the invention can be administered simultaneously or sequentially with the other therapeutic agents in separate unit dosage forms, or can be administered simultaneously with the other therapeutic agents in a single unit dosage form. Specific implementation plan

[0069] In one embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0070] in,

[0071] Z is selected from O, S, NH or CH2;

[0072] X1 is selected from CH or N;

[0073] X2 is selected from CH or N;

[0074] R is selected from 4-12 membered heterocyclic groups,

[0075] R1 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl;

[0076] R2 is C 3-8 Cycloalkyl or 3-12 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4, 5 or 6 R x replace;

[0077] Ring A is selected from 5-12 membered heterocyclyl or 5-14 membered heteroaryl, which is optionally substituted by 1-10 R b replace;

[0078] Ring B is absent or is selected from a 5-12 membered heterocyclyl or a 5-14 membered heteroaryl, which is optionally substituted by 1-10 R b replace;

[0079] R x Selected from H, D, halogen, -(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 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic group; and R x Optionally further substituted with 1, 2, 3, 4, 5 or 6 halogen, ═CH 2 , ═CHF or ═CF 2 ;

[0080] or two R on the same atom x Together they form =CH2, =CHF or =CF2;

[0081] R b Selected from H, -(CH2) p -halogen, -(CH2) p -CN, -(CH2) p -OH, -(CH2) p -NH2、-LC(O)R a 、-LC(O)OR a 、-LC(O)N(R a )(R a '),-NHC(O)OR a 、-(CH2) p -OR a 、-(CH2) p -SR a 、-LS(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10 aryl or -L-5-10 membered heteroaryl; and Rb Optionally further 1, 2, 3, 4, 5 or 6 R c replace;

[0082] or two R on the same atom b Together they form =O, =S, =NH, =CH2, =CHF or =CF2;

[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 Haloalkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10 aryl or -L-5-10 membered heteroaryl; and R a and R a 'optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, CN, -(CH2) p -OH, -(CH2) p -NH2、-C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution;

[0084] p is selected from 0, 1, 2, 3, 4, 5 or 6;

[0085] R c Selected from H, D, halogen, OH, NH2, -L-CN, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2N(R a )(R a '), C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; and R c Optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, -L-CN, OH, NH2, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6Alkoxy substitution;

[0086] or two R on the same atom c Together they form =O, =S or =NH;

[0087] L is selected from a bond, -C(O)-, -C(S)-, C 1-6 Alkylene or C 1-6 haloalkylene;

[0088] Each of the radical definitions recited is optionally substituted with 1, 2, 3, 4, 5 or more D, up to full deuteration.

[0089] Z

[0090] In one embodiment, Z is O; in another embodiment, Z is S; in another embodiment, Z is NH; in another embodiment, Z is CH2.

[0091] X1 and X2

[0092] In one embodiment, X1 is CH; in another embodiment, X1 is N.

[0093] In one embodiment, X2 is CH; in another embodiment, X2 is N.

[0094] R

[0095] In one embodiment, R is a 4-12 membered heterocyclyl; in another embodiment, R is In another embodiment, R is In another embodiment, R is

[0096] R1

[0097] In one embodiment, R1 is H; in another embodiment, R1 is D; in another embodiment, R1 is halogen; in another embodiment, R1 is CN; in another embodiment, R1 is C 1-6 Alkyl; in another embodiment, R1 is C 1-6 Deuterated alkyl; in another embodiment, R1 is C 1-6 In another embodiment, R1 is C 3-6 Cycloalkyl.

[0098] R2

[0099] In one embodiment, R2 is C 3-8 In another embodiment, R2 is a 3-12 membered heterocyclyl; in another embodiment, R2 is optionally substituted by 1, 2, 3, 4, 5 or 6 Rx replace.

[0100] Ring A

[0101] In one embodiment, Ring A is a 5-12 membered heterocyclyl; in another embodiment, Ring A is a 5-14 membered heteroaryl; in another embodiment, Ring A is optionally substituted with 1-10 R b Substituted, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 R b .

[0102] Ring B

[0103] In one embodiment, Ring B is absent; in another embodiment, Ring B is a 5-12 membered heterocyclyl; in another embodiment, Ring B is a 5-14 membered heteroaryl; in another embodiment, Ring B is optionally substituted with 1-10 R b Substituted, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 R b .

[0104] R x

[0105] In one embodiment, R x is H; in another embodiment, R x is D; in another embodiment, R x is halogen; in another embodiment, R x -(CH2) p CN; In another embodiment, R x -(CH2) p -OR a In another embodiment, R x -(CH2) p -NH2; In another embodiment, R x -C(O)R a In another embodiment, R x For-SR a In another embodiment, R x is -S(O)2R a In another embodiment, R x -S(O)R a In another embodiment, R x -S(O)2N(R a )(R a '); In another embodiment, R x -(CH2) p -C(O)OR a In another embodiment, Rx -(CH2) p -C(O)N(R a )(R a '); In another embodiment, R x -(CH2) p -NHC(O)OR a In another embodiment, R x -(CH2) p -OC(O)N(R a )(R a '); In another embodiment, R x is -O-phenyl-; in another embodiment, R x -(CH2) p -phenyl; in another embodiment, R x C 1-6 Alkyl; in another embodiment, R x C 1-6 Deuterated alkyl; in another embodiment, R x C 1-6 haloalkyl; in another embodiment, R x C 2-6 alkenyl; in another embodiment, R x C 2-6 Alkynyl; in another embodiment, R x C 1-6 Alkoxy; in another embodiment, R x C 1-6 haloalkoxy; in another embodiment, R x For-LC 3-8 Cycloalkyl; in another embodiment, R x is -L-4-8 membered heterocyclyl; in another embodiment, R x Optionally further substituted with 1, 2, 3, 4, 5 or 6 halogen, ═CH 2 , ═CHF or ═CF 2 .

[0106] In another embodiment, two R on the same atom x Together they form =CH2, =CHF or =CF2.

[0107] R b

[0108] In one embodiment, R b is H; in another embodiment, R b -(CH2) p -halogen; in another embodiment, R b -(CH2)p -CN; In another embodiment, R b -(CH2) p -OH; In another embodiment, R b -(CH2) p -NH2; In another embodiment, R b -LC(O)R a In another embodiment, R b -LC(O)OR a In another embodiment, R b -LC(O)N(R a )(R a '); In another embodiment, R b -NHC(O)OR a In another embodiment, R b -(CH2) p -OR a In another embodiment, R b -(CH2) p -SR a In another embodiment, R b -LS(O)2R a In another embodiment, R b C 1-6 Alkyl; in another embodiment, R b C 1-6 haloalkyl; in another embodiment, R b C 1-6 Alkoxy; in another embodiment, R b For-LC 3-8 Cycloalkyl; in another embodiment, R b is -L-4-8 membered heterocyclyl; in another embodiment, R b For-LC 6-10 Aryl; in another embodiment, R b is -L-5-10 membered heteroaryl; in another embodiment, R b Optionally further 1, 2, 3, 4, 5 or 6 R c replace.

[0109] In another embodiment, two R on the same atom b Together they form =O, =S, =NH, =CH2, =CHF or =CF2.

[0110] R a and R a '

[0111] In one embodiment, R a is H; in another embodiment, R a is -L-CN; in another embodiment, R a -(CH2) p -OC 1-6 Alkyl; in another embodiment, R a C 1-6 Alkyl; in another embodiment, R a C 1-6 haloalkyl; in another embodiment, R a For-LC 1-6 Alkoxy; in another embodiment, R a For-LC 3-8 Cycloalkyl; in another embodiment, R a is -L-4-8 membered heterocyclyl; in another embodiment, R a For-LC 6-10 Aryl; in another embodiment, R a is -L-5-10 membered heteroaryl; in another embodiment, R a Optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, CN, -(CH2) p -OH, -(CH2) p -NH2、-C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution.

[0112] In one embodiment, R a ' is H; in another embodiment, R a ' is -L-CN; in another embodiment, R a ' is -(CH2) p -OC 1-6 Alkyl; in another embodiment, R a ' for C 1-6 Alkyl; in another embodiment, R a ' for C 1-6 haloalkyl; in another embodiment, R a ' for -LC 1-6 Alkoxy; in another embodiment, R a ' for -LC 3-8 Cycloalkyl; in another embodiment, R a' is -L-4-8 membered heterocyclyl; in another embodiment, R a ' for -LC 6-10 Aryl; in another embodiment, R a ' is -L-5-10 membered heteroaryl; in another embodiment, R a 'optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, CN, -(CH2) p -OH, -(CH2) p -NH2、-C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution.

[0113] p

[0114] In one embodiment, p is 0; in another embodiment, p is 1; in another embodiment, p is 2; in another embodiment, p is 3; in another embodiment, p is 4; in another embodiment, p is 5; in another embodiment, p is 6.

[0115] R c

[0116] In one embodiment, R c is H; in another embodiment, R c is D; in another embodiment, R c is halogen; in another embodiment, R c is OH; in another embodiment, R c is NH2; in another embodiment, R c is -L-CN; in another embodiment, R c -C(O)C 1-6 Alkyl; in another embodiment, R c -S(O)2C 1-6 Alkyl; in another embodiment, R c -S(O)2N(R a )(R a ') yl; In another embodiment, R c C 1-6 Alkyl; in another embodiment, R c C 1-6 haloalkyl; in another embodiment, R c C 1-6 Alkoxy; in another embodiment, R c C3-12 Cycloalkyl; in another embodiment, R c is a 4-12 membered heterocyclyl; in another embodiment, R c C 6-10 Aryl; in another embodiment, R c is a 5-10 membered heteroaryl; in another embodiment, R c Optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, -L-CN, OH, NH2, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1- 6 alkoxy substitution.

[0117] In another embodiment, two R on the same atom c Together they form =O, =S or =NH.

[0118] L

[0119] In one embodiment, L is a bond; in another embodiment, L is -C(O)-; in another embodiment, L is -C(S)-; in another embodiment, L is C 1-6 Alkylene; in another embodiment, L is C 1- 6 haloalkylene.

[0120] 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 and any technical solution of L or any combination thereof. The present invention is intended to include combinations of all these technical solutions, which are not listed one by one due to space limitations.

[0121] In a more specific embodiment, the present invention relates to the following technical solutions:

[0122] Technical Solution 1. A compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0123] in,

[0124] Z is selected from O, S, NH or CH2;

[0125] X1 is selected from CH or N;

[0126] X2 is selected from CH or N;

[0127] R is selected from 4-12 membered heterocyclic groups,

[0128] R1 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl;

[0129] R2 is C 3-8 Cycloalkyl or 3-12 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4, 5 or 6 R x replace;

[0130] Ring A is selected from 5-12 membered heterocyclyl or 5-14 membered heteroaryl, which is optionally substituted by 1-10 R b replace;

[0131] Ring B is absent or is selected from a 5-12 membered heterocyclyl or a 5-14 membered heteroaryl, which is optionally substituted by 1-10 R b replace;

[0132] R x Selected from H, D, halogen, -(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 Halogenated alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic group; and R x optionally further substituted with 1, 2, 3, 4, 5 or 6 halogen, ═CH 2 , ═CHF or ═CF 2 ;

[0133] or two R on the same atom x Together they form =CH2, =CHF or =CF2;

[0134] R b Selected from H, -(CH2) p -halogen, -(CH2) p -CN, -(CH2) p -OH, -(CH2) p -NH2、-LC(O)R a 、-LC(O)OR a 、-LC(O)N(R a )(R a '),-NHC(O)OR a 、-(CH2) p -OR a 、-(CH2) p -SR a 、-LS(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10 aryl or -L-5-10 membered heteroaryl; and R b Optionally further 1, 2, 3, 4, 5 or 6 R c replace;

[0135] or two R on the same atom b Together they form =O, =S, =NH, =CH2, =CHF or =CF2;

[0136] R a and R a 'Independently selected from H, -L-CN, -(CH2) p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 1-6 Alkoxy, -LC 3-8Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10 aryl or -L-5-10 membered heteroaryl; and R a and R a 'optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, CN, -(CH2) p -OH, -(CH2) p -NH2、-C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution;

[0137] p is selected from 0, 1, 2, 3, 4, 5 or 6;

[0138] R c Selected from H, D, halogen, OH, NH2, -L-CN, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2N(R a )(R a '), C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; and R c Optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, -L-CN, OH, NH2, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution;

[0139] or two R on the same atom c Together they form =O, =S or =NH;

[0140] L is selected from a bond, -C(O)-, -C(S)-, C 1-6 Alkylene or C 1-6 haloalkylene;

[0141] Each of the radical definitions recited is optionally substituted with 1, 2, 3, 4, 5 or more Ds, up to full deuteration.

[0142] Technical Solution 2. The compound of Technical Solution 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein:

[0143] Z is selected from O, NH or CH2;

[0144] X1 is selected from CH or N;

[0145] X2 is selected from CH or N;

[0146] R is selected from 5-12 membered heterocyclic group,

[0147] R1 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl;

[0148] R2 is a 3-12 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4, 5 or 6 R x replace;

[0149] Ring A is selected from 5-7 membered heterocyclyl or 5-6 membered heteroaryl, which is optionally substituted by 1-10 R b replace;

[0150] Ring B is absent;

[0151] R x Selected from H, D, halogen, -(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 Halogenated alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic group; and R x optionally further substituted with 1, 2, 3, 4, 5 or 6 halogen, ═CH 2 , ═CHF or ═CF 2 ;

[0152] or two R on the same atom x Together they form =CH2, =CHF or =CF2;

[0153] R b Selected from H, -(CH2) p -halogen, -(CH2) p -CN, -(CH2) p -OH, -(CH2) p -NH2、-LC(O)R a 、-LC(O)OR a 、-LC(O)N(R a )(R a '),-NHC(O)OR a 、-(CH2) p -OR a 、-(CH2) p -SR a 、-LS(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10 aryl or -L-5-10 membered heteroaryl; and R b Optionally further 1, 2, 3, 4, 5 or 6 R c replace;

[0154] or two R on the same atom b Together they form =O, =S, =NH, =CH2, =CHF or =CF2;

[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 Haloalkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10aryl or -L-5-10 membered heteroaryl; and R a and R a 'optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, CN, -(CH2) p -OH, -(CH2) p -NH2、-C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution;

[0156] p is selected from 0, 1, 2, 3, 4, 5 or 6;

[0157] R c Selected from H, D, halogen, OH, NH2, -L-CN, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2N(R a )(R a '), C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6- 10 aryl or 5-10 membered heteroaryl; and R c Optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, -L-CN, OH, NH2, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution;

[0158] or two R on the same atom c Together they form =O, =S or =NH;

[0159] L is selected from a bond or C 1-6 alkyl;

[0160] Each of the radical definitions recited is optionally substituted with 1, 2, 3, 4, 5 or more D, up to full deuteration.

[0161] Technical Solution 3. The compound of Technical Solution 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, has the structure of Formula (II):

[0162] in,

[0163] M1, M2 and M3 are each independently selected from O, S, N, NH, CH, -C(=O)-, -C(=S)- or CH2;

[0164] R1 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl;

[0165] R x1 Selected from -(CH2) p -CN、-C(O)R a 、-C(O)OR a 、-(CH2) p -OR a 、-S(O)2R a 、C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0166] R x2 Selected from H, D, halogen, -(CH2) p CN, -(CH2) p -OR a 、-(CH2) p -NH2、-C(O)R a 、-SR a 、-S(O)2R 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 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -LC 3-8Cycloalkyl or -L-4-8 membered heterocyclic group; and R x optionally further substituted with 1, 2, 3, 4, 5 or 6 halogen, ═CH 2 , ═CHF or ═CF 2 ;

[0167] or two R on the same atom x2 Together they form =CH2, =CHF or =CF2;

[0168] R b Selected from H, -(CH2) p -halogen, -(CH2) p -CN, -(CH2) p -OH, -(CH2) p -NH2、-LC(O)R a 、-LC(O)OR a 、-LC(O)N(R a )(R a '),-NHC(O)OR a 、-(CH2) p -OR a 、-(CH2) p -SR a 、-LS(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10 aryl or -L-5-10 membered heteroaryl; and R b Optionally further 1, 2, 3, 4, 5 or 6 R c replace;

[0169] or two R on the same atom b Together they form =O, =S, =NH, =CH2, =CHF or =CF2;

[0170] R a and R a 'Independently selected from H, -L-CN, -(CH2) p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10 aryl or -L-5-10 membered heteroaryl; and R a and R a'optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, CN, -(CH2) p -OH, -(CH2) p -NH2、-C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution;

[0171] R c Selected from H, D, halogen, OH, NH2, -L-CN, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2N(R a )(R a '), C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6- 10 aryl or 5-10 membered heteroaryl; and R c Optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, -L-CN, OH, NH2, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution;

[0172] or two R on the same atom c Together they form =O, =S or =NH;

[0173] L is selected from a bond, -C(O)-, -C(S)-, C 1-6 Alkylene or C 1-6 haloalkylene;

[0174] Each of the groups defined above is optionally substituted with 1, 2, 3, 4, 5 or more D, up to full deuteration;

[0175] n is selected from 0, 1 or 2;

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

[0177] p is selected from 0, 1, 2, 3, 4 or 5.

[0178] Technical Solution 4. The compound of Technical Solution 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, has the structure of Formula (II-1) or (II-2):

[0179] in,

[0180] M3 is selected from N or CH;

[0181] R1 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl;

[0182] R x2 Selected from H, D, halogen, CN, NH2, -C(O)R a 、-NHC(O)OR a 、-(CH2) p -OR a 、-SR a 、-S(O)2R a 、-(CH2) p -C(O)OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkoxy;

[0183] n is selected from 0, 1 or 2;

[0184] R b Selected from H, D, halogen, NH2, -L-CN, -L-OH, -C(O)R a 、-C(O)OR a 、-C(O)NHR a 、-C(O)N(R a )(R a '),-NHC(O)OR a 、-(CH2) p -OR a 、-SR、S(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -LC 3-6 Cycloalkyl or -L-4-6 membered heterocyclic group; R b Can be further replaced by 1 or 2 R c replace;

[0185] m is selected from 0, 1, 2 or 3;

[0186] R a and R a 'Independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group;

[0187] p is selected from 0, 1, 2, 3 or 4;

[0188] R c Selected from H, C 1-6 Alkyl, halogen, OH, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, CN, NH2, C 3-6 Cycloalkyl or 4-12 membered heterocyclic group;

[0189] or two R on the same atom c Together they form =O, =S or =NH;

[0190] L is selected from a bond, -C(O)- or C 1-6 alkylene;

[0191] Each of the radical definitions recited is optionally substituted with 1, 2, 3, 4, 5 or more Ds, up to full deuteration.

[0192] Technical Solution 5. The compound of Technical Solution 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, has the structure of Formula (II-3):

[0193] in,

[0194] M2 is selected from NH, -C(=O)-, -C(=S)- or CH2;

[0195] R1 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl;

[0196] R x Selected from H, D, halogen, -(CH2) p CN, -(CH2) p -OR a 、-(CH2) p -NH2、-C(O)R a 、-SR a 、-S(O)2R 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 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic group; and R x optionally further substituted with 1, 2, 3, 4, 5 or 6 halogen, ═CH 2 , ═CHF or ═CF 2 ;

[0197] n is selected from 0, 1 or 2;

[0198] R b Selected from H, -(CH2) p -halogen, -(CH2) p -CN, -(CH2) p -OH, -(CH2) p -NH2、-LC(O)R a 、-LC(O)OR a 、-LC(O)N(R a )(R a '),-NHC(O)OR a 、-(CH2) p -OR a 、-(CH2) p -SR a 、-LS(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10 aryl or -L-5-10 membered heteroaryl; and R b Optionally further 1, 2, 3, 4, 5 or 6 R c replace;

[0199] m is selected from 0, 1, 2, 3, 4 or 5;

[0200] or two R on the same atom b Together they form =O, =S, =NH, =CH2, =CHF or =CF2;

[0201] R a and R a 'Independently selected from H, -L-CN, -(CH2) p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10 aryl or -L-5-10 membered heteroaryl; and R a and R a 'optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, CN, -(CH2) p -OH, -(CH2) p -NH2、-C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution;

[0202] R c Selected from H, D, halogen, OH, NH2, -L-CN, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2N(R a )(R a '), C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6- 10 aryl or 5-10 membered heteroaryl; and R c Optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, -L-CN, OH, NH2, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution;

[0203] or two R on the same atom c Together they form =O, =S or =NH;

[0204] p is selected from 0, 1, 2, 3, 4, 5 or 6;

[0205] L is selected from a bond, -C(O)- or C 1-6 alkylene;

[0206] Each of the radical definitions recited is optionally substituted with 1, 2, 3, 4, 5 or more D, up to full deuteration.

[0207] Technical Solution 6. The compound of Technical Solution 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, has the structure of Formula (IV), (IV-1) or (IV-2):

[0208] in,

[0209] Z is selected from O, S, NH or CH2;

[0210] R1 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl;

[0211] R2 is selected from C 3-8 Cycloalkyl or 4-8 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4, 5 or 6 R x replace;

[0212] R b Selected from H, -(CH2) p -halogen, -(CH2) p -CN, -(CH2) p -OH, -(CH2) p -NH2、-LC(O)R a 、-LC(O)OR a 、-LC(O)N(R a )(R a '),-NHC(O)OR a 、-(CH2) p -OR a 、-(CH2) p -SR a 、-LS(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10aryl or -L-5-10 membered heteroaryl; and R b Optionally further 1, 2, 3, 4, 5 or 6 R c replace;

[0213] m is selected from 0, 1, 2, 3, 4 or 5;

[0214] or two R on the same atom b Together they form =O, =S, =NH, =CH2, =CHF or =CF2;

[0215] R x Selected from H, D, halogen, -(CH2) p CN, -(CH2) p -OR a 、-(CH2) p -NH2、-C(O)R a 、-SR a 、-S(O)2R a 、-O-phenyl-、-(CH2) p -phenyl, -(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 '), C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic group; and R x Optionally further substituted with 1, 2, 3, 4, 5 or 6 halogen, ═CH 2 , ═CHF or ═CF 2 ;

[0216] or two R on the same atom x Together they form =CH2, =CHF or =CF2;

[0217] R a and R a 'Independently selected from H, -L-CN, -(CH2) p -OC 1-6 Alkyl, C1-6 Alkyl, C 1-6 Haloalkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10 aryl or -L-5-10 membered heteroaryl; and R a and R a 'optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, CN, -(CH2) p -OH, -(CH2) p -NH2、-C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution;

[0218] p is selected from 0, 1, 2, 3, 4, 5 or 6;

[0219] R c Selected from H, D, halogen, OH, NH2, -L-CN, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2N(R a )(R a '), C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6- 10 aryl or 5-10 membered heteroaryl; and R c Optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, -L-CN, OH, NH2, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution;

[0220] or two R on the same atom c Together they form =O, =S or =NH;

[0221] L is selected from a bond, -C(O)-, -C(S)-, C 1-6 Alkylene or C 1-6 haloalkylene;

[0222] Each of the radical definitions recited is optionally substituted with 1, 2, 3, 4, 5 or more D, up to full deuteration.

[0223] Technical Solution 7. The compound of Technical Solution 6, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, has the structure of Formula (V), (V-1) or (V-2):

[0224] in,

[0225] Z is selected from O, S, NH or CH2;

[0226] R1 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl;

[0227] R2 is a 5-8 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R x replace;

[0228] R b Selected from H, -(CH2) p -halogen, -(CH2) p -CN, -(CH2) p -OH, -(CH2) p -NH2、-C(O)R a 、-C(O)OR a 、-C(O)N(R a )(R a '),-NHC(O)OR a 、-(CH2) p -OR a 、-(CH2) p -SR a 、-(CH2) p -S(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -LC 3-6 Cycloalkyl or -L-4-6 membered heterocyclic group; and R b Optionally further 1, 2, 3, 4, 5 or 6 R c replace;

[0229] R x Selected from H, D, halogen, -(CH2) p -CN, -(CH2) p -OR a 、-(CH2) p -NH2、-C(O)R a、-NHC(O)OR a 、-SR a 、-S(O)2R a 、-(CH2) p -C(O)OR a 、-(CH2) p -C(O)N(R a )(R a '), -O-phenyl-, -(CH2) p -phenyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0230] R a and R a 'Independently selected from H, -L-CN, -(CH2) p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 1-6 Alkoxy, -LC 3-6 Cycloalkyl, -L-4-6 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; and R a and R a 'optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, CN, -(CH2) p -OH, -(CH2) p -NH2、-C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution;

[0231] p is selected from 0, 1, 2, 3 or 4;

[0232] R c Selected from H, D, halogen, OH, NH2, -L-CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; and R cOptionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, OH, NH2, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution;

[0233] L is selected from a bond, -C(O)- or C 1-6 alkylene;

[0234] Each of the radical definitions recited is optionally substituted with 1, 2, 3, 4, 5 or more D, up to full deuteration.

[0235] Technical Solution 8. A compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein the compound is selected from:

[0236] Technical Solution 9. A compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein the compound is selected from:

[0237] Technical Solution 10. A pharmaceutical composition comprising a compound according to any one of Technical Solutions 1 to 9, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and a pharmaceutically acceptable excipient; preferably, it further comprises other therapeutic agents.

[0238] Technical Solution 11. Use of the compound of any one of Technical Solutions 1-9 or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof in the preparation of a medicament for treating and / or preventing KRAS-mediated diseases.

[0239] Technical Solution 12. A method for treating and / or preventing a KRAS-mediated disease in a subject, comprising administering to the subject a compound of any one of Technical Solutions 1-9 or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or the pharmaceutical composition of Technical Solution 10.

[0240] Technical Solution 13. The compound of any one of Technical Solutions 1-9 or its pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer, or the pharmaceutical composition of Technical Solution 10, for treating and / or preventing KRAS-mediated diseases.

[0241] Technical Solution 14. The use of Technical Solution 11 or the method of Technical Solution 12 or the use of the compound or composition of Technical Solution 13, wherein the KRAS-mediated disease is cancer, preferably, the cancer is selected from: colorectal cancer (such as colon cancer, rectal cancer, large intestine adenocarcinoma), non-small cell lung cancer (NSCLC) or pancreatic cancer, etc.

[0242] The compounds of the present invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and / or diastereomeric forms. For example, the compounds of the present 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 enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0243] The compounds of the present invention may also exist as tautomers. For compounds that exist in different tautomeric forms, a compound is not limited to any specific tautomer, but is intended to encompass all tautomeric forms.

[0244] The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (A) except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually 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, 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 36Cl. Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those in which radioactive isotopes (e.g. 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. 2 H, because greater metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, and thus may be preferred in some cases. Isotopically labeled compounds of formula (A) of the present invention and prodrugs thereof can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when carrying out the processes disclosed in the following schemes and / or the Examples and Preparations.

[0245] Pharmaceutical compositions and kits

[0246] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.

[0247] Pharmaceutically acceptable excipients used in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0248] The present invention also includes kits (e.g., pharmaceutical packaging). The kits provided may include a compound of the 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 compound of the invention and other therapeutic agents. In some embodiments, the kit provided may also optionally include a third container containing a pharmaceutical excipient for diluting or suspending the compound of the invention and / or other therapeutic agents. In some embodiments, the compound of the invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0249] Drug administration

[0250] Pharmaceutical compositions provided by the invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant or other modes of administration. For example, parenteral administration used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration, intrathecal administration, intralesional administration, and intracranial injection or infusion technology.

[0251] Typically, an effective amount of the compounds provided herein is administered. The amount of compound actually administered can be determined by a physician based on the relevant circumstances, including the condition being treated, the route of administration selected, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0252] When used to prevent the conditions described herein, the compounds provided herein are administered to a subject at risk of developing the condition, typically based on the advice and under the supervision of a physician, at dosage levels as described above. Subjects at risk of developing a particular condition typically include those with a family history of the condition, or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0253] The pharmaceutical compositions provided herein can also be administered long-term ("chronic administration"). Long-term administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration can continue indefinitely, e.g., for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of the compound in the blood over an extended period of time, e.g., within the therapeutic window.

[0254] 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 injection, for example, in order 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 ingredient by the body, for example, an intramuscular or subcutaneous bolus dose slowly releases the active ingredient, and the bolus (for example, by IV intravenous drip) delivered directly to the vein can be delivered more quickly so that the concentration of the active ingredient in the blood is rapidly increased to an effective level. In other embodiments, the pharmaceutical composition can be given in a continuous infusion form, for example, by IV intravenous drip, so as to provide a steady-state concentration of the active ingredient in the subject's body. In addition, in other embodiments, the pharmaceutical composition of the bolus dose can be first given, and then continuous infusion.

[0255] Oral compositions can be in the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, in order to facilitate accurate dosing, the compositions are provided in unit dosage form. 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 amount of active substance suitable for producing the desired therapeutic effect and a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions. In such compositions, the compound is typically a minor 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 and processing aids useful for forming the desired dosage form.

[0256] For oral dosage, a representative regimen is one to five oral doses per day, particularly two to four oral doses, typically three oral doses. Using these dosage administration modes, each dose provides about 0.01 to about 20 mg / kg of the compound of the invention, with preferred doses each providing about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg.

[0257] To provide blood levels similar to, or lower than, those obtained with an injectable 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, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

[0258] From about 1 to about 120 hours, and particularly from 24 to 96 hours, the injected dose level is in the range of about 0.1 mg / kg / hour to at least 10 mg / kg / hour. To achieve adequate steady-state levels, a preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered. For a 40 to 80 kg human patient, the maximum total dose may not exceed about 2 g / day.

[0259] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous carrier and buffers, suspending and dispersing agents, colorants, flavorings, etc. Solid forms may include, for example, any of the following components, or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor.

[0260] Injectable compositions are typically based on sterile saline or phosphate buffered saline for injection, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

[0261] Typically, transdermal compositions are formulated as topical ointments or creams containing the active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream together with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other components that enhance the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by the present invention.

[0262] The compounds of the present invention may also be administered by transdermal devices.Thus, transdermal administration may be achieved using patches of the reservoir or porous membrane type, or various solid matrices.

[0263] The above components for oral administration, injection or topical administration are representative only. 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.

[0264] The compounds of the invention can also be administered in sustained release form or from a sustained release delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0265] The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present 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 consisting of 6, 7, and 8 α-1,4-linked glucose units, respectively, which optionally include one or more substituents on the linked sugar portion, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (e.g., in water, 10-50%).

[0266] Example

[0267] The reagents used in the present invention are commercial reagents purchased directly or synthesized using common methods well known in the art.

[0268] Notes on commonly used abbreviations:

[0269] Example 1: Preparation of intermediates

[0270] Preparation of intermediate a1

[0271] Step 1: At 10°C, under nitrogen, starting material a1-1 (20.0 g, 117.5 mmol) and starting material allyl acetate a1-2 (15.3 g, 152.7 mmol) were dissolved in 51 mL of a mixture of toluene and water (v / v, 50 / 1). Tetramethylguanidine (27.1 g, 235.0 mmol) was added, and the mixture was stirred at 10°C for 30 minutes. The catalyst, allylpalladium chloride dimer (30 mg, 0.08 mmol), and the ligand (SS)-DACH-Phenyl Trost (130 mg, 0.19 mmol) were added to the reaction mixture. The reaction was continued at this temperature for 12 hours, after which the reaction was terminated. The mixture was added with 250 mL of saturated aqueous ammonium chloride, extracted with MTBE, dried over anhydrous sodium sulfate, and concentrated to afford compound a1-3 (16.6 g) in a 67% yield.

[0272] Step 2: Under nitrogen at 10°C, the intermediate a1-3 from the previous step (16.2 g, 77.0 mmol) was dissolved in 65 mL of ethylene glycol. TMSCl (20.9 g, 192.6 mmol) was added dropwise, and the mixture was reacted at 10°C for 12 hours. Aqueous NaOH (65 mL, 2N) was added to the reaction solution, which was extracted with MTBE, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 9 / 1) to afford a1-4 (16.0 g) as a yellow oil in an 82% yield.

[0273] Step 3: Dissolve the intermediate a1-4 (16.0 g, 62.9 mmol) and the starting materials in 25 mL of anhydrous tetrahydrofuran in an ice bath under nitrogen. Add 9-BBN (0.5 M in THF) (121 mL, 75.5 mmol) dropwise. The mixture is reacted in an ice bath for 1 hour. Methyl chloroacetate a1-5 (8.9 g, 81.78 mmol) is added to the reaction solution. The temperature is lowered to -45°C, and LiHMDS (1 M, 207 mL) is added dropwise. After completion of the addition, the mixture is reacted at room temperature for 12 hours. Aqueous NaOH (40 mL, 2N) and 50 mL of ethanol are added to the reaction solution. The temperature is raised to 70°C and the reaction is continued for 8 hours to terminate the reaction. 400 mL of ice water was added to the reaction solution, extracted with MTBE, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 3 / 1) to obtain a yellow oil a1 (12.3 g). Yield: 87%. LCMS ESI-MS m / z: 225 [M+H] + .

[0274] Preparation of intermediates a2-a3

[0275] Step 1: In an ice bath, under nitrogen, intermediate a1 (1.9 g, 8.44 mmol) and starting material ethyl 2-chloropyrimidine-4-carboxylate a2-1 (1.05 g, 5.63 mmol) were dissolved in 10 mL of anhydrous dichloromethane. EtOMgBr2 (2M in THF) (4.9 g, 19.1 mmol) and DIEA (2.2 g, 16.9 mmol) were added dropwise. The mixture was reacted at room temperature for 72 hours, after which the reaction was stopped. Dilute hydrochloric acid (20 mL, 1 M) was added to the reaction solution, which was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 10 / 1) to afford a2-2 (932 mg) as a yellow oil in a 45% yield. LCMS ESI-MS m / z: 365 [M+H] + .

[0276] Step 2: Dissolve the intermediate a2-2 (930 mg, 2.55 mmol) and NH2OH.HCl (220 mg, 3.14 mmol) in 19 mL of anhydrous pyridine. The mixture is reacted at room temperature for 48 hours, after which the reaction is stopped. Dilute hydrochloric acid (20 mL, 1 M) is added to the reaction solution, which is then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product is separated by column chromatography (PE / EA, 10 / 1) to afford a2-3 and a2-4 (765 mg) as yellow oils in a 79% yield. LCMS ESI-MS m / z: 380 [M+H] + .

[0277] Step 3: Dissolve the intermediate mixture from the previous step (765 mg, 2.01 mmol) in 8 mL of tetrahydrofuran and add dilute hydrochloric acid (4 M, 8 mL). The mixture is allowed to react at room temperature for 12 hours, after which the reaction is stopped. Add 40 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (PE / EA, 10 / 1) to afford a2 (228 mg), a yellow solid, in a 36% yield. LCMS ESI-MS m / z: 318 [M+H] + .

[0278] Referring to the synthetic route of intermediate a2, similar raw materials / compounds were used to synthesize the following intermediates.

[0279] Preparation of intermediate a4

[0280] Step 1: In an ice bath, under nitrogen, intermediate a1 (3.0 g, 13.6 mmol) and starting material a4-1 (3.0 g, 12.4 mmol) were dissolved in 30 mL of anhydrous acetonitrile. EtOMgBr2 (2 M in THF) (7.6 g, 29.7 mL) and DIEA (5.0 g, 37.1 mmol) were added dropwise. After completion of the addition, the mixture was heated to 80°C and reacted for 12 hours, after which the reaction was stopped. Dilute hydrochloric acid (1 M) was added to adjust the pH to approximately 6. The reaction solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 5 / 1) to afford a4-2 (2.0 g) as a yellow solid in a 38% yield. LCMS ESI-MS m / z: 421 [M+H] + .

[0281] Step 2: Dissolve the intermediate a4-2 (2.0 g, 4.75 mmol) and HCOOH (0.3 g, 7.12 mmol) in 10 mL of 1,4-dioxane. Add NH2OH.HCl (240 mg, 7.1 mmol, 50%). The mixture is allowed to react at room temperature for 12 hours, then the reaction is stopped. Dilute hydrochloric acid (20 mL, 1 M) is added to the reaction solution, which is then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to afford a4-3 as a yellow solid. LCMS ESI-MS m / z: 436 [M+H] + .

[0282] Step 3: Dissolve the intermediate mixture a4-3 (2.2 g, 5.04 mmol) from the previous step in 22 mL of 1,4-dioxane and add dilute hydrochloric acid (4 M, 44 mL). The mixture is allowed to react at room temperature for 12 hours, after which the reaction is stopped. Add 40 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse-phase column chromatography (C18; CH3CN / H2O, 4 / 1) to afford a4 (800 mg) as a yellow solid. The total yield for the two steps is 45%. LCMS ESI-MS m / z: 374 [M+H] + .

[0283] Preparation of intermediate a5

[0284] Step 1: Dissolve intermediate a1 (50.0 g, 222.9 mmol) in 500 mL of anhydrous tetrahydrofuran under nitrogen in an ice bath. Add LiHMDS (1 M in THF) (245 mL) dropwise. Stir under ice bath for 1 hour. Add ethyl oxalate (39.1 g, 267.5 mmol) dropwise to the reaction mixture, warm to room temperature, and react for 2 hours to obtain a mixture. Dissolve acetyl chloride (39.3 g, 501.6 mmol) in 200 mL of ethanol and stir under ice bath for 1 hour to prepare reaction solution S1. Add reaction solution S1 and NH2OH.HCl (16.2 g, 234.1 mmol) to the mixture, heat to 65°C, and continue the reaction for 12 hours. Stop the reaction, and remove the solvent under reduced pressure. Add 500 mL of ice water to the reaction mixture, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The mixture was redissolved in 100 mL of 1,4-dioxane, and the pH was adjusted to about 2 with dilute hydrochloric acid (1 M). The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to obtain a5-1 (21.5 g) as a white solid. LCMS ESI-MS m / z: 278 [M+H] + .

[0285] Step 2: Dissolve the intermediate a5-1 (21.5 g, 77.5 mmol) and aqueous ammonia (129 mL) in 44 mL of ethanol. The mixture is reacted at room temperature for 12 hours, and the reaction is stopped. Add 200 mL of water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain a5-2 (18.0 g) as a yellow solid. LCMS ESI-MS m / z: 249 [M+H] + .

[0286] Step 3: Dissolve the intermediate mixture a5-2 (18.0 g, 72.5 mmol) and pyridine (13.7 g, 174 mmol) in 72 mL of acetonitrile. Add TFAA (18.2 g, 87.0 mmol) dropwise. The mixture is allowed to react at room temperature for 0.5 hours, then the reaction is stopped. Add 400 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain a5 (15.0 g) as a yellow oil. The total yield for the three steps is 29%. LCMS ESI-MS m / z: 231 [M+H] + .

[0287] Preparation of intermediates a6-a7

[0288] Step 1: Dissolve intermediate a5 (15.0 g, 65.1 mmol) and MeONa (2.93 g, 16.3 mmol) in 40 mL of anhydrous methanol in an ice bath under nitrogen protection and react at room temperature for 2 hours. Add NH4Cl (3.8 g, 71.65 mmol) to the reaction solution, raise the temperature to 30°C, and continue the reaction for 12 hours. Stop the reaction and remove the solvent under reduced pressure. Add 500 mL of ice water to the reaction solution, adjust the pH to approximately 8 with saturated sodium bicarbonate aqueous solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. A white solid a6-1 (14.0 g) is obtained in an 87% yield. LCMS ESI-MS m / z: 248 [M+H] + .

[0289] Step 2: Dissolve the intermediate a6-1 (4.0 g, 16.2 mmol) and the starting material a6-2 (8.65 g, 48.6 mmol) in 44 mL of DMF. Add DBU (7.39 g, 48.5 mmol). Heat the mixture to 90°C and react for 12 hours, then stop the reaction. Add 200 mL of water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse-phase column chromatography (column: C18; CH3CN / H2O = 1 / 1) to obtain a6-2 (3.3 g) as a white solid in a 61% yield. LCMS ESI-MS m / z: 334 [M+H] + .

[0290] Step 3: Dissolve the intermediate a6-2 (3.0 g, 9.0 mmol) and POCl3 (9.0 mL) in 18 mL of N,N-diethylaniline. Heat the mixture to 80°C and react for 12 hours, then stop the reaction. Add 100 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (PE / EA, 4 / 1) to obtain a6 (1.6 g) as a white solid in a 48% yield. LCMS ESI-MS m / z: 370 [M+H] + .

[0291] Referring to the synthetic route of intermediate a6, similar raw materials / compounds were used to synthesize the following intermediates.

[0292] Preparation of intermediate a8

[0293] Step 1: In an ice bath, under nitrogen, intermediate a6-1 (1.0 g, 4.04 mmol) and TEA (820 mg, 8.1 mmol) were dissolved in 20 mL of tert-butanol. Raw material a8-1 (2.1 g, 8.1 mmol) was added to the reaction mixture, and the temperature was raised to 90°C for 1 hour. The reaction was stopped and the solvent was removed under reduced pressure. 500 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 HPLC (column: Xbridge Prep phenyl OBD Colum, 30 x 150 mm, 5 μm; mobile phase A: H₂O (10 mmol / L NH₄HCO₃), mobile phase B: CH₃CN; flow rate: 100 mL / min; retention time: 23 min) to afford a8-2 (1.1 g) as a white solid in a 62% yield. LCMS ESI-MS m / z: 441 [M+H] + .

[0294] Step 2: Intermediate a8-2 (1.1 g, 2.5 mmol) and PPh3 (1.3 g, 4.99 mmol) from the previous step were dissolved in 14 mL of dichloroethane. CCl4 (1.2 g, 7.49 mmol) was added, and the mixture was heated to 70°C for 2 hours to terminate the reaction. 50 mL of ice 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 HPLC (column: Xbridge Prep phenyl OBD Colum, 30*150 mm, 5 μm; mobile phase A: H2O (10 mmol / L NH4HCO3), mobile phase B: CH3CN; flow rate: 100 mL / min; retention time: 24 min) to afford a8 (600 mg) as a yellow solid in a 52% yield. LCMS ESI-MS m / z: 459 [M+H] + .

[0295] Preparation of intermediates a9-a12

[0296] Step 1: Dissolve raw materials a9-1 (6.0 g, 18.85 mmol) and Cs2CO3 (18.4 g, 56.6 mmol) in 120 mL of acetonitrile in an ice bath under nitrogen. Add intermediate b3 (3.3 g, 18.85 mmol) to the reaction mixture, heat to 80°C, and react for 12 hours. Stop the reaction and remove the solvent under reduced pressure. Add 500 mL of ice water to the reaction mixture, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (PE / EtOAc, 3 / 1) to obtain a9-2 (4.2 g) as a yellow oil in a 49% yield. LCMS ESI-MS m / z: 457 [M+H] + .

[0297] Step 2: Under carbon monoxide (30 atm), intermediate a9-2 (4.1 g, 8.96 mmol) and TEA (4.5 g, 44.8 mmol) from the previous step were dissolved in 44 mL of methanol. Catalyst Pd(dppf)Cl2 (660 mg, 0.89 mmol) was added. The mixture was heated to 120°C and reacted for 12 hours, after which the reaction was stopped. 150 mL of ice water was added to the reaction solution, which was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (column: C18; CH3CN / H2O, 4 / 1) to afford a9 (2.2 g) as a white solid in a 51% yield. LCMS ESI-MS m / z: 481 [M+H] + .

[0298] Referring to the synthetic route of intermediate a9, similar raw materials / compounds were used to synthesize the following intermediates.

[0299] Preparation of intermediates a13-a16

[0300] Procedure: In an ice bath, under nitrogen, intermediate a9 (1.6 g, 3.37 mmol) and DIEA (652 mg, 5.05 mmol) were dissolved in 32 mL of anhydrous dichloromethane. Intermediate a1 (1.13 g, 5.05 mmol) and Et2OMgBr2 (1.31 g, 5.05 mmol) were added to the reaction mixture. The mixture was heated to 50°C and reacted for 12 hours. The reaction was stopped and the solvent was evaporated under reduced pressure. 50 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 flash reverse-phase column chromatography (column: C18; CH3CN / H2O, 5 / 1) to obtain a13 (200 mg) as a yellow oil in a 9% yield. LCMS ESI-MS m / z: 673 [M+H] + .

[0301] Referring to the synthetic route of intermediate a9, similar raw materials / compounds were used to synthesize the following intermediates.

[0302] Preparation of intermediate b1-b2

[0303] Step 1: Dissolve raw material b1-1 (24.0 g, 97.9 mmol) and triethylamine (14.9 g, 147 mmol) in 240 mL of anhydrous dichloromethane in an ice bath under nitrogen. Add methylsulfonyl chloride (16.8 g, 147 mmol) dropwise. The mixture is allowed to react at room temperature for 3 hours, then the reaction is stopped. Add 100 mL of ice water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (PE / EA, 10 / 1) to obtain b1-2 (30 g) as a yellow oil in a 95% yield.

[0304] Step 2: Dissolve the intermediate b1-2 (30 g, 92.8 mmol) and potassium thioacetate (16.0 g, 139 mmol) in 200 mL of anhydrous DMF. The mixture is heated to 50°C and reacted for 10 hours, after which the reaction is terminated. Add 500 mL of ice water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (PE / EA, 10 / 1) to afford b1-3 (26 g) as a yellow oil in a 92% yield. LCMS ESI-MS m / z: 304 [M+H] + .

[0305] Step 3: Dissolve the intermediate b1-3 (23.0 g, 75.8 mmol) from the previous step in 390 mL of methanol, add a 1 M aqueous solution of NaOH (83.3 mL) and dimethyl sulfate (11.5 g, 91.0 mmol), and allow the mixture to react at room temperature for 1 hour, after which the reaction is stopped. A 1 M aqueous solution of NaOH (166 mL) is added to the reaction solution, and after stirring for 30 minutes, the solvent is evaporated under reduced pressure. Dilute hydrochloric acid is added to adjust the pH to approximately 3, and the product is extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product is separated by column chromatography (PE / EA, 5 / 1) to afford b1 (18 g) as a colorless oil in a 91% yield. LCMS ESI-MS m / z: 262 [M+H] + .

[0306] Referring to the synthetic route of intermediate b1, similar raw materials / compounds were used to synthesize the following intermediates.

[0307] Preparation of intermediates b3-b11

[0308] Step 1: In an ice bath, under nitrogen, intermediate b2 (5.5 g, 21.5 mmol), N,O-dimethylhydroxylamine hydrochloride b3-1 (1.4 g, 23.1 mmol), and DIEA (8.2 g, 63.1 mmol) were dissolved in 110 mL of anhydrous dichloromethane. HOBT (2.8 g, 21.5 mmol) and EDCI (6.1 g, 31.6 mmol) were added. The mixture was reacted at room temperature for 2 hours, and then the reaction was stopped. 100 mL of ice water was added to the reaction solution, which was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 1 / 1) to obtain b3-2 (4.3 g), a yellow solid, in a 67% yield. LCMS ESI-MS m / z: 305 [M+H] + .

[0309] Step 2: Dissolve the intermediate b3-2 (4.3 g, 14.1 mmol) in 86 mL of anhydrous tetrahydrofuran in an ice bath. Add a 1 M solution of MeMgBr (21.2 mL) in tetrahydrofuran dropwise. Incubate the mixture in an ice bath for 3 hours, then stop the reaction. Add 100 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (PE / EA, 1 / 1) to obtain b3-3 (3.1 g) as a yellow oil in an 85% yield. LCMS ESI-MS m / z: 260 [M+H] + .

[0310] Step 3: Under nitrogen at -15°C, dissolve borane dimethyl sulfide complex BH3-Me2S (7.5 mL, 15.04 mmol) in a tetrahydrofuran solution (1.5 mL) of R-2-Me-CBS-oxazaborolidine (1 M, 2.31 mL). After stirring for 1 hour, a tetrahydrofuran solution (10 mL) of intermediate b3-3 (3.0 g, 11.6 mmol) from the previous step was added dropwise. The mixture was warmed to room temperature and reacted for 2 hours to terminate the reaction. 50 mL of icy methanol was added to the reaction solution, which was stirred for 30 minutes. Then, 100 mL of ice water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 2 / 1) to obtain b3-4 (2.5 g) as a colorless oil in an 83% yield. LCMS ESI-MS m / z: 262 [M+H] + .

[0311] Step 4: Dissolve the intermediate b3-4 (2.5 g, 9.6 mmol) in 13 mL of anhydrous tetrahydrofuran under nitrogen in an ice bath. Add a solution of LiAlH4 (19.1 mL, 19.13 mmol) in tetrahydrofuran (5 mL). Heat to 55°C and react for 2 hours to stop the reaction. Add 50 mL of saturated aqueous ammonium chloride to the reaction solution, stir for 30 minutes, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to obtain a colorless oil b3 (450 mg) in a 27% yield. LCMS ESI-MS m / z: 176 [M+H] + .

[0312] Referring to the synthetic route of intermediate b3, similar raw materials / compounds were used to synthesize the following intermediates.

[0313] Synthesis of intermediates C1-C6

[0314] Step 1: Under nitrogen, intermediate a6 (1.0 g, 2.70 mmol), DIEA (1.1 g, 8.10 mmol), and intermediate b9 (520 mg, 4.05 mmol) were dissolved in 20 mL of acetonitrile. The mixture was heated to 30°C for 12 hours, after which the reaction was stopped. 100 mL of ice water was added to the reaction solution, which was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (C18; CH3CN / H2O, 1 / 1) to afford c1-1 (1.0 g) as a pale yellow solid in 80% yield. LCMS ESI-MS m / z: 463 [M+H] + .

[0315] Step 2: Dissolve the intermediate c1-1 (180 mg, 0.38 mmol) and the starting material c1-2 (44 mg, 0.58 mmol) in 4 mL of DMSO in an ice bath. DIEA (151 mg, 1.16 mmol) was added dropwise. The mixture was reacted at room temperature for 13 hours, after which the reaction was stopped. Add 50 mL of ice water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product was separated by flash reverse-phase column chromatography (C18; CH3CN / H2O, 2 / 1) to afford c1 (140 mg) as a white solid in a 72% yield. LCMS ESI-MS m / z: 502 [M+H] + .

[0316] Referring to the synthetic route of intermediate c1, similar raw materials / compounds were used to synthesize the following intermediates.

[0317] Synthesis of intermediates C12-C15

[0318] Step 1: Dissolve the raw material c12-1 (3.0 g, 20.8 mmol) and oxalyl chloride (COCl) 2 (3.9 g, 31.2 mmol) in 15 mL of dichloromethane under an ice bath. Slowly add DMF (5 drops) to the system. After the addition is complete, react at room temperature for 2 hours. Stop the reaction and remove the solvent under reduced pressure. Dissolve the mixture in 5 mL of dichloromethane to prepare reagent S1. Dissolve the raw material (R)-3-fluoro-tetrahydropyrrole hydrochloride c12-2 (2.8 g, 22.9 mmol) and TEA (6.3 g, 62.4 mmol) in 10 mL of anhydrous dichloromethane. Add reagent S1 dropwise. After the addition is complete, react at room temperature for 3 hours and stop the reaction. 30 mL of ice water was added to the reaction mixture, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 1 / 2) to obtain a yellow oil c12-3 (3.5 g) in a yield of 78%. LCMS ESI-MS m / z: 216 [M+H] + .

[0319] Step 2: Dissolve the intermediate c12-3 (3.0 g, 13.9 mmol) from the previous step in 20 mL of anhydrous tetrahydrofuran under nitrogen in an ice bath. Add LiAlH4 (1.3 g, 34.84 mmol) and stir for 2 hours under ice bath to stop the reaction. Pour the reaction solution into 100 mL of ice water, extract with ethyl acetate, wash with saturated brine, and concentrate. The crude product is separated by column chromatography (100% EtOAc) to obtain oily compound c12 (1.3 g) in a yield of 54%. LCMS ESI-MS m / z: 174 [M+H] + .

[0320] Referring to the synthetic route of intermediate c12, similar raw materials / compounds were used to synthesize the following intermediates.

[0321] Synthesis of intermediates d1-d9, d16-d17

[0322] Step 1: Under nitrogen, intermediate a3 (631 mg, 1.58 mmol), DIEA (1.1 g, 7.90 mmol), and intermediate b3 (332 mg, 1.90 mmol) were dissolved in 13 mL of acetonitrile. The mixture was heated to 60°C for 12 hours, after which the reaction was stopped. 100 mL of ice water was added to the reaction solution, which was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 10 / 1) to afford d1-1 (470 mg) as a pale yellow solid in a 55% yield. LCMS ESI-MS m / z: 538 [M+H] + .

[0323] Step 2: Dissolve the intermediate d1-1 (470 mg, 0.87 mmol) and formic acid (61 mg, 1.31 mmol) in 2 mL of 1,4-dioxane in an ice bath. Add 50 mL of a 50% aqueous solution of NH2OH dropwise. The mixture is allowed to react at room temperature for 13 hours, after which the reaction is stopped. Add 10 mL of ice water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to afford d1-2 (390 mg) as a yellow solid in an 81% yield. LCMS ESI-MS m / z: 553 [M+H] + .

[0324] Step 3: Under nitrogen, the intermediate d1-2 (390 mg, 0.70 mmol) from the previous step was dissolved in 2 mL of 1,4-dioxane. Dilute hydrochloric acid (3.9 mL, 4 M) was added dropwise. After completion of the addition, the mixture was heated to 40°C and allowed to react for 12 hours, after which the reaction was stopped. 50 mL of ice water was added to the reaction solution, 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 column chromatography (DCM / MeOH, 10 / 1) to afford d1 (290 mg) as a white solid in an 83% yield. LCMS ESI-MS m / z: 491 [M+H] + .

[0325] Referring to the synthetic route of intermediate d1, similar raw materials / compounds were used to synthesize the following intermediates.

[0326] Synthesis of intermediates d10-d15

[0327] Step 1: Under nitrogen, intermediate a3 (955 mg, 5.51 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran. LiHMDS (1 M in THF) (7.5 mL, 7.51 mmol) was added dropwise and stirred at room temperature for 30 minutes. Intermediate c12 (2.0 g, 5.01 mmol) was added to the reaction solution, and the mixture was heated to 60°C for 1 hour, after which 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 column chromatography (PE / EA, 4 / 1) to afford d10-1 (1.1 g) as a pale yellow solid in a 39% yield. LCMS ESI-MS m / z: 536 [M+H] + .

[0328] Step 2: Dissolve the intermediate d10-1 (956 mg, 1.78 mmol) and formic acid (123 mg, 2.68 mmol) in 4 mL of 1,4-dioxane in an ice bath. Add 50 mL of a 50% aqueous solution of NH2OH dropwise. The mixture is allowed to react at room temperature for 2 hours, after which the reaction is stopped. Add 50 mL of ice water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to afford d10-2 (950 mg) as a yellow solid in a 97% yield. LCMS ESI-MS m / z: 551 [M+H] + .

[0329] Step 3: Under nitrogen, the intermediate d10-2 (950 mg, 1.72 mmol) from the previous step was dissolved in 5 mL of 1,4-dioxane. Dilute hydrochloric acid (9.5 mL, 4 M) was added dropwise. After completion of the addition, the mixture was heated to 40°C and allowed to react for 12 hours, after which the reaction was stopped. The reaction mixture was added with 60 mL of ice water 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 column chromatography (DCM / MeOH, 10 / 1) to afford d10 (615 mg) as a yellow solid in a 73% yield. LCMS ESI-MS m / z: 489 [M+H] + .

[0330] Referring to the synthetic route of intermediate d10, similar raw materials / compounds were used to synthesize the following intermediates.

[0331] Synthesis of intermediates d18-d22

[0332] Procedure: Under nitrogen, intermediate a8 (500 mg, 1.09 mmol) and DIEA (845 mg, 6.53 mmol) were dissolved in 10 mL of anhydrous DMSO. Intermediate b9 (422 mg, 3.27 mmol) and 4A molecular sieves (1.5 g) were added. The reaction mixture was heated to 90°C for 12 hours, then cooled to room temperature to terminate the reaction. 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 HPLC (column: Xbridge Prep phenyl OBD Colum, 30 x 150 mm, 5 μm; mobile phase A: H2O (0.05% TFA), mobile phase B: CH3CN; flow rate: 80 mL / min; retention time: 24 min) to afford a9 (240 mg) as a yellow solid in a 40% yield. LCMS ESI-MS m / z: 552 [M+H] + .

[0333] Referring to the synthetic route of intermediate d18, similar raw materials / compounds were used to synthesize the following intermediates.

[0334] Synthesis of intermediates d23-d26

[0335] Step 1: Under nitrogen, intermediate d20 (1000 mg, 1.62 mmol) and TMSCl (0.5 g, 4.88 mmol) were dissolved in 10 mL of DCM. Ethylene glycol (10 mL) and 4A molecular sieves (1.5 g) were added and the mixture was allowed to react at room temperature for 12 hours, after which the reaction was stopped. 100 mL of ice water was added to the reaction solution, which was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. A white solid, d23 (300 mg), was obtained in a 36% yield. LCMS ESI-MS m / z: 514 [M+H] + .

[0336] Referring to the synthetic route of intermediate d23, similar raw materials / compounds were used to synthesize the following intermediates.

[0337] Synthesis of intermediate e1

[0338] Step 1: Under nitrogen, raw material e1-2 (1000 mg, 6.36 mmol) and TEA (1.9 g, 19.1 mmol) were dissolved in 20 mL of anhydrous NMP. Raw material 1,1-difluoro-2-iodoethane e1-1 (1.8 g, 9.54 mmol) and 4A molecular sieves (1.5 g) were added. The reaction mixture was heated to 100°C for 12 hours, cooled to room temperature, and stopped. 100 mL of ice water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (column: C18; CH3CN / H2O (10 mmol / L NH4HCO3) = 1 / 1) to obtain e1-3 (1.2 g) as a yellow oil in an 85% yield. LCMS ESI-MS m / z: 222 [M+H] + .

[0339] Step 2: Under nitrogen, the intermediate e1-3 (1.2 g, 5.42 mmol) and LiOH (0.3 g, 10.9 mmol) from the previous step were dissolved in 25 mL of a 4 / 1 mixture of tetrahydrofuran and water. The mixture was allowed to react at room temperature for 6 hours, after which the reaction was stopped. Dilute hydrochloric acid was added to the reaction solution to adjust the pH to approximately 3. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative HPLC (column: Atlantis T3 Prep OBD, 19 x 250 mm, 5 μm; mobile phase A: Water (0.1% HCl), mobile phase B: CH3CN; flow rate: 25 mL / min; retention time: 7.23 min) to afford e1 (50 mg) as a white solid in a 5% yield. LCMS ESI-MS m / z: 194 [M+H] + .

[0340] Example 2: Synthesis of the molecule of the present invention

[0341] Synthesis of target molecules P1-P5

[0342] Step 1: Under nitrogen in an ice bath, intermediate b3 (253 mg, 1.44 mmol) was dissolved in 8 mL of anhydrous tetrahydrofuran. NaH (35 mg, 1.44 mmol) was added and stirred for 30 minutes. Intermediate a4 (360 mg, 0.96 mmol) was then added to the reaction mixture. The mixture was warmed to room temperature and reacted for 12 hours. 50 mL of ice water was added to the reaction mixture, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (C18; CH3CN / H2O, 3 / 2) to afford P1-1 (40 mg) as a pale yellow solid in 8% yield. LCMS ESI-MS m / z: 513 [M+H] + .

[0343] Step 2: Under nitrogen, compound P1-1 (40 mg, 0.078 mmol), ammonium acetate (12 mg, 0.12 mmol), and elemental S (4.1 mg, 0.12 mmol) were dissolved in 1 mL of ethanol. The mixture was heated to 60°C for 1 hour. Malononitrile (8.7 mg, 0.13 mmol) was added to the reaction solution, and the temperature was raised to 80°C for 1 hour to terminate the reaction. 5 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 preparative HPLC (column: Xselect CSH Prep C18 OBD Colum, 19*250 4 mm, 5 μm; mobile phase A: H2O (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; retention time: 8.8 min) to obtain the target molecule P1 (4.3 mg) in a yield of 9%. LCMS ESI-MS m / z:593[M+H] + .

[0344] 1 H NMR (300MHz, DMSO-d6) δ7.94(d,J=5.9Hz,1H),7.51(d,J=5.9Hz,1H),6.99(s,2H),5.57(t,J=6.3Hz,1H),3.37–3.06(m,4H),2.9 1(d,J=6.6Hz,1H),2.71(s,1H),2.56(s,1H),2.41(s,3H),2.21(t,J=8.5Hz,2H),1.98(d,J=67.0Hz,12H),1.39(d,J=6.3Hz,3H).

[0345] Step 1: In an ice bath, under nitrogen protection, intermediate a13 (203 mg, 0.29 mmol) and hydroxylamine hydrochloride (31 mg, 0.45 mmol) were dissolved in 1 mL of 1,4-dioxane. HCOOH (21 mg, 0.45 mmol) was added and stirred for 30 minutes. The mixture was then heated to 35°C and reacted for 12 hours. 5 mL of ice water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow solid P4-1 (200 mg). LCMS ESI-MS m / z: 688 [M+H] + .

[0346] Step 2: Dissolve compound P4-1 (200 mg, 0.29 mmol) in 1 mL of 4 M hydrogen chloride in 1,4-dioxane in an ice bath. Warm the mixture to 35°C and react for 12 hours. Add 5 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain a crude yellow solid (50 mg). Dissolve the crude product in 1 mL of dichloromethane, add ethylenediamine (50 mg, 0.09 mmol), and react at room temperature for 1 hour. Then stop the reaction. The solvent was evaporated under reduced pressure, and the crude product was separated by preparative HPLC chromatography (chromatographic column: Xbridge Prep phenyl OBD Colum, 19*250mm, 5μm; mobile phase A: H2O (10mmol / L NH4HCO3), mobile phase B: MeOH; flow rate: 20mL / min; retention time: 12.5min) to obtain compound P4-2 (10mg), yield: 21%, LCMS ESI-MS m / z: 496[M+H] + .

[0347] Step 3: Under nitrogen, compound P4-2 (10 mg, 0.02 mmol), ammonium acetate (3.1 mg, 0.03 mmol), and elemental S (1.1 mg, 0.03 mmol) were dissolved in 1 mL of ethanol. The mixture was heated to 60°C for 1 hour. Malononitrile (2.2 mg, 0.03 mmol) was added to the reaction solution, and the temperature was raised to 80°C for 1 hour to terminate the reaction. 5 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 preparative HPLC (column: Xselect CSH Prep Fluoro-phenyl Column, 19*250 mm, 5 μm; mobile phase A: H2O (0.1% formic acid), mobile phase B: CH3CN; flow rate: 20 mL / min; retention time: 12.7 min) to obtain the target molecule P4 (1.7 mg) in a yield of 15%. LCMS ESI-MS m / z:576[M+H] + .

[0348] 1H NMR (400MHz, DMSO-d6) δ7.46 (t, J = 2.9 Hz, 1H), 6.94 (s, 2H), 6.51 (dd, J = 3.5, 1. 7Hz,1H),5.54(q,J=6.3Hz,1H),3.31(dd,J=9.0,6.4Hz,2H),3.27–3.11(m,2H), 2.96–2.85(m,1H),2.77–2.66(m,1H),2.54(d,J=4.5Hz,2H),2.41(s,3H),2.18 (q,J=12.0,10.3Hz,2H),2.07(s,3H),1.93–1.73(m,9H),1.34(d,J=6.3Hz,3H).

[0349] Referring to the synthetic route of target molecule P1 or P4, similar raw materials / intermediates (such as intermediates b3-b11, a3-a16) were used to synthesize the following target molecules.

[0350] Example 3:

[0351] Synthesis of target molecule H1

[0352] Step 1: Under nitrogen, intermediate d18 (240 mg, 0.44 mmol), ammonium acetate (91 mg, 1.18 mmol), and elemental S (15.3 mg, 0.48 mmol) were dissolved in 5 mL of ethanol. The mixture was heated to 60°C for 0.5 hours. Malononitrile (47.4 mg, 0.72 mmol) was added to the reaction solution, and the temperature was raised to 80°C for 1 hour to terminate the reaction. The reaction solution was added with 5 mL of ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative HPLC (column: Xselect CSH Prep C18 OBD Colum, 30 x 150 mm, 5 μm; mobile phase A: H2O (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; retention time: 11 minutes) to obtain compound H1-1 (200 mg) in a yield of 73%. LCMS ESI-MS m / z:632[M+H] + .

[0353] Step 2: Dissolve the compound H1-1 (200 mg, 0.32 mmol) from the previous step in 8 mL of a 4 M solution of hydrogen chloride in 1,4-dioxane. The mixture is allowed to react at room temperature for 1 hour. Add 50 mL of ice water to the reaction solution, adjust the pH to approximately 8 with a saturated aqueous sodium bicarbonate solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse-phase column chromatography (C18 column; CH3CN / H2O, 3 / 2, 1% HCOOH) to obtain the target molecule H1 (150 mg) in an 89% yield. LCMS ESI-MS m / z: 532 [M+H] + .

[0354] H1-3HCOOH salts: 1 H NMR(300MHz,DMSO-d6)δ5.37(t,J=6.3Hz,1H),4.14(s,4H),3.17-3.05(m,3H),2.53–2.52(m,2H) ),2.47–2.37(m,4H),2.08–1.91(m,8H),1.86(s,1H),1.78–1.73(m,4H),1.32(d,J=6.0Hz,3H).

[0355] Referring to the synthetic route of the target molecule H1, similar raw materials / intermediates (such as intermediates d18-d22) were used to synthesize the following key intermediates.

[0356] Example 4:

[0357] Synthesis of target molecules H2-H3, H39-H44, H52-H53, and H77

[0358] Step 1: In an ice bath, under nitrogen, compound H1 (70 mg, 0.13 mmol), starting material H2-1 (15 mg, 0.14 mmol), and acetic acid (0.15 mL) were dissolved in 1 mL of dichloroethane. The mixture was stirred for 0.5 hours. Na(OAc)3BH (39 mg, 0.18 mmol) was added to the reaction mixture, and the reaction was allowed to proceed at room temperature for 2 hours to terminate the reaction. 5 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 preparative HPLC (column: Xselect CSH Prep C18 OBD Colum, 19 x 250 mm, 5 μm; mobile phase A: H2O (0.1% formic acid), mobile phase B: CH3CN; flow rate: 20 mL / min; retention time: 10.2 min) to afford compounds H2a (3.9 mg) and H2b (3.8 mg) in a 10% yield. LCMS ESI-MS m / z:616[M+H] + .

[0359] 1 H NMR of H2a: (300MHz, DMSO-d6) δ6.96(s,2H),5.38(p,J=6.3Hz,1H),3.96(s,2H),3.89(d,J=4.3Hz ,2H),3.84–3.68(m,2H),3.63(q,J=7.6Hz,1H),3.40(dd,J=8.4,5.9Hz,1H),3.05(dd,J=16 .0,4.7Hz,1H),3.00–2.92(m,1H),2.79–2.55(m,6H),2.44(d,J=7.2Hz,1H),2.34(s,3H),2 .24–2.16(m,1H),2.07(s,1H),2.04–1.80(m,9H),1.72–1.52(m,4H),1.27(d,J=6.3Hz,3H).

[0360] 1H NMR of H2b: (300MHz, DMSO-d6) δ6.96 (s, 2H), 5.38 (p, J = 6.2Hz, 1H), 4.02–3.84 (m, 4H), 3.82– 3.70(m,2H),3.63(q,J=7.6Hz,1H),3.41(dd,J=8.5,5.9Hz,1H),3.05(dd,J=16.0,4.5 Hz,1H),2.99–2.92(m,1H),2.78–2.55(m,6H),2.44(d,J=7.2Hz,1H),2.35(s,3H),2.2 0(q,J=8.4,7.7Hz,1H),2.05–1.79(m,10H),1.70–1.52(m,4H),1.27(d,J=6.3Hz,3H).

[0361] Referring to the synthetic route of target molecule H2, similar raw materials / intermediates (such as intermediates b3-b11, d1-d20) were used to synthesize the following target molecules.

[0362] Example 5:

[0363] Synthesis of target molecules H4-H10, H16-H26, H56, H59, and H66

[0364] Procedure: Compound H1 (40 mg, 0.07 mmol), starting material H4-1 (12 mg, 0.11 mmol), and DIEA (49 mg, 0.37 mmol) were dissolved in 1 mL of DMF under nitrogen in an ice bath. The mixture was stirred for 5 minutes. EDCI (22 mg, 0.11 mmol) and HOBT (15 mg, 0.11 mmol) were added to the reaction mixture and allowed to react at room temperature for 2 hours, after which the reaction was stopped. 5 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 preparative HPLC (column: Xselect CSH Prep C18 OBD Colum, 300 x 150 mm, 5 μm; mobile phase A: H2O (0.1% formic acid), mobile phase B: CH3CN; flow rate: 60 mL / min; retention time: 6.2 min) to afford compound H4 (3.1 mg) in a yield of 6%. LCMS ESI-MS m / z:616[M+H] + .

[0365] 1H NMR(300MHz,DMSO-d6)δ8.28(s,1H),6.97(s,2H),5.48–5.37(m,1H),4.84–4.62(m,6H) ),4.65–4.52(m,2H),4.26–4.15(m,1H),3.06(d,J=16.6Hz,1H),3.00–2.92(m,1H),2. 70–2.52(m,4H),2.36(d,J=3.1Hz,3H),2.22(qd,J=8.0,6.8,3.4Hz,1H),2.13–1.91(m ,4H),1.91–1.75(m,5H),1.68(tq,J=9.2,6.2,5.1Hz,3H),1.30(dd,J=6.3,3.2Hz,3H).

[0366] Referring to the synthetic route of target molecule H4, similar raw materials / intermediates (such as intermediates b3-b11, d1-d20, e1, etc.) were used to synthesize the following target molecules.

[0367] Example 6:

[0368] Synthesis of target molecules H11-H14, H54, H58, H73-H74

[0369] Procedure: Dissolve compound H1 (20 mg, 0.035 mmol) and TEA (71 mg, 0.7 mmol) in 1 mL of dichloromethane in an ice bath under nitrogen. Stir the mixture for 5 minutes. Add methyl chloroformate H11-1 (3.8 mg, 0.04 mmol) to the reaction mixture, allow to react at room temperature for 2 hours, and then stop the reaction. Add 5 mL of ice water to the reaction mixture, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by preparative HPLC to obtain compound H11 (3.8 mg) in a yield of 19%. LCMS ESI-MS m / z: 590 [M+H] + .

[0370] H11: 1H NMR(300MHz,DMSO-d6)δ6.96(s,2H),5.39(td,J=6.4,2.3Hz,1H),4.66(d,J=12.7Hz,2H),4.5 7(dd,J=15.3,7.3Hz,2H),3.69(d,J=2.0Hz,3H),3.06(dd,J=16.3,4.8Hz,1H),2.96(dt,J=8. 9,4.3Hz,1H),2.63(tt,J=11.3,5.6Hz,2H),2.54(d,J=5.3Hz,2H),2.35(d,J=2.3Hz,3H),2.2 1(q,J=8.3Hz,1H),2.11–1.76(m,9H),1.68(q,J=8.0,6.9Hz,3H),1.30(dd,J=6.3,3.7Hz,3H).

[0371] Procedure: Dissolve compound H1 (60 mg, 0.113 mmol) and DIEA (43 mg, 0.33 mmol) in 1 mL of methanol in an ice bath under nitrogen protection, and stir the mixture for 5 minutes. Add raw material H73-1 (40 mg, 0.22 mmol) to the reaction solution, react at room temperature for 2 hours, and then stop the reaction. Add 5 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse column chromatography to obtain compound H73 (3.0 mg) in a yield of 4%. LCMS ESI-MS m / z: 615 [M+H] + .

[0372] H73: 1 H NMR (300MHz, DMSO-d6) δ7.87(s,1H),6.96(s,2H),5.47–5.33(m,1H),4.30(d,J=13.5Hz,2H),4.00(dd,J=28.3,14.9Hz,2H),3. 56(t,J=8.8Hz,1H),3.23–2.95(m,4H),2.73–2.53(m,4H),2.37–2.14(m,5H),2.07–1.60(m,13H),1.28(dd,J=6.3,1.4Hz,3H).

[0373] Referring to the synthetic routes of target molecules H11 or H73, similar raw materials / intermediates (such as intermediates b3-b11, d1-d20) were used to synthesize the following target molecules.

[0374] Example 7:

[0375] Synthesis of target molecules H27-H31, H57, H86-H87

[0376] Step 1: Dissolve compound H1 (50 mg, 0.094 mmol) and TEA (95 mg, 0.94 mmol) in 1 mL of anhydrous tetrahydrofuran in an ice bath under nitrogen protection. Stir the mixture for 5 minutes. Add 4-nitro-phenyl chloroformate H27-1 (19 mg, 0.094 mmol) to the reaction solution and allow to react for 2 hours in an ice bath. Stop the reaction. Add 5 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain crude compound H27-2. LCMS ESI-MS m / z: 697 [M+H] + .

[0377] Step 2: In an ice bath, under nitrogen, the raw materials H27-3 (4.3 mg, 0.058 mmol) and NaH (1.4 mg, 0.058 mmol) were dissolved in 1 mL of anhydrous tetrahydrofuran. The crude compound H27-2 (20 mg, 0.029 mmol) from the previous step was added and reacted at room temperature for 2 hours, after which the reaction was stopped. 5 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 obtain the crude compound. The crude product was separated by flash reverse-phase column chromatography (column: C18; CH3CN / H2O (10 mmol / L NH4HCO3 + 0.05% NH3-H2O) = 2 / 3) to obtain the target molecule H27 (3.2 mg) in a yield of 18%. LCMS ESI-MS m / z: 632 [M+H] + .

[0378] 1 H NMR(300MHz,DMSO-d6)δ6.97(s,2H),5.50–5.36(m,2H),4.86–4.73(m,3H), 4.73–4.63(m,2H),4.57(q,J=5.9Hz,3H),3.12–3.03(m,1H),2.96(s,1H),2 .68–2.57(m,2H),2.54(s,1H),2.40–2.30(m,3H),2.21(q,J=8.8,8.2Hz,1H ),2.13–1.90(m,5H),1.90–1.75(m,5H),1.67(s,3H),1.30(d,J=6.3Hz,3H).

[0379] Referring to the synthetic route of the target molecule H27, similar raw materials / intermediates (such as intermediates b3-b11, d1-d20) were used to synthesize the following target molecules.

[0380] Example 8:

[0381] Synthesis of target molecules H32-H38, H45-H47, H55, H64-H65, and H88

[0382] Procedure: In an ice bath, under nitrogen, the starting materials H32-1 (2.7 mg, 0.04 mmol) and TEA (4.0 mg, 0.04 mmol) were dissolved in 1 mL of anhydrous dichloromethane. Triphosgene (3.7 mg, 0.013 mmol) was added and the mixture was allowed to react at room temperature for 1 hour. Compound H1 (20 mg, 0.038 mmol) and TEA (12 mg, 0.12 mmol) were added to the reaction mixture and the reaction was continued for 1 hour before stopping. The reaction mixture was added with 5 mL of ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (C18 column; CH3CN / H2O (0.1% HCOOH) = 2 / 3) to obtain the target molecule H32 (4.2 mg) in an 18% yield. LCMS ESI-MS m / z: 628 [M+H] + .

[0383] 1 H NMR (300MHz, DMSO-d6) δ6.96 (s, 2H), 5.42 (p, J = 6.3Hz, 1H), 4.83–4.73 (m, 2H), 4. 73–4.61(m,2H),3.07(dd,J=16.5,4.9Hz,1H),3.00(s,4H),2.70–2.59(m,2H),2.5 5(d,J=5.2Hz,2H),2.36(d,J=2.5Hz,3H),2.22(td,J=9.1,6.8Hz,1H),2.13–1.92( m,4H),1.92–1.73(m,5H),1.67(tt,J=8.9,6.0,4.8Hz,3H),1.31(d,J=6.3Hz,3H).

[0384] Referring to the synthetic route of the target molecule H32, similar raw materials / intermediates (such as intermediates b3-b11, d1-d20) were used to synthesize the following target molecules.

[0385] Example 9:

[0386] Synthesis of target molecules H48-H51

[0387] Procedure: In an ice bath, under nitrogen, compound H1 (50 mg, 0.094 mmol) and Cs2CO3 (153 mg, 0.47 mmol) were dissolved in 1 mL of DMF. Bromoacetone H48-1 (19.4 mg, 0.14 mmol) was added and allowed to react at room temperature for 6 hours. 5 mL of ice water was added to the reaction mixture, which was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (C18 column; CH3CN / H2O (0.1% HCOOH) = 1 / 1) to afford the target molecule H48 (45 mg) in an 82% yield. LCMS ESI-MS m / z: 588 [M+H] + .

[0388] 1 H NMR(400MHz,DMSO-d6)δ6.95(s,2H),5.39(q,J=6.0Hz,1H),4.14–3.92(m,4H) ,3.75(s,2H),3.11–3.00(m,1H),2.96(dd,J=8.4,5.2Hz,1H),2.58(ddd,J=22 .4,11.6,6.2Hz,4H),2.35(s,3H),2.24–2.16(m,1H),2.10(s,3H),2.05–1.90 (m,4H),1.89–1.75(m,5H),1.67(tt,J=7.4,3.7Hz,3H),1.28(d,J=6.3Hz,3H).

[0389] Procedure: In an ice bath, under nitrogen, compound H48 (25 mg, 0.043 mmol) was dissolved in 1 mL of methanol. NaBH4 (4.9 mg, 0.13 mmol) and 1 drop of acetic acid were added and allowed to react at room temperature for 6 hours. The reaction mixture was added with 20 mL of ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (C18 column; CH3CN / H2O (0.1% HCOOH) = 1 / 1) to afford the target molecule H49 (3.0 mg) in a 12% yield. LCMS ESI-MS m / z: 590 [M+H] + .

[0390] 1H NMR (400MHz, DMSO-d6) δ8.28(s,1H),6.96(s,2H),5.38(p,J=6.4Hz,1H),4.02–3.91(m ,4H),3.81(q,J=6.1Hz,1H),3.06(dd,J=16.0,4.9Hz,1H),2.99–2.91(m,1H),2.69–2.5 7(m,4H),2.36(s,3H),2.21(td,J=9.0,6.7Hz,1H),2.05–1.78(m,9H),1.67(dtt,J=12. 0,8.8,3.8Hz,3H),1.28(d,J=6.3Hz,3H),1.24(d,J=3.3Hz,2H),1.09(d,J=6.2Hz,3H).

[0391] Referring to the synthetic routes of target molecules H48 or H49, similar raw materials / intermediates were used to synthesize the following target molecules.

[0392] Example 10:

[0393] Synthesis of target molecules H60-H63, H67-H72, H76, H78-H85

[0394] Step 1: In an ice bath, under nitrogen, compound H1 (100 mg, 0.19 mmol), starting material H60-1 (38 mg, 0.19 mmol), and acetic acid (0.01 mL) were dissolved in 1 mL of methanol and stirred for 0.5 hours. NaBH3CN (59 mg, 0.94 mmol) was added to the reaction solution and allowed to react at room temperature for 12 hours, after which the reaction was stopped. 5 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 reverse-phase column chromatography (C18 column; CH3CN / H2O (10 mmol / L NH4HCO3) = 4 / 1) to afford compound H60-2 (90 mg) in a 67% yield. LCMS ESI-MS m / z: 715 [M+H] + .

[0395] Step 2: Dissolve the compound H60-2 (90 mg, 0.13 mmol) in 1 mL of dichloromethane in an ice bath. Add a 1,4-dioxane solution of hydrogen chloride (1 mL, 4 M) to the reaction mixture. Allow to react at room temperature for 1 hour, then stop the reaction. Evaporate the solvent under reduced pressure to obtain crude compound H60-3 (70 mg) in a 90% yield. LCMS ESI-MS m / z: 615 [M+H] + .

[0396] Step 3: Dissolve compound H60-3 (35 mg, 0.057 mmol) and TEA (29 mg, 0.285 mmol) in 1 mL of dichloromethane in an ice bath, and stir the mixture for 0.5 hours. Add acetyl chloride (5.0 mg, 0.06 mmol) to the reaction solution, react at room temperature for 1 hour, and then stop the reaction. Add 5 mL of ice water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse column chromatography (chromatographic column: C18; CH3CN / H2O=1 / 1) to obtain compound H60 (7 mg), yield: 18%. LCMS ESI-MS m / z: 657 [M+H] + .

[0397] 1 H NMR(400MHz, DMSO-d6)δ6.95(s,2H),5.40(h,J=5.9Hz,1H),4.05–3.85(m,4H),3.68–3.38(m,3H),3.26–2.91(m,4H),2.80–2.52 (m,6H),2.35(s,3H),2.20(q,J=8.4,7.7Hz,1H),2.14–1.91(m,7H),1.91–1.74(m,5H),1.73–1.49(m,4H),1.28(d,J=6.3Hz,3H).

[0398] Procedure: In an ice bath, under nitrogen, compound H1 (50 mg, 0.08 mmol) and starting material 2-amino-3-acetylpyridine H67-1 (26 mg, 0.19 mmol) were dissolved in 1 mL of methanol and stirred for 0.5 h. NaBH3CN (25 mg, 0.40 mmol) was added to the reaction mixture, and the reaction was allowed to proceed at room temperature for 12 h, after which the reaction was stopped. 5 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 flash reverse-phase column chromatography (C18 column; CH3CN / H2O (10 mmol / L NH4HCO3) = 4 / 1) to afford compound H67 (5 mg) in a 10% yield. LCMS ESI-MS m / z: 652 [M+H] + .

[0399] H67: 1H NMR (300MHz, DMSO-d6) δ7.88 (dd, J=4.9, 1.8Hz, 1H), 7.38 (dt, J=7.4, 2.0Hz, 1H), 6.96 (s ,2H),6.55(dd,J=7.3,4.9Hz,1H),6.07(s,2H),5.40(p,J=6.4Hz,1H),4.07(d,J=14.8Hz, 1H),3.91–3.70(m,4H),3.09–2.88(m,2H),2.56(d,J=9.9Hz,4H),2.32(d,J=2.0Hz,3H),2 .25–2.10(m,1H),2.08–1.59(m,12H),1.40(d,J=6.5Hz,3H),1.25(dd,J=6.4,2.4Hz,3H).

[0400] Referring to the synthetic routes of target molecules H60 or H67, similar raw materials / intermediates (such as H1b-H1d) were used to synthesize the following target molecules.

[0401] Example 11:

[0402] Synthesis of target molecule H75

[0403] Step 1: Dissolve compound H1 (40 mg, 0.075 mmol) and TEA (76 mg, 0.75 mmol) in 1 mL of dichloromethane in an ice bath under nitrogen. Stir the mixture for 0.5 hour. Add chloromethyl chloroformate (15 mg, 0.11 mmol) to the reaction mixture, allow to react at room temperature for 1 hour, and then stop the reaction. Add 5 mL of ice water to the reaction mixture, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse-phase column chromatography (column: C18; CH3CN / H2O = 1 / 1) to obtain compound H75-1 (30 mg) in a 64% yield. LCMS ESI-MS m / z: 624 [M+H] + .

[0404] Step 2: Under nitrogen, compound H75-1 (40 mg, 0.064 mmol) and NaCN (16 mg, 0.32 mmol) from the previous step were dissolved in 1 mL of DMSO and allowed to react at room temperature for 4 hours, after which the reaction was stopped. 5 mL of ice water was added to the reaction solution, which was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (C18 column; CH3CN / H2O (10 mmol / L NH4HCO3) = 3 / 2) to afford compound H75 (8 mg), yield: 20%. LCMS ESI-MS m / z: 615 [M+H] + .

[0405] 1 H NMR (400MHz, DMSO-d6) δ6.95 (s, 2H), 5.43–5.37 (m, 1H), 5.04 (d, J = 5.2Hz, 2H) ,4.72(d,J=11.2Hz,2H),4.63(dd,J=14.0,8.3Hz,2H),3.07(d,J=14.7Hz,1H), 2.96(t,J=6.8Hz,1H),2.72–2.54(m,4H),2.36(d,J=2.2Hz,3H),2.27–2.18(m, 1H), 2.10–1.91 (m, 4H), 1.85 (s, 5H), 1.68 (s, 3H), 1.31 (dd, J = 6.4, 4.1Hz, 3H).

[0406] Example 12:

[0407] Synthesis of target molecules H89-H93

[0408] Step 1: Under nitrogen, compound d23 (150 mg, 0.29 mmol), K2CO3 (101 mg, 0.73 mmol), and 3-fluoro-2-nitropyridine H89-1 (83 mg, 0.58 mmol) were dissolved in 3 mL of CH3CN. The ligand Xphos (42 mg, 0.09 mmol) and the catalyst Pd2(dba)3 (54 mg, 0.06 mmol) were added. The mixture was heated to 80°C for 12 hours and filtered. The reaction mixture was added with 5 mL of ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse phase column chromatography (C18 column; CH3CN / H2O (0.1% TFA) = 3 / 2) to afford compound H89-2 (120 mg) in a 65% yield. LCMS ESI-MS m / z: 636 [M+H] + .

[0409] Step 2: Dissolve compound H89-2 (120 mg, 0.19 mmol) and Pd / C (12 mg, 10%) in 6 mL of methanol. React under hydrogen (4 atm) at room temperature for 14 hours, stop the reaction, and filter. Add 15 mL of ice water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to obtain compound H89-3 (60 mg) in a yield of 52%. LCMS ESI-MS m / z: 606 [M+H] + .

[0410] Step 3: Dissolve compound H89-3 (60 mg, 0.11 mmol) in 3 mL of 6M hydrogen chloride in 1,4-dioxane. Allow to react at room temperature for 12 hours, then stop the reaction. Evaporate the solvent under reduced pressure to obtain compound H89-4 (40 mg) in a 65% yield. LCMS ESI-MS m / z: 562 [M+H] + .

[0411] Step 3: Under nitrogen, compound H89-4 (40 mg, 0.07 mmol), ammonium acetate (8.8 mg, 0.11 mmol), and elemental S (3.7 mg, 0.11 mmol) were dissolved in 2 mL of ethanol and the mixture was heated to 60°C for 0.5 hours. Malononitrile (7.8 mg, 0.12 mmol) was added to the reaction solution, and the temperature was raised to 80°C for 5 hours to terminate the reaction. The reaction solution was added with 5 mL of ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative HPLC (XSelect CSH Prep C18 OBD Column, 30 x 150 mm, 5 μm; mobile phase A: H2O (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; retention time: 8.73 min) to obtain compound H89 (10.8 mg) in a yield of 24%. LCMS ESI-MS m / z:642[M+H] + .

[0412] 1H NMR (300MHz, DMSO-d6) δ7.67(dd,J=4.9,1.5Hz,1H),7.40(dd,J=7.8,1.6Hz,1H),6.96( s,2H),6.57(dd,J=7.7,4.9Hz,1H),5.70(s,2H),5.44(p,J=6.3Hz,1H),5.18(d,J=55.5 Hz,1H),4.63–4.34(m,4H),3.43(s,1H),3.32(d,J=4.7Hz,1H),3.09(d,J=13.1Hz,1H), 2.99(m,1H),2.73–2.53(m,3H),2.43(s,3H),2.18–1.79(m,10H),1.31(d,J=6.3Hz,3H).

[0413] Referring to the synthetic route of the target molecule H89, similar raw materials / intermediates (such as H1b-H1d) were used to synthesize the following target molecules.

[0414] Example 13:

[0415] Synthesis of target molecule H94

[0416] Step 1: In an ice bath, under nitrogen, compound H1b (150 mg, 0.27 mmol) and starting material H53-1 (24 mg, 0.27 mmol) were dissolved in 2 mL of methanol and stirred for 0.5 hours. NaBH3CN (86 mg, 1.37 mmol) was added to the reaction solution, and the temperature was raised to 50°C for 1 hour to terminate the reaction. 15 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 reverse-phase column chromatography (C18 column; CH3CN / H2O (0.1% formic acid) = 1 / 1) to obtain compound H94-1 (57 mg) in a 34% yield. LCMS ESI-MS m / z: 620 [M+H] + .

[0417] Step 2: Compound H94-1 (57 mg, 0.09 mmol) from the previous step was dissolved in 0.5 mL of 1,4-dioxane, and DDQ (8.4 mg, 0.04 mmol) was added. The mixture was reacted at room temperature for 0.5 h, after which the reaction was stopped. The solvent was evaporated under reduced pressure, and the crude product was separated by preparative HPLC (column: Xbridge Prep OBD C18 Column, 30 x 150 mm, 5 μm; mobile phase A: H2O (10 mmol / L NH4HCO3 + 0.05% NH3·H2O), mobile phase B: CH3CN; flow rate: 60 mL / min, retention time: 8.62 min) to obtain compound H94 (1.8 mg), yield: 3%. LCMS ESI-MS m / z: 618 [M+H] + .

[0418] 1 H NMR (400MHz, DMSO-d6) δ7.64(s,2H),6.94(s,2H),5.60–5.58(m,1H),5.28–5.12(m,2H),4.15–4.12(m,1H),4.04–3.91(m,2H),3.85– 3.81(m,1H),3.14–3.10(m,3H),2.68–2.60(m,4H),2.58–2.56(m,3H),2.32–2.18(m,1H),2.10–1.75(m,11H),1.33(d,J=6.3Hz,3H).

[0419] Example 14:

[0420] Compounds for KRAS G12D Mediated p-ERK inhibition test (directly reflects the cellular level inhibitory effect of the test compound). Details are as follows:

[0421] AGS cells cultured in F-12K medium (Gibco, Cat. No. 30-2004) containing 10% fetal bovine serum and 1% penicillin-streptomycin were seeded onto 384-well microplates and incubated overnight at 37°C in 5% carbon dioxide. 200 nL of various compound concentrations (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 blocked for 1 hour at room temperature. After removing the blocking solution, phospho-p44 / 42 MAPK (T202 / Y204) Rabbit mAb (CST, Cat. No. 4370S) and GAPDH (D4C6R) Mouse mAb (CST, Cat. No. 97166S) antibody working solutions were added to each well and incubated overnight at 4°C. The microplate was washed three times with PBS containing 0.1% Tween-80 (PBST), and 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 were added, and the microplate was incubated 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 read using an Odyssey CLx (LI-COR) instrument to record the signal value.

[0422] IC 50 The calculation formula

[0423] Calculate compound IC using nonlinear regression equation 50 Value: Y = lower platform signal + (upper platform signal - lower platform signal) / (1 + 10^((LogIC 50 -X)*Hill slope); X=logarithm of compound concentration.

[0424] Table 14.1 Target molecules for AGS (KRAS G12D ) cells pERK inhibition effect ND = Not Tested # = Absolute chiral configuration (S or R) not determined, inferred configuration

[0425] After testing, the molecule of the present invention has an effect on KRAS G12D Mutated tumor cells have a good inhibitory effect and are expected to be able to inhibit KRAS G12Dto achieve better tumor suppression effects.

[0426] Example 15:

[0427] Compounds for KRAS G12V Mediated p-ERK inhibition test (directly reflects the cellular level inhibitory effect of the test compound). Details are as follows:

[0428] SW480 cells cultured in DMEM (Gibco, Cat. No. 11995065) containing 10% fetal bovine serum and 1% penicillin-streptomycin were seeded onto 384-well microplates and incubated overnight at 37°C in 5% carbon dioxide. 200 nL of various compound concentrations (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 blocked for 1 hour at room temperature. After removing the blocking solution, phospho-p44 / 42 MAPK (T202 / Y204) Rabbit mAb (CST, Cat. No. 4370S) and GAPDH (D4C6R) Mouse mAb (CST, Cat. No. 97166S) antibody working solutions were added to each well and incubated overnight at 4°C. The microplate was washed three times with PBS containing 0.1% Tween-80 (PBST), and IRDye800CW 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 were added, and the microplate was incubated 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 read using an Odyssey CLx (LI-COR) instrument to record the signal value.

[0429] IC 50 The calculation formula

[0430] Calculate compound IC using nonlinear regression equation 50 Value: Y = lower platform signal + (upper platform signal - lower platform signal) / (1 + 10^((LogIC 50 -X)*Hill slope); X=logarithm of compound concentration.

[0431] Table 15.1 Target molecules for SW480 (KRAS G12V) cells pERK inhibition effect ND = Not Tested # = Absolute chiral configuration (S or R) not determined, inferred configuration

[0432] After testing, the molecule of the present invention has an effect on KRAS G12V Mutated tumor cells have a good inhibitory effect and are expected to be able to inhibit KRAS G12V to achieve better tumor suppression effects.

[0433] Some invented molecules (such as H2a, H2b, H3, H4, H11, H41, H53, etc.) are effective for KRAS G12V Mutations compared to KRAS G12D Mutations have better inhibitory effects.

[0434] Example 16:

[0435] Compounds for more KRAS G12V p-ERK inhibition test of mutant cells (directly reflects the cellular level inhibitory effect of the test compound). Details are as follows:

[0436] SW620 cells cultured in DMEM (Gibco, Cat. No. 11995065) supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin were seeded onto 384-well microplates and incubated overnight at 37°C in 5% carbon dioxide. 200 nL of various compound concentrations (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 blocked for 1 hour at room temperature. After removing the blocking solution, phospho-p44 / 42 MAPK (T202 / Y204) Rabbit mAb (CST, Cat. No. 4370S) and GAPDH (D4C6R) Mouse mAb (CST, Cat. No. 97166S) antibody working solutions were added to each well and incubated overnight at 4°C. The microplate was washed three times with PBS containing 0.1% Tween-80 (PBST), and IRDye800CW 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 were added, and the microplate was incubated 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 read using an Odyssey CLx (LI-COR) instrument to record the signal value.

[0437] IC 50 The calculation formula

[0438] Calculate compound IC using nonlinear regression equation 50 Value: Y = lower platform signal + (upper platform signal - lower platform signal) / (1 + 10^((LogIC 50 -X)*Hill slope); X=logarithm of compound concentration.

[0439] Table 16.1 Target molecules for SW620 (KRAS G12V ) cells pERK inhibition effect

[0440] After testing, the molecule of the present invention has an effect on KRAS G12V Mutated tumor cells have a good inhibitory effect and are expected to be able to inhibit KRAS G12V to achieve better tumor suppression effects.

[0441] Example 17: Antiproliferative Effects of Compounds on KRAS Mutant Cell Lines

[0442] Basic Information:

[0443] The 3D anti-proliferative effects of the compound on the KRAS G12D mutant pancreatic cancer HPAC cell line are as follows:

[0444] Cell culture: HPAC pancreatic cancer cells were cultured in T75 flasks in RPMI 1640 medium containing 10% fetal bovine serum and 1% penicillin / streptomycin.

[0445] Cell culture: SW620 colorectal cancer cells were cultured in T75 flasks in RPMI 1640 medium containing 10% fetal bovine serum and 1% penicillin / streptomycin.

[0446] Test process: 200 nL of the diluted test compound (1000 nM, 4-fold dilution) was added to a 384-well low-adsorption cell culture plate using a nanoliter pipetting system. After the cells were plated, the culture plate was placed in a 37°C, 5% CO2 constant temperature incubator under 3D conditions. After the test compound and cells were incubated for 5 days, the test compound was added to each well. 3D reagent, using Envision multifunctional microplate reader (Perkin Elmer, catalog number Envision 2104) to read the luminescence value. The light signal is proportional to the amount of ATP in the system, and the ATP content directly represents the number of viable cells in the system. Finally, the IC value of the compound was obtained using the nonlinear fitting formula using XLFIT software. 50 (half inhibitory concentration).

[0447] Inhibition rate (%) = 100 × (negative control average value - compound reading) / (negative control average value - positive control average value)

[0448] Negative control: DMSO. Positive control: culture medium.

[0449] Table 17.1: Compounds for KRAS G12D Antiproliferative effect of mutant HPAC cells at half effective concentration

[0450] Table 17.2: Compounds for KRAS G12V Antiproliferative effect of half effective concentration of mutant SW620 cells

[0451] Example 18:

[0452] The compound's liver microsome stability test is as follows:

[0453] The compounds of the present invention were subjected to a liver microsome stability test. The test compounds were co-incubated with liver microsomes of different species with or without the addition of NADPH. The final concentration of the test compound in the test system was 1 μM, the final concentration of NADPH was 1 mM, and the final concentration of liver microsomes was 0.5 mg / mL. The concentration of the compound in the incubation supernatant at different time points within 15, 30, 45, and 60 minutes was measured and the pharmacokinetic parameters (such as clearance Cl) were calculated. int ).

[0454] The remaining percentage of the test compound was plotted against the reaction time, T 1 / 2 =0.693 / k, as the half-life of the compound.

[0455] Table 18.1: Results of the stability test of the compounds on human liver microsomes in vitro.

[0456] Some molecules of the present invention have good metabolic stability in human liver microsomes.

[0457] Example 19: Pharmacokinetic evaluation experiment in mice

[0458] CD1 female mice were used as test animals and the drug was administered orally / intravenously (oral dosage: 10 mg / kg, intravenous dosage: 2 mg / kg).

[0459] Experimental protocol: Oral administration (vehicle: 0.5% hydroxyethyl cellulose + 5% HPβCD + 94.5% saline) consisted of three mice per group, and intravenous administration (vehicle: 5% DMSO-95% (20% HPβCD) saline) consisted of three mice per group. Oral administration: Plasma samples were collected before (0 h) and after (0.25, 0.5, 1, 2, 4, 8, and 24 h) administration; intravenous administration: Plasma samples were collected before (0 h) and after (0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h) administration. Plasma concentrations in mice following oral and intravenous administration were determined by LC / MS / MS. Data were calculated using AB Sciex QTRAP 6500 software. The results are as follows:

[0460] Table 19.1: PK results of compounds in mice.

[0461] The above results show that some molecules of the present invention have good oral absorption.

[0462] The above is a further detailed description of the present invention in conjunction with specific preferred embodiments, and the specific implementation of the present invention should not be considered to be limited to these descriptions. For those skilled in the art of the present invention, without departing from the concept of the present invention, several simple deductions or substitutions can be made, which should be considered to fall 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, Z is selected from O, S, NH or CH2; X1 is selected from CH or N; X2 is selected from CH or N; R is selected from 4-12 membered heterocyclic groups, R1 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; R2 is C 3-8 Cycloalkyl or 3-12 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4, 5 or 6 R x replace; Ring A is selected from 5-12 membered heterocyclyl or 5-14 membered heteroaryl, which is optionally substituted by 1-10 R b replace; Ring B is absent or is selected from a 5-12 membered heterocyclyl or a 5-14 membered heteroaryl, which is optionally substituted by 1-10 R b replace; R x Selected from H, D, halogen, -(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 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic group; and R x Optionally further substituted with 1, 2, 3, 4, 5 or 6 halogen, ═CH 2 , ═CHF or ═CF 2 ; or two R on the same atom x Together they form =CH2, =CHF or =CF2; R b Selected from H, -(CH2) p -halogen, -(CH2) p -CN, -(CH2) p -OH, -(CH2) p -NH2、-LC(O)R a 、-LC(O)OR a 、-LC(O)N(R a )(R a '),-NHC(O)OR a 、-(CH2) p -OR a 、-(CH2) p -SR a 、-LS(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10 aryl or -L-5-10 membered heteroaryl; and R b Optionally further 1, 2, 3, 4, 5 or 6 R c replace; or two R on the same atom b Together they form =O, =S, =NH, =CH2, =CHF or =CF2; R a and R a 'Independently selected from H, -L-CN, -(CH2) p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10 aryl or -L-5-10 membered heteroaryl; and R a and R a 'optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, CN, -(CH2) p -OH, -(CH2) p -NH2, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution; p is selected from 0, 1, 2, 3, 4, 5 or 6; R c Selected from H, D, halogen, OH, NH2, -L-CN, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2N(R a )(R a '), C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; and R c Optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, -L-CN, OH, NH2, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution; or two R on the same atom c Together they form =O, =S or =NH; L is selected from a bond, -C(O)-, -C(S)-, C 1-6 Alkylene or C 1-6 haloalkylene; Each of the radical definitions recited is optionally substituted with 1, 2, 3, 4, 5 or more D, up to full deuteration.

2. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein Z is selected from O, NH or CH2; X1 is selected from CH or N; X2 is selected from CH or N; R is selected from 5-12 membered heterocyclic group, R1 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; R2 is a 3-12 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4, 5 or 6 R x replace; Ring A is selected from 5-7 membered heterocyclyl or 5-6 membered heteroaryl, which is optionally substituted by 1-10 R b replace; Ring B is absent; R x Selected from H, D, halogen, -(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 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic group; and R x Optionally further substituted with 1, 2, 3, 4, 5 or 6 halogen, ═CH 2 , ═CHF or ═CF 2 ; or two R on the same atom x Together they form =CH2, =CHF or =CF2; R b Selected from H, -(CH2) p -halogen, -(CH2) p -CN, -(CH2) p -OH, -(CH2) p -NH2、-LC(O)R a 、-LC(O)OR a 、-LC(O)N(R a )(R a '),-NHC(O)OR a 、-(CH2) p -OR a 、-(CH2) p -SR a 、-LS(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10 aryl or -L-5-10 membered heteroaryl; and R b Optionally further 1, 2, 3, 4, 5 or 6 R c replace; or two R on the same atom b Together they form =O, =S, =NH, =CH2, =CHF or =CF2; R a and R a 'Independently selected from H, -L-CN, -(CH2) p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10 aryl or -L-5-10 membered heteroaryl; and R a and R a 'optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, CN, -(CH2) p -OH, -(CH2) p -NH2, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution; p is selected from 0, 1, 2, 3, 4, 5 or 6; R c Selected from H, D, halogen, OH, NH2, -L-CN, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2N(R a )(R a '), C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6- 10 aryl or 5-10 membered heteroaryl; and R c Optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, -L-CN, OH, NH2, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution; or two R on the same atom c Together they form =O, =S or =NH; L is selected from a bond or C 1-6 alkyl; Each of the radical definitions recited is optionally substituted with 1, 2, 3, 4, 5 or more D, up to full deuteration.

3. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the structure of formula (II): in, M1, M2 and M3 are each independently selected from O, S, N, NH, CH, -C(=O)-, -C(=S)- or CH2; R1 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; R x1 Selected from -(CH2) p -CN、-C(O)R a 、-C(O)OR a 、-(CH2) p -OR a 、-S(O)2R a 、C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; R x2 Selected from H, D, halogen, -(CH2) p CN, -(CH2) p -OR a 、-(CH2) p -NH2、-C(O)R a 、-SR a 、-S(O)2R 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 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic group; and R x Optionally further substituted with 1, 2, 3, 4, 5 or 6 halogen, ═CH 2 , ═CHF or ═CF 2 ; or two R on the same atom x2 Together they form =CH2, =CHF or =CF2; R b Selected from H, -(CH2) p -halogen, -(CH2) p -CN, -(CH2) p -OH, -(CH2) p -NH2、-LC(O)R a 、-LC(O)OR a 、-LC(O)N(R a )(R a '),-NHC(O)OR a 、-(CH2) p -OR a 、-(CH2) p -SR a 、-LS(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10 aryl or -L-5-10 membered heteroaryl; and R b Optionally further 1, 2, 3, 4, 5 or 6 R c replace; or two R on the same atom b Together they form =O, =S, =NH, =CH2, =CHF or =CF2; R a and R a 'Independently selected from H, -L-CN, -(CH2) p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10 aryl or -L-5-10 membered heteroaryl; and R a and R a 'optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, CN, -(CH2) p -OH, -(CH2) p -NH2, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution; R c Selected from H, D, halogen, OH, NH2, -L-CN, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2N(R a )(R a '), C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6- 10 aryl or 5-10 membered heteroaryl; and R c Optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, -L-CN, OH, NH2, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution; or two R on the same atom c Together they form =O, =S or =NH; L is selected from a bond, -C(O)-, -C(S)-, C 1-6 Alkylene or C 1-6 haloalkylene; Each of the groups defined above is optionally substituted with 1, 2, 3, 4, 5 or more D, up to full deuteration; n is selected from 0, 1 or 2; m is selected from 0, 1, 2, 3, 4 or 5; p is selected from 0, 1, 2, 3, 4 or 5.

4. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the structure of formula (II-1) or (II-2): in, M3 is selected from N or CH; R1 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; R x2 Selected from H, D, halogen, CN, NH2, -C(O)R a 、-NHC(O)OR a 、-(CH2) p -OR a 、-SR a 、-S(O)2R a 、-(CH2) p -C(O)OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkoxy; n is selected from 0, 1 or 2; R b Selected from H, D, halogen, NH2, -L-CN, -L-OH, -C(O)R a 、-C(O)OR a 、-C(O)NHR a 、-C(O)N(R a )(R a '),-NHC(O)OR a 、-(CH2) p -OR a 、-SR、S(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -LC 3-6 Cycloalkyl or -L-4-6 membered heterocyclic group; R b Can be further replaced by 1 or 2 R c replace; m is selected from 0, 1, 2 or 3; R a and R a 'Independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group; p is selected from 0, 1, 2, 3 or 4; R c Selected from H, C 1-6 Alkyl, halogen, OH, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, CN, NH2, C 3-6 Cycloalkyl or 4-12 membered heterocyclic group; or two R on the same atom c Together they form =O, =S or =NH; L is selected from a bond, -C(O)- or C 1-6 alkylene; Each of the radical definitions recited is optionally substituted with 1, 2, 3, 4, 5 or more D, up to full deuteration.

5. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the structure of formula (II-3): in, M2 is selected from NH, -C(=O)-, -C(=S)- or CH2; R1 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; R x Selected from H, D, halogen, -(CH2) p CN, -(CH2) p -OR a 、-(CH2) p -NH2、-C(O)R a 、-SR a 、-S(O)2R 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 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic group; and R x Optionally further substituted with 1, 2, 3, 4, 5 or 6 halogen, ═CH 2 , ═CHF or ═CF 2 ; n is selected from 0, 1 or 2; R b Selected from H, -(CH2) p -halogen, -(CH2) p -CN, -(CH2) p -OH, -(CH2) p -NH2、-LC(O)R a 、-LC(O)OR a 、-LC(O)N(R a )(R a '),-NHC(O)OR a 、-(CH2) p -OR a 、-(CH2) p -SR a 、-LS(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10 aryl or -L-5-10 membered heteroaryl; and R b Optionally further 1, 2, 3, 4, 5 or 6 R c replace; m is selected from 0, 1, 2, 3, 4 or 5; or two R on the same atom b Together they form =O, =S, =NH, =CH2, =CHF or =CF2; R a and R a 'Independently selected from H, -L-CN, -(CH2) p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10 aryl or -L-5-10 membered heteroaryl; and R a and R a 'optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, CN, -(CH2) p -OH, -(CH2) p -NH2, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution; R c Selected from H, D, halogen, OH, NH2, -L-CN, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2N(R a )(R a '), C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6- 10 aryl or 5-10 membered heteroaryl; and R c Optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, -L-CN, OH, NH2, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution; or two R on the same atom c Together they form =O, =S or =NH; p is selected from 0, 1, 2, 3, 4, 5 or 6; L is selected from a bond, -C(O)- or C 1-6 alkylene; Each of the radical definitions recited is optionally substituted with 1, 2, 3, 4, 5 or more D, up to full deuteration.

6. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the structure of formula (IV), (IV-1) or (IV-2): in, Z is selected from O, S, NH or CH2; R1 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; R2 is selected from C 3-8 Cycloalkyl or 4-8 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4, 5 or 6 R x replace; R b Selected from H, -(CH2) p -halogen, -(CH2) p -CN, -(CH2) p -OH, -(CH2) p -NH2、-LC(O)R a 、-LC(O)OR a 、-LC(O)N(R a )(R a '),-NHC(O)OR a 、-(CH2) p -OR a 、-(CH2) p -SR a 、-LS(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10 aryl or -L-5-10 membered heteroaryl; and R b Optionally further 1, 2, 3, 4, 5 or 6 R c replace; m is selected from 0, 1, 2, 3, 4 or 5; or two R on the same atom b Together they form =O, =S, =NH, =CH2, =CHF or =CF2; R x Selected from H, D, halogen, -(CH2) p CN, -(CH2) p -OR a 、-(CH2) p -NH2、-C(O)R a 、-SR a 、-S(O)2R a 、-O-phenyl-、-(CH2) p -phenyl, -(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 '), C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -LC 3-8 Cycloalkyl or -L-4-8 membered heterocyclic group; and R x Optionally further substituted with 1, 2, 3, 4, 5 or 6 halogen, ═CH 2 , ═CHF or ═CF 2 ; or two R on the same atom x Together they form =CH2, =CHF or =CF2; R a and R a 'Independently selected from H, -L-CN, -(CH2) p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-4-8 membered heterocyclic group, -LC 6-10 aryl or -L-5-10 membered heteroaryl; and R a and R a 'optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, CN, -(CH2) p -OH, -(CH2) p -NH2, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution; p is selected from 0, 1, 2, 3, 4, 5 or 6; R c Selected from H, D, halogen, OH, NH2, -L-CN, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -S(O)2N(R a )(R a '), C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group, C 6- 10 aryl or 5-10 membered heteroaryl; and R c Optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, -L-CN, OH, NH2, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution; or two R on the same atom c Together they form =O, =S or =NH; L is selected from a bond, -C(O)-, -C(S)-, C 1-6 Alkylene or C 1-6 haloalkylene; Each of the radical definitions recited is optionally substituted with 1, 2, 3, 4, 5 or more D, up to full deuteration.

7. The compound of claim 6, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the structure of formula (V), (V-1) or (V-2): in, Z is selected from O, S, NH or CH2; R1 is selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; R2 is a 5-8 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R x replace; R b Selected from H, -(CH2) p -halogen, -(CH2) p -CN, -(CH2) p -OH, -(CH2) p -NH2、-C(O)R a 、-C(O)OR a 、-C(O)N(R a )(R a '),-NHC(O)OR a 、-(CH2) p -OR a 、-(CH2) p -SR a 、-(CH2) p -S(O)2R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -LC 3-6 Cycloalkyl or -L-4-6 membered heterocyclic group; and R b Optionally further 1, 2, 3, 4, 5 or 6 R c replace; R x Selected from H, D, halogen, -(CH2) p -CN, -(CH2) p -OR a 、-(CH2) p -NH2、-C(O)R a 、-NHC(O)OR a 、-SR a 、-S(O)2R a 、-(CH2) p -C(O)OR a 、-(CH2) p -C(O)N(R a )(R a '), -O-phenyl-, -(CH2) p -phenyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; R a and R a 'Independently selected from H, -L-CN, -(CH2) p -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, -LC 1-6 Alkoxy, -LC 3-6 Cycloalkyl, -L-4-6 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; and R a and R a 'optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, CN, -(CH2) p -OH, -(CH2) p -NH2, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution; p is selected from 0, 1, 2, 3 or 4; R c Selected from H, D, halogen, OH, NH2, -L-CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; and R c Optionally further substituted by 1, 2, 3, 4, 5 or 6 halogens, OH, NH2, -C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy substitution; L is selected from a bond, -C(O)- or C 1-6 alkylene; Each of the radical definitions recited is optionally substituted with 1, 2, 3, 4, 5 or more D, up to full deuteration.

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

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

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and a pharmaceutically acceptable excipient; preferably, further comprising other therapeutic agents.

11. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof in the preparation of a medicament for treating and / or preventing a KRAS-mediated disease.

12. A method for treating and / or preventing a KRAS-mediated disease in a subject, comprising administering to the subject a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutical composition according to claim 10.

13. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutical composition according to claim 10, for use in treating and / or preventing a KRAS-mediated disease.

14. The use of claim 11 or the method of claim 12 or the use of the compound or composition of claim 13, wherein the KRAS-mediated disease is cancer, preferably, the cancer is selected from colorectal cancer (e.g., colon cancer, rectal cancer, large intestine adenocarcinoma), non-small cell lung cancer (NSCLC) or pancreatic cancer, etc.

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