The invention relates to a hexahydrospiro [cyclopropane-1, 2apos; pyrrolizine] compounds

Abstract

The invention belongs to the field of medicines, and relates to a series of compounds containing hexahydrospiro [cyclopropane-1, 2 '-pyrazine], in particular to a compound as shown in a formula (III), a stereoisomer and pharmaceutically acceptable salt thereof, a preparation method of the compound, a pharmaceutical composition and application of the compound in treating diseases. # imgabs0 #

Description

Compounds containing hexahydrospiro[cyclopropane-1,2′-pyrrolizine]

[0001] The present invention claims the following priority:

[0002] CN202211130261.6, application date: September 16, 2022;

[0003] CN202211644282.X, application date: December 20, 2022;

[0004] CN202211718544.2, application date: December 29, 2022;

[0005] CN202310075954.8, application date: January 16, 2023;

[0006] CN202310172820.8, application date: February 27, 2023;

[0007] CN202311162136.8, application date: September 8, 2023. Technical Field

[0008] The present disclosure relates to a series of compounds containing hexahydrospiro[cyclopropane-1,2'-pyrrolizine], and specifically to compounds represented by formula (III), stereoisomers thereof, and pharmaceutically acceptable salts thereof. Background Art

[0009] KRAS is a member of the ubiquitously expressed RAS protein family (KRAS, NRAS, and HRAS). It regulates the transduction of extracellular signals to downstream intracellular pathways by binding to GTP (on) or GDP (off). However, mutations in this protein often impair its GTP hydrolase activity, leading to prolonged activation and overactivation of downstream molecules, thus promoting abnormal cell proliferation and cancerous transformation. Due to the shallow GTP binding pocket in the KRAS protein, which is abundant in cells, effective KRAS-targeted inhibitors have remained elusive despite over three decades of research, leading to the KRAS gene being termed "undruggable." The sluggish progress in targeted therapy for KRAS mutations has resulted in patients with KRAS mutations remaining primarily treated with traditional chemotherapy and radiotherapy, depriving them of the benefits of modern precision medicine. In recent years, advances in drug discovery and the emergence of novel approaches have led to the successful development of covalent inhibitors for the KRAS G12C mutation, rekindling hopes for the development of inhibitors that directly target KRAS. The most common KRAS mutations occur at glycine 12 (G12), glycine 13 (G13), and glutamine 61 (Q61) residues, with G12 mutations accounting for 83%. G12D mutations are a relatively common subtype of KRAS mutations, which involve the conversion of glycine 12 (G) to aspartic acid (D). KRAS G12D mutations are most common in pancreatic cancer. According to data reported in the literature (Nat Rev Drug Discov 2014;13:828-851), approximately 46% of pancreatic cancers, 15% of colorectal cancers, and 5% of non-small cell lung cancers harbor KRAS G12D mutations.

[0010] As a cutting-edge target, the KRAS G12D mutant protein has yet to see any small molecule inhibitors enter clinical development, with only limited preclinical studies reported. In 2021, MIRATI THERAPEUTICS, INC. published a patent (WO2021041671) for a KRAS G12D small molecule inhibitor, which discloses a series of pyridopyrimidine compounds with high KRAS G12D activity.

[0011] Summary of the Invention

[0012] The present disclosure provides a compound of formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0013] in,

[0014] n is selected from 0, 1, 2, 3, 4, or 5;

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

[0016] R6 is selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy;

[0017] R7 is selected from H, -NR 7a R 7b 、-C(O)R 7b 、-C(O)OR 7b 、-C(O)OC 1-6 Alkylene OC(O)R 7b 、-C(O)OC 1-6 Alkylene NR 7a C(O)R 7b 、 -C(O)NR 7a R 7b 、-C(O)NR 7a C 1-6 Alkylene NR 7a C(O)R 7b , or -C(O)NR 7a C 1-6 Alkylene OC(O)R 7b ;

[0018] R 7a Independently selected from H, or C 1-6 alkyl;

[0019] R 7b independently selected from H, or optionally substituted by one or more R 7c Substituted with the following groups: C 1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, 3-12 membered cycloalkyl C 1-6 Alkylene, or 3-12 membered heterocyclic group C 1-6 alkylene;

[0020] Each R 7c independently selected from deuterium, oxo, halogen, -OH, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino;

[0021] Each R8 is independently selected from halogen, -CN, -OH, -NH2, or optionally substituted by one or more R 8a Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, tri-C 1-6 Alkylsilyl, C 1-3 Alkoxy C 1-3 Alkylene, C 1-3 Alkylthio C 1-3 Alkylene, C 1-3 Alkylamino C 1-3 Alkylene, di-C 1-3 Alkylamino C 1-3 Alkylene, or tri-C 1-3 Alkylsilyl C 1-3 alkylene;

[0022] Each R 8a independently selected from deuterium, oxo, halogen, -OH, -NH2, or -CN;

[0023] Each R9 is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, or optionally substituted by one or more R 9a Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, or di-C 1-6 Alkylamino;

[0024] Each R 9a independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, or di-C 1-4 Alkylamino.

[0025] In some embodiments, n is selected from 0, 1, 2, 3, or 4.

[0026] In some embodiments, n is selected from 1, 2, 3, or 4.

[0027] In some embodiments, n is selected from 3 or 4.

[0028] In some embodiments, m is selected from 0, 1, 2, 3, or 4.

[0029] In some embodiments, m is selected from 1, 2, 3, or 4.

[0030] In some embodiments, m is selected from 1 or 2.

[0031] In some embodiments, R6 is selected from H, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1- 4 alkoxy.

[0032] In some embodiments, R6 is selected from H, halogen, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl or halogenated C 1- 3 alkoxy.

[0033] In some embodiments, the R6 is selected from H, -F, -Cl, -Br, -I, -CN, methyl, methoxy, difluoromethyl, trifluoromethyl, or trifluoromethoxy.

[0034] In some embodiments, the R6 is selected from H, halogen. In some embodiments, the R6 is selected from H, -F, or -Cl.

[0035] In some embodiments, the R6 is selected from halogen. In some embodiments, the R6 is selected from -F, or -Cl.

[0036] In some embodiments, said R7 is independently selected from H, -NR 7a R 7b 、-C(O)R 7b 、-C(O)OR 7b 、-C(O)OC 1-4 Alkylene OC(O)R 7b 、-C(O)OC 1-4 Alkylene NR 7a C(O)R 7b 、-C(O)NR 7a R 7b 、-C(O)NR 7a C 1-4 Alkylene NR 7a C(O)R 7b , or -C(O)NR 7a C 1-4 Alkylene OC(O)R 7b .

[0037] In some embodiments, said R7 is independently selected from H, -NR 7a R 7b、-C(O)R 7b 、-C(O)OR 7b , or -C(O)OC 1-4 Alkylene OC(O)R 7b .

[0038] In some embodiments, said R7 is independently selected from H, -NR 7a R 7b 、-C(O)OR 7b , or -C(O)OC 1-4 AlkyleneOC(O)R 7b .

[0039] In some embodiments, said R7 is independently selected from H, or -C(O)OC 1-4 Alkylene OC(O)R 7b .

[0040] In some embodiments, said R7 is independently selected from H, -NH2, -N(CH3)2,

[0041] In some embodiments, said R7 is independently selected from H, -NH2, -N(CH3)2,

[0042] In some embodiments, said R7 is independently selected from H. In some embodiments, said R7 is independently selected from

[0043] In some embodiments, said R7 is independently selected from

[0044] In some embodiments, said R7 is independently selected from H, -NH2, -N(CH3)2,

[0045] In some embodiments, said R7 is independently selected from H,

[0046] In some embodiments, the R 7a Independently selected from H, or C 1-4 alkyl.

[0047] In some embodiments, the R 7a Independently selected from H, or C 1-3 alkyl.

[0048] In some embodiments, the R7a Independently selected from H, methyl, ethyl, or isopropyl.

[0049] In some embodiments, the R 7a Independently selected from H or methyl.

[0050] In some embodiments, the R 7b independently selected from H, or optionally substituted by one or more R 7c Substituted with the following groups: C 1-6 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocyclic group, 3-6 membered cycloalkyl C 1-3 Alkylene, or 4-6 membered heterocyclic group C 1-3 Alkylene.

[0051] In some embodiments, the R 7b independently selected from optionally one or more R 7c Substituted with the following groups: C 1-6 Alkyl, 3-6 membered cycloalkyl, or 3-6 membered cycloalkyl C 1-3 Alkylene.

[0052] In some embodiments, the R 7b independently selected from optionally one or more R 7c Substituted C 1-6 alkyl.

[0053] In some embodiments, the R 7b independently selected from H, or optionally substituted by one or more R 7c Substituted groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, dioxolyl, cyclopropyl, C 1-3 Alkylene, cyclobutyl C 1-3 Alkylene, cyclopentyl C 1-3 Alkylene, cyclohexyl C 1-3 Alkylene, azetidinyl C 1-3 Alkylene, oxetane C 1-3 Alkylene, pyrrolidyl C 1-3 Alkylene, tetrahydrofuranyl C 1-3 Alkylene, piperidinyl C 1-3 Alkylene, tetrahydropyranyl C 1-3 Alkylene, piperazinyl C 1-3 Alkylene, morpholinyl C 1-3 Alkylene, or dioxolyl C 1-3 Alkylene.

[0054] In some embodiments, the R 7b independently selected from H, or optionally substituted by one or more R 7c Substituted groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclopentyl C 1-3 Alkylene, tetrahydropyranyl C 1-3 Alkylene, or dioxolyl C 1-3 Alkylene.

[0055] In some embodiments, the R 7b independently selected from H, or optionally substituted by one or more R 7c Substituted groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclopentylmethylene,

[0056] In some embodiments, the R 7b Independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, Cyclopentyl, cyclopentylmethylene,

[0057] In some embodiments, the R 7b independently selected from H, or optionally substituted by one or more R 7c Substituted C 1-6 alkyl.

[0058] In some embodiments, the R 7b independently selected from H, or optionally substituted by one or more R 7c Substituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0059] In some embodiments, the R 7b Independently selected from H, methyl, ethyl, or isopropyl.

[0060] In some embodiments, the R 7b Independently selected from methyl, or isopropyl.

[0061] In some embodiments, each of said R 7c independently selected from deuterium, oxo, halogen, -OH, -CN, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, halogenated C1-3 Alkyl, halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylthio, halo C 1-3 Alkylamino, or halogenated di-C 1-3 Alkylamino.

[0062] In some embodiments, each of said R 7c Independently selected from deuterium, oxo, -F, -Cl, -Br, -I, -OH, -CN, -NH2, methyl, ethyl, isopropyl, methoxy, methylthio, methylamino, dimethylamino, diethylamino, fluoromethyl, or fluoromethoxy.

[0063] In some embodiments, each of said R 7c Independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, methyl, methoxy, methylthio, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.

[0064] In some embodiments, each of said R 7c Independently selected from deuterium, oxo, -F, -Cl, -OH, -NH2, or methyl.

[0065] In some embodiments, each R8 is independently selected from halogen, -CN, -OH, -NH2, or optionally substituted by one or more R 8a Substituted with the following groups: C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, tri-C 1-4 Alkylsilyl, C 1-2 Alkoxy C 1-2 Alkylene, C 1-2 Alkylthio C 1-2 Alkylene, C 1-2 Alkylamino C 1-2 Alkylene, di-C 1-2 Alkylamino C 1-2 Alkylene, or tri-C 1-2 Alkylsilyl C 1-2 Alkylene.

[0066] In some embodiments, each R8 is independently selected from halogen, -CN, -OH, -NH2, or optionally substituted by one or more R 8a Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, tri-C 1-4Alkylsilyl, C 1-2 Alkylthio C 1-2 Alkylene, di-C 1-2 Alkylamino C 1-2 Alkylene, or tri-C 1-2 Alkylsilyl C 1-2 Alkylene.

[0067] In some embodiments, each R8 is independently selected from halogen, -CN, -OH, -NH2, or optionally substituted by one or more R 8a Substituted with the following groups: C 1-4 Alkyl or C 1-4 Alkoxy.

[0068] In some embodiments, each R8 is independently selected from -F, -Cl, -Br, -I, -CN, -OH, -NH2, or optionally substituted by one or more R 8a Substituted groups include methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, isopropoxy, methylthio, methylamino, dimethylamino, trimethylsilyl, methoxymethylene, methylthiomethylene, methylaminomethylene, dimethylaminomethylene, and trimethylsilylmethylene.

[0069] In some embodiments, each R8 is independently selected from -F, -Cl, -Br, -I, -CN, -OH, -NH2, or optionally substituted by one or more R 8a Substituted groups include methyl, ethyl, methoxy, trimethylsilyl, methylthiomethylene, dimethylaminomethylene, and trimethylsilylmethylene.

[0070] In some embodiments, each R8 is independently selected from -F, -Cl, -NH2, or optionally substituted by one or more R 8a Substituted groups include methyl and methoxy.

[0071] In some embodiments, each R8 is independently selected from -F, -Cl, -Br, -I, -CN, -OH, -NH2, methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, trimethylsilyl,

[0072] In some embodiments, each R8 is independently selected from -F, -Cl, -OH, -NH2, methyl, methoxy, trimethylsilyl, trifluoromethyl, trifluoromethoxy, In some embodiments, each R8 is independently selected from -F, -Cl, -NH2, methyl, trimethylsilyl, trifluoromethyl, trifluoromethoxy, In some embodiments, each R8 is independently selected from -F, -Cl, -NH2, methyl, trifluoromethyl, or trifluoromethoxy.

[0073] In some embodiments, each of said R 8a Independently selected from deuterium, -F, -Cl, -Br, -OH, -NH2, or -CN.

[0074] In some embodiments, each of said R 8a Independently selected from -F, -Cl, -Br, or methyl.

[0075] In some embodiments, each of said R 8a are independently selected from halogen.

[0076] In some embodiments, each of said R 8a Independently selected from -F or -Cl.

[0077] In some embodiments, the structural unit Selected from

[0078] In some embodiments, the structural unit Selected from

[0079] In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from

[0080] In some embodiments, each R9 is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, or optionally substituted by one or more R 9a Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, or di-C 1-4 Alkylamino.

[0081] In some embodiments, each R9 is independently selected from deuterium, oxo, -F, -Cl, -Br, -I, -OH, -NH2, -CN, or optionally substituted by one or more R 9a Substituted groups include methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, ethylamino, or dimethylamino.

[0082] In some embodiments, each R9 is independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, trifluoromethoxy, or dimethylaminomethylene.

[0083] In some embodiments, each R9 is independently selected from halogen. 9 Independently selected from -F or -Cl.

[0084] In some embodiments, each of said R 9a independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, or di-C 1-3 Alkylamino.

[0085] In some embodiments, each of said R 9a are independently selected from deuterium, oxo, -F, -Cl, -Br, -I, -OH, -NH2, -CN, methoxy, ethoxy, methylthio, methylamino, ethylamino, dimethylamino, or diethylamino.

[0086] In some embodiments, each of said R 9a Independently selected from -F or -Cl.

[0087] In some embodiments, the structural unit Selected from

[0088] In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from

[0089] In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from

[0090] The present disclosure provides a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0091] in,

[0092] R1, R2 and R3 are as defined above for R8;

[0093] R4 and R5 are as defined above for R9;

[0094] R6 and R7 are as defined above.

[0095] The present disclosure provides a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0096] Wherein, R1 and R2 are independently selected from -NH2, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, The C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl and C 2-4 Alkynyl is optionally substituted with 1, 2, 3, and 4 halogens;

[0097] R3 is selected from -NH2;

[0098] R4 and R5 are independently selected from H, halogen, C 1-4 Alkyl and C 1-4 Alkoxy, the C 1-4 Alkyl and C 1-4 Alkoxy is optionally substituted with 1, 2, 3, and 4 halogens;

[0099] R6 is selected from halogen;

[0100] R7 is selected from H, -N(R 10 )2, -C(=O)OC 1-4 Alkyl and -C(=O)OC 1-4 Alkylene-OC(=O)C 1-4 Alkyl, the C 1-4 Alkyl is optionally substituted with 1, 2, 3, and 4 halogens;

[0101] Each R 10 Each independently selected from H and C 1-4 alkyl.

[0102] The present disclosure also provides a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0103] in,

[0104] R1 is selected from -CF3, -OCF3, and -NH2;

[0105] R2 is selected from -CH3, -Cl and

[0106] R3 is selected from -NH2;

[0107] R4 is selected from H and -F;

[0108] R5 is selected from H and -F;

[0109] R6 is selected from -F;

[0110] R7 is selected from H, -NH2, -C(=O)OCH2CH3, -C(=O)OCH(CH3)OC(=O)CH(CH3)2 and -C(=O)OCH2OC(=O)CH3.

[0111] The present disclosure also provides a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0112] in,

[0113] R1 is selected from -CF3, -OCF3,

[0114] R2 is selected from -CH3, -Cl and

[0115] R3 is selected from -NH2;

[0116] R4 is selected from H and -F;

[0117] R5 is selected from H and -F;

[0118] R6 is selected from -F;

[0119] R7 is selected from H, -NH2, -C(=O)OCH2CH3 and -C(=O)OCH(CH3)OC(=O)CH(CH3)2.

[0120] The present disclosure also provides a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0121] in,

[0122] R1 is selected from -CF3 and -OCF3;

[0123] R2 is selected from -CH3 and -Cl;

[0124] R3 is selected from -NH2;

[0125] R4 is selected from H and -F;

[0126] R5 is selected from H and -F;

[0127] R6 is selected from -F;

[0128] R7 is selected from H, -NH2, -C(=O)OCH2CH3 and -C(=O)OCH(CH3)OC(=O)CH(CH3)2.

[0129] The present disclosure also provides a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0130] in,

[0131] R1 is selected from -CF3 and -OCF3;

[0132] R2 is selected from -CH3 and -Cl;

[0133] R3 is selected from -NH2;

[0134] R4 is selected from H and -F;

[0135] R5 is selected from H and -F;

[0136] R6 is selected from -F;

[0137] R7 is selected from -NH2, -C(=O)OCH2CH3 and -C(=O)OCH(CH3)OC(=O)CH(CH3)2.

[0138] The present disclosure also provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0139] in,

[0140] R1 is selected from -CF3 and -OCF3;

[0141] R2 is selected from -CH3 and -Cl;

[0142] R3 is selected from -NH2;

[0143] R4 is selected from H and -F;

[0144] R5 is selected from H and -F;

[0145] R6 is selected from -F.

[0146] In some embodiments of the present disclosure, the above R1 is selected from -NH2, -F, -Cl, -Br, -I, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH(CH3)2, -CF3, -OCF3, Other variables are as defined in this disclosure.

[0147] In some embodiments of the present disclosure, the above R2 is selected from -NH2, -F, -Cl, -Br, -I, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH(CH3)2, -CF3, -OCF3, Other variables are as defined in this disclosure.

[0148] In some embodiments of the present disclosure, the above R1 is selected from -CF3, -OCF3, and -NH2, and other variables are as defined in the present disclosure.

[0149] In some embodiments of the present disclosure, the above R2 is selected from -CF3, -OCF3, and -NH2, and other variables are as defined in the present disclosure.

[0150] In some embodiments of the present disclosure, the above-mentioned R4 is selected from H, -F, -Cl, -Br, -I, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH(CH3)2, -CF3 and -OCF3, and other variables are as defined in the present disclosure.

[0151] In some embodiments of the present disclosure, the above-mentioned R5 is selected from H, -F, -Cl, -Br, -I, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH(CH3)2, -CF3 and -OCF3, and other variables are as defined in the present disclosure.

[0152] In some embodiments of the present disclosure, the above R4 is selected from H and -F, and the other variables are as defined in the present disclosure.

[0153] In some embodiments of the present disclosure, the above R5 is selected from H and -F, and the other variables are as defined in the present disclosure.

[0154] In some embodiments of the present disclosure, the above R7 is selected from H, -NH2, -C(=O)OCH2CH3, -C(=O)OCH(CH3)OC(=O)CH(CH3)2, and -C(=O)OCH2OC(=O)CH3, with other variables as defined in the present disclosure.

[0155] In some embodiments, the C 1-12 Selected from C 1-10 、C 1-8 、C 1-6 、C 1-4 、C 1-3 , or C 1-2 .

[0156] In some embodiments, the C1-6 Alkyl is selected from C 1-4 Alkyl, C 1-3 Alkyl, or C 1-2 alkyl.

[0157] In some embodiments, the C 1-6 Alkylene is selected from C 1-4 Alkylene, C 1-3 Alkylene, or C 1-2 Alkylene.

[0158] In some embodiments, the halogen is selected from -F, -Cl, -Br, or -I.

[0159] In some embodiments, the halo is selected from fluoro, chloro, or bromo. In some embodiments, the halo is selected from fluoro or chloro. In some embodiments, the halo is selected from fluoro.

[0160] In some embodiments, the 3-12-membered is selected from 3-10-membered, 3-8-membered, 3-6-membered, 4-10-membered, 4-9-membered, 4-8-membered, 4-7-membered, 4-6-membered, 5-10-membered, 5-8-membered, or 5-6-membered.

[0161] In some embodiments, the heterocyclyl contains 1 or 2 heteroatoms selected from N, O, or S.

[0162] In some embodiments, the heterocyclyl contains 1 or 2 N atoms.

[0163] In some embodiments, the heterocyclyl contains 1 N atom and 1 O atom.

[0164] In some embodiments, the heterocyclyl contains 1 N atom and 1 S atom.

[0165] In some embodiments, the heterocyclic group is selected from a monocyclic, spirocyclic, fused, or bridged ring.

[0166] In some embodiments, the heterocyclyl group is selected from heterocycloalkenyl or heterocycloalkyl.

[0167] Some other solutions of the present disclosure are obtained by any combination of the above variables.

[0168] The present disclosure also provides compounds, stereoisomers thereof, and pharmaceutically acceptable salts thereof, which are selected from,

[0169] In some embodiments of the present disclosure, the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt thereof is selected from,

[0170] In some embodiments, the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from Compound 3 having one of the following structures: In some embodiments, the configuration of compound 3 is consistent with compound 3-3A. In some embodiments, compound 3 is synthesized via compound 3-3A.

[0171] In some embodiments, compound 3-3A is one of the following structures:

[0172] In some embodiments, compound 3-3A is the compound with the shortest retention time in chiral chromatography among the following compounds: In some embodiments, the chiral chromatography uses a DAICEL CHIRALPAK IE model chiral chromatography column. In some embodiments, the chiral chromatography uses n-hexane as mobile phase A and ethanol containing 0.1% aqueous ammonia as mobile phase B. In some embodiments, the retention time of compound 3-3A in chiral HPLC (column model: DAICEL CHIRALPAK IE (50*250mm, 10μm); mobile phase A: n-hexane; mobile phase B: ethanol containing 0.1% aqueous ammonia; gradient (B%): 50%-50%) is 1.739 min.

[0173] In some embodiments, the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from Compound 7 having one of the following structures: In some embodiments, the configuration of compound 7 is consistent with compound 3-3A. In some embodiments, compound 7 is synthesized via compound 3-3A.

[0174] In some embodiments, the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from Compound 8 having one of the following structures: In some embodiments, the configuration of compound 8 is consistent with compound 3. In some embodiments, the configuration of compound 8 is consistent with compound 3-3A. In some embodiments, compound 8 is synthesized via compound 3. In some embodiments, compound 8 is synthesized via compound 3-3A.

[0175] In some embodiments, the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from Compound 9 having one of the following structures: In some embodiments, the configuration of compound 9 is consistent with compound 7. In some embodiments, the configuration of compound 9 is consistent with compound 3-3A. In some embodiments, compound 9 is synthesized via compound 7. In some embodiments, compound 9 is synthesized via compound 3-3A.

[0176] In some embodiments, the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from Compound 10 having one of the following structures: In some embodiments, the configuration of compound 10 is consistent with compound 3-3A. In some embodiments, compound 10 is synthesized via compound 3-3A.

[0177] In some embodiments, the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from Compound 11 having one of the following structures: In some embodiments, the configuration of compound 11 is consistent with compound 3-3A. In some embodiments, compound 11 is synthesized via compound 3-3A.

[0178] In some embodiments, the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from Compound 12 having one of the following structures: In some embodiments, the configuration of compound 12 is consistent with compound 7. In some embodiments, the configuration of compound 12 is consistent with compound 3-3A. In some embodiments, compound 12 is synthesized via compound 7. In some embodiments, compound 12 is synthesized via compound 3-3A.

[0179] In some embodiments, the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from Compound 13 having one of the following structures: In some embodiments, the configuration of compound 13 is consistent with compound 3-3A. In some embodiments, compound 13 is synthesized via compound 3-3A.

[0180] In some embodiments, the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from Compound 14 having one of the following structures: In some embodiments, the configuration of compound 14 is consistent with compound 3-3A. In some embodiments, compound 14 is synthesized via compound 3-3A.

[0181] In some embodiments, the configuration of the disclosed compounds is consistent with compound 3-3A. In some embodiments, the configuration of the disclosed compounds of formula (I) or formula (II) or formula (III) is consistent with compound 3-3A.

[0182] The present disclosure also provides a pharmaceutical composition comprising the compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments of the present disclosure, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0184] The present disclosure also provides a method for treating a disease in a mammal, comprising administering a therapeutically effective amount of the compound of the present disclosure, its stereoisomer, or its pharmaceutically acceptable salt, or pharmaceutical composition to a mammal, preferably a human, in need of such treatment.

[0185] The present disclosure also provides use of the compound of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of the present disclosure in preparing a drug for treating a disease.

[0186] The present disclosure also provides uses of the compounds of the present disclosure, their stereoisomers, or their pharmaceutically acceptable salts, or the pharmaceutical compositions of the present disclosure in treating diseases.

[0187] The present disclosure also provides the compound of the present disclosure, its stereoisomer, or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present disclosure for use in treating a disease.

[0188] In some embodiments of the present disclosure, the above-mentioned disease is selected from diseases associated with KRAS G12D mutation.

[0189] In some embodiments of the present disclosure, the aforementioned KRAS G12D mutation-related disease is selected from KRAS G12D mutation cancers (eg, pancreatic cancer or colorectal cancer).

[0190] Technical Effects

[0191] The disclosed compounds exhibited high anti-proliferative activity against KRAS G12D mutant colorectal cancer cells (GP2D). They also exhibited excellent pharmacokinetic properties and good oral bioavailability, demonstrated significant tumor inhibition in in vivo efficacy studies, and were well tolerated by animals.

[0192] Definition and Description

[0193] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0194] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0195] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present disclosure, which are prepared by reacting the compounds of the present disclosure with relatively nontoxic acids or bases. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in a neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in a neat solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids such as arginine, and salts of organic acids such as glucuronic acid. Certain specific compounds of the present disclosure contain basic and acidic functional groups and can be converted into either base or acid addition salts.

[0196] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two.

[0197] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0198] The term "substituted" means that a specific atom or group can be replaced by a specified other atom or group. For example, one, two, or three -CH2- in -CH2CH2CH2- can be replaced by O, S, or NH to obtain -O-CH2-CH2-, -O-CH2-, -CH2-O-CH2-, -CH2-O-, -CH2-CH2-O-, -O-, etc.

[0199] The term "optionally" or "optionally" means that the event or circumstance described subsequently may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that would be sterically impossible and / or incomposable to synthesize will be introduced.

[0200] As used herein, "the configuration is consistent with compound 3-3A" means that the compound has a configuration consistent with the hexahydrospiro[cyclopropane-1,2'-pyrrolizine] moiety in compound 3-3A. For example, "the configuration of compound 3 is consistent with compound 3-3A" means that the configuration of the hexahydrospiro[cyclopropane-1,2'-pyrrolizine] moiety in compound 3 is consistent with the configuration of the hexahydrospiro[cyclopropane-1,2'-pyrrolizine] moiety in compound 3.

[0201] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0202] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0203] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0204] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0205] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0206] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond or straight dashed key

[0207] The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.

[0208] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to different functional group isomers that are in dynamic equilibrium at room temperature and can quickly convert into each other. If tautomers are possible (such as in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur through the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one.

[0209] The compounds of the present disclosure may have one or more atropisomers. Unless otherwise specified, atropisomers refer to optically active isomers resulting from the obstruction of free rotation between single bonds. The compounds of the present disclosure containing a chiral axis can be isolated in racemic form. When the energy barrier for free rotation between single bonds of the compounds of the present disclosure containing a chiral axis is sufficiently high, the atropisomers can be isolated in optically pure form.

[0210] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of that isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0211] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0212] The compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For another example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are included within the scope of this disclosure.

[0213] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where 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 incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123I. 125 I and 36 Cl et al.

[0214] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0215] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.

[0216] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0217] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0218] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0219] When the listed linking groups do not specify their connection direction, the connection direction is arbitrary. For example, in ALZ, the linking group L is -MW-, which means that the structure can be AMWZ or AWMZ.

[0220] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy lines For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if an H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group. It means that R can be connected to either end of the double bond, that is, When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0221] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1- 3. C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 , and C 9-12Similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

[0222]

[0046] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0223] The term "alkylene" refers to a group of the formula C n H 2n A saturated straight or branched chain divalent hydrocarbon group typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. For example, the term "C 1-6 "Alkylene" refers to an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2- or -CH2CH(CH3)-), butylene (-CH2CH2CH2CH2-, -CH2CH(CH3)CH2- or -CH2CH2CH(CH3)-), and the like. The alkylene group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0224] The term "alkyl" refers to a group of the formula C n H 2n+1The alkyl group is a saturated hydrocarbon group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. The alkyl group can be straight or branched, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4 or 1 to 3 carbon atoms. For example, the term "C1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). The alkyl group is optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxyl, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy. Similarly, the alkyl moieties (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio groups have the same definition as above.

[0225] The term "alkoxy" refers to an -O-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0226] The term "alkylamino" refers to an -NH-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0227] The term "dialkylamino" refers to -N(alkyl)2, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0228] The term "trialkylsilyl" refers to -Si(alkyl)3, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0229] The term "alkylthio" refers to an -S-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0230] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one double bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like. The alkenyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0231] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), 1,3-butadiynyl (-C≡CC≡CH), and the like. The alkynyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0232] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 10-membered ring, a 4- to 8-membered ring, a 5- to 8-membered ring, or a 5- to 6-membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc. The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0233] Term " heterocyclic radical " refers to fully saturated or partially undersaturated (but not fully unsaturated heteroaromatic) and can be with monocycle, bridged ring, and ring or spirocyclic non-aromatic ring.Unless otherwise indicated, the heterocycle is generally 3 to 12 yuan, 3 to 10 yuan, 4 to 8 yuan, 5 to 8 yuan, 5 to 6 yuan, 3 to 7 yuan or 4 to 6 yuan ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulphur, oxygen, nitrogen, phosphorus, silicon and / or boron.The limiting examples of heterocyclic radical include but are not limited to oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N- methylpyrrolidinyl, dihydropyrrolyl, piperidyl, piperazinyl, pyrazolidinyl, 4H- pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl etc. The heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)- Alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0234] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3-12-membered, 3-10-membered, 4-8-membered, 5-8-membered, 5-6-membered, 3-7-membered, or 4-6-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, thioethane, and aziridinyl groups; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl groups; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl groups; and examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl groups. The heterocycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O) -alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0235] The term "heterocyclenyl" refers to a non-aromatic ring that is partially undersaturated (but not completely unsaturated heteroaromatic) and can exist as a monocycle, a bridged ring, a ring or a spirocycle. Unless otherwise indicated, the heterocycle is typically 3 to 12, 3 to 10, 4 to 8, 5 to 8, 5 to 6, 3 to 7 or 4 to 6 rings containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and / or boron. Non-limiting examples of heterocyclenyl include but are not limited to dihydrofuranyl, dihydropyrrolyl, dioxolyl etc. The heterocycloalkenyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O) -alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0236] The term "treating" means administering a compound or formulation of the present disclosure to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0237] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0238] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0239] The term "preventing" or "preventing" means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with the disease, including preventing the disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0240] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0241] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0242] The term "pharmaceutically acceptable excipient" refers to excipients that have no significant irritating effect on organisms and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable excipients, and can be formulated, for example, into solid, semisolid, liquid, or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, and aerosols.

[0243] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0244] The pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0245] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the invention to be formulated into tablets, pills, lozenges, dragees, capsules, gels, slurries, suspensions, and the like for oral administration to a patient.

[0246] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0247] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0248] In all administration methods of the compounds described herein, the daily dosage is 0.01 to 200 mg / kg body weight. The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0249] The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0250] The compound of formula (III) disclosed herein can be synthesized by referring to the following route:

[0251] wherein X is selected from halogen, such as -Cl, -Br, or -I; Y is selected from -Br, -I, or -OTf; R' is selected from an amino protecting group, such as tert-butyloxycarbonyl;

[0252] R6, R7, R8, R9, n and m are as defined in the present disclosure.

[0253] The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

[0254] Each product obtained by the reaction in the above-mentioned route can be obtained by conventional separation techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. The starting materials can be synthesized by themselves or purchased from commercial institutions (such as, but not limited to, Adrich or Sigma). These raw materials can be characterized using conventional means, such as physical constants and spectral data. The compounds described in this disclosure can be obtained as single isomers or mixtures of isomers using synthetic methods.

[0255] The structures of the compounds disclosed herein can be confirmed by conventional methods known to those skilled in the art. If the disclosure relates to the absolute configuration of a compound, such absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is performed by collecting diffraction intensity data on a cultured single crystal using a Bruker D8 venture diffractometer, using CuKα radiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0256] The abbreviations of the present disclosure are as follows: TMS is trimethylsilyl (-Si(CH3)3); Pd(dppf)Cl2 is dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium; NIS represents N-iodosuccinimide; NMP is N-methylpyrrolidone; TLC is thin layer chromatography; Boc is tert-butyl; and Boc anhydride is di-tert-butyl dicarbonate.

[0257] The solvents used in the present disclosure are commercially available. DETAILED DESCRIPTION

[0258] The present disclosure is described in detail below by way of examples, but is not intended to limit the present disclosure in any way. The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present disclosure. It will be apparent to those skilled in the art that various changes and improvements will be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

[0259] Reference Example 1: Intermediate 1-12

[0260] first step:

[0261] Under a nitrogen atmosphere, compound 1-1 (10 g) and pinacol borane (14.80 g) were added to a mixture of bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I) (510.97 mg) and 4,4'-di-tert-butyl-2,2'-bipyridine (413.79 mg). The reaction mixture was allowed to react at 90°C for 14 hours. The reaction mixture was concentrated, and the residue was purified on a silica gel column (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 1-2. 1 H NMR (400MHz, DMSO-d6) δ7.93(s,1H),7.77(s,1H),1.31(s,12H).

[0262] Step 2:

[0263] To a solution of compound 1-2 (22 g) in formamide (440 mL) under an oxygen atmosphere were added potassium carbonate (7.89 g) and copper acetate monohydrate (1.14 g) in sequence. The reaction mixture was reacted at 25°C under an oxygen atmosphere (15 psi) for 14 hours. Aqueous ammonia (40 mL) and water (200 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined and washed with saturated brine (200 mL x 2). The organic phases were concentrated, and the residue was purified on a silica gel column (petroleum ether / ethyl acetate = 5 / 1) to provide compound 1-3.

[0264] Step 3:

[0265] To a solution of compound 1-3 (11 g) in ethanol (120 ml) was added water (30 ml) and concentrated sulfuric acid (50.60 g) at 90°C. The reaction mixture was allowed to react at 90°C for 2 hours. The reaction mixture was slowly poured into a saturated aqueous sodium carbonate solution (300 ml) and concentrated under reduced pressure to remove the ethanol. The residue was extracted with ethyl acetate (200 ml x 2). The combined organic phases were concentrated and the residue was purified on a silica gel column (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain compound 1-4. LC-MS (ESI) m / z: 274.0, 276.0 (M+1) + .

[0266] Step 4:

[0267] Under a nitrogen atmosphere, to a solution of compound 1-4 (2 g) in 1,4-dioxane (40 ml) were added bis(pinacol)boronate (5.55 g), Pd(dppf)Cl2 (533.19 mg), and potassium acetate (2.15 g) in sequence. The reaction mixture was incubated at 80°C for 14 hours. The reaction mixture was concentrated, and the residue was purified on a silica gel column (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 1-12. LC-MS (ESI) m / z: 320.0 (M-1). - ; 1H NMR (400MHz, CDCl3) δ6.73 (d, J = 2.0 Hz, 1H), 6.56 (d, J = 2.3 Hz, 1H), 3.99 (br s, 2H), 1.36 (s, 12H).

[0268] Reference Example 2: Intermediate 1-11

[0269] first step:

[0270] At 20-30°C, NIS (6.05 g) was added to a DMF (50 ml) solution of compound 1-5 (5 g). The reaction solution was reacted at 25°C for 12 hours. The reaction solution was added to water (150 ml), then extracted with ethyl acetate (150 ml * 2), the organic phases were combined, quenched with saturated sodium sulfite solution (150 ml), separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to obtain compound 1-6. LC-MS (ESI) m / z: 311.8, 313.7 (M+1) + .

[0271] Step 2:

[0272] To a solution of compound 1-6 (6.9 g) in dichloromethane (70 ml) at 0°C, triethylamine (4.48 g) was added, followed by the slow addition of acetyl chloride (2.08 g). The reaction mixture was allowed to react at 25°C for 12 hours. The reaction mixture was added to water (70 ml), filtered, and the solid was collected and dried to obtain compound 1-7. LC-MS (ESI) m / z: 353.9 (M+1) + .

[0273] Step 3:

[0274] To a solution of compound 1-7 (3.5 g) in NMP (70 ml) was added hexamethylphosphoramide (8.7 g), cuprous iodide (9.24 g), and methyl fluorosulfonyldifluoroacetate (9.32 g) at 20-30°C. The reaction mixture was purged with nitrogen three times and allowed to react at 80°C for 12 hours. Ethyl acetate (50 ml) was added to the reaction mixture, filtered, and the filtrate was washed with saturated brine (50 ml * 2). The organic phase was concentrated. The residue was purified by preparative HPLC (column model: Phenomenex Synergi Max-RP 250*50 mm*10 μm, mobile phase A: water (formic acid), mobile phase B: acetonitrile, gradient (B%): 40%-65%, 21 minutes) to obtain compound 1-8. LC-MS (ESI) m / z: 295.8 (M+1) + .

[0275] Step 4:

[0276] At 20-30°C, hydrochloric acid (6 mol / L, 20 ml) was added to a solution of compound 1-8 (2 g) in ethanol (70 ml). The reaction solution was reacted at 25°C for 12 hours. The reaction solution was concentrated to obtain a residue, to which a saturated sodium carbonate solution was added until the pH was ~8, and the residue was extracted with ethyl acetate (20 ml * 2). The combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to obtain compound 1-10. LC-MS (ESI) m / z: 253.8 (M+1) + .

[0277] Step 5:

[0278] Under nitrogen, Pd(dppf)Cl2 (288.02 mg), potassium acetate (1.16 g), and bis(pinacolato)boron ester (3 g) were added to a solution of compound 1-10 (1 g) in dioxane (20 ml). The reaction mixture was incubated at 100°C for 12 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (column model: Welch Ultimate XB-CN 250*70*10 μm, mobile phase A: n-hexane, mobile phase B: ethanol, gradient (B%): 1%-30% over 20 minutes) to obtain compound 1-11. LCMS (ESI) m / z: 301.9 (M+1). + .

[0279] Example 1: Compound 3, Compound 4, Compound 5 and Compound 6

[0280] first step:

[0281] At 0 ° C and under nitrogen protection, compound 2-1 (2 g) was added to a solution of (trifluoromethyl)trimethylsilane (3.64 g) and sodium iodide (1.54 g) in tetrahydrofuran (40 ml) and stirred at 70 ° C for 2 hours. Water (30 ml) was added to the reaction solution and extracted with ethyl acetate (30 ml * 2). The combined organic phase was washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 3-1. LC-MS (ESI) m / z: 246.1 (M+1) + .

[0282] Step 2:

[0283] To a solution of compound 3-1 (0.6 g) in tetrahydrofuran (15 ml) at 0°C, lithium aluminum tetrahydride (371.42 mg) was added, and the mixture was stirred at 70°C for 2 hours. The reaction solution was cooled to 0°C, and sodium sulfate decahydrate (3.7 g) was added to quench the reaction, followed by stirring at 20°C for 30 minutes. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 3-2. 1 H NMR (400MHz, CDCl3) δ3.45-3.21(m,2H),3.19-2.91(m,2H),2.88-2.62(m,2H),2.08-1.64(m,6H),1.40-1.20(m,2H); LC-MS(ESI)m / z:204.2(M+1) + .

[0284] Step 3:

[0285] At 0 ° C and under nitrogen protection, sodium hydrogen (180.44 mg) was added to a solution of compound 1-9 (1 g) and compound 3-2 (458.38 mg) in tetrahydrofuran (20 ml) and stirred at 25 ° C for 1 hour. The reaction solution was quenched with water (10 ml), and the aqueous phase was extracted with ethyl acetate (20 ml * 2). The combined organic phase was washed with saturated brine (30 ml * 2), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to give isomer 1 (petroleum ether / ethyl acetate = 1 / 1, Rf = 0.15) and isomer 2 (petroleum ether / ethyl acetate = 1 / 1, Rf = 0.05). Isomer 1 was purified by preparative chiral HPLC (column model: DAICEL CHIRALPAK IE (50*250mm, 10μm); mobile phase A: n-hexane; mobile phase B: ethanol containing 0.1% ammonia; gradient (B%): 50%-50%, 15 minutes) to obtain compound 3-3A (LC-MS (ESI) m / z: 595.1 (M+1) + ) and compound 3-3B (LC-MS (ESI) m / z: 595.1 (M+1) + Isomer 2 was purified by preparative SFC (column model: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase A: ethanol containing 0.1% ammonia water; mobile phase B: supercritical carbon dioxide; gradient (A%): 25%-25%, 3.5 minutes) to obtain compound 3-3C (LC-MS (ESI) m / z: 595.3 (M+1) + ) and compound 3-3D (LC-MS (ESI) m / z: 595.3 (M+1)+ ).

[0286] Compound 3-3A and compound 3-3B were analyzed by chiral HPLC (column model: DAICEL CHIRALPAK IE (50*250mm, 10μm); mobile phase A: n-hexane; mobile phase B: ethanol containing 0.1% ammonia water; gradient (B%): 50%-50%) to obtain: the retention time of compound 3-3A was 1.739min, and the ee value was 100%; the retention time of compound 3-3B was 2.059min, and the ee value was 100%.

[0287] Compound 3-3C and compound 3-3D were analyzed by SFC detection (column model: Chiralpak AD-3 50×4.6mm ID, 3um; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol containing 0.05% diethylamine; gradient (B%): 5%-40%) to obtain: the retention time of compound 3-3C was 1.311min, and the ee value was 100%; the retention time of compound 3-3D was 1.471min, and the ee value was 100%.

[0288] Step 4:

[0289] Under nitrogen protection, a mixed solution of compound 3-3A (80 mg), compound 1-11 (82.58 mg), potassium phosphate (84.35 mg), and 1,1-di(tert-butylphosphino)ferrocenepalladium chloride (17.27 mg) in dioxane (1.6 ml) and water (0.8 ml) was heated to 90°C and stirred for 16 hours. Anhydrous sodium sulfate was added to the reaction solution, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 3-4. LC-MS (ESI) m / z: 734.3 (M+1) + .

[0290] Referring to the synthesis method of compound 3-4, compound 3-3B was used instead of compound 3-3A to synthesize compound 4-1. LC-MS m / z (ESI): 734.3 (M+1) +

[0291] Referring to the synthesis method of compound 3-4, compound 3-3C was used instead of compound 3-3A to synthesize compound 5-1. LC-MS m / z (ESI): 734.2 (M+1) +

[0292] Referring to the synthesis method of compound 3-4, compound 3-3D was used instead of compound 3-3A to synthesize compound 6-1. LC-MS m / z (ESI): 734.2 (M+1) +

[0293] Step 5:

[0294] To a solution of compound 3-4 (70 mg, 95.40 μL) in ethyl acetate (2 mL) was added a hydrogen chloride / ethyl acetate solution (4 mol / L, 2 mL), and the mixture was stirred at 25°C for 0.5 h. The reaction solution was concentrated at 20°C. The resulting crude product was purified by preparative HPLC (column model: Waters Xbridge C18 150*50 mm*10 μm; mobile phase A: aqueous solution containing ammonium bicarbonate; mobile phase B: acetonitrile; gradient (B%): 38%-68% over 9 minutes) to yield compound 3.

[0295] Referring to the synthesis method of compound 3, compound 4 was synthesized by using compound 4-1 instead of compound 3-4.

[0296] Referring to the synthesis method of compound 3, compound 5 was synthesized by using compound 5-1 instead of compound 3-4.

[0297] Referring to the synthesis method of compound 3, compound 6 was synthesized by using compound 6-1 instead of compound 3-4.

[0298] Compound 3: 1 H NMR (400MHz, DMSO-d6) δ9.02 (s, 1H), 6.60 (s, 1H), 6.31 (d, J = 2.0Hz, 1H), 5.89 (s, 2H), 4.38 (br d,J=11.8Hz,2H),4.27-4.07(m,2H),3.63-3.49(m,4H),3.34-3.23(m,1H ),3.14-2.93(m,2H),2.70(d,J=11.9Hz,1H),2.55-2.51(m,1H),2.35(br d,J=2.0Hz,3H),2.10-2.02(m,1H),2.01-1.93(m,1H),1.87(d,J=13.3Hz,1H),1.85-1.39(m,9H).LC-MS(ESI)m / z:634.2(M+1) + .

[0299] Compound 4: 11H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 6.61 (s, 1H), 6.33 (d, J = 1.9 Hz, 1H), 5.90 (s, 2H), 4.39 (br d, J = 12.0 Hz, 2H), 4.25 - 4.09 (m, 2H), 3.66 - 3.51 (m, 4H), 3.33 - 3.31 (m, 1H), 3.13 - 2.94 (m, 2H), 2.75 - 2.69 (m, 1H), 2.57 - 2.53 (m, 1H), 2.37 (br d, J = 1.9 Hz, 3H), 2.11 - 2.03 (m, 1H), 2.03 - 1.94 (m, 1H), 1.89 (d, J = 13.3 Hz, 1H), 1.83 - 1.51 (m, 8H), 1.51 - 1.41 (m, 1H). LC-MS m / z (ESI): 634.2 (M+1) + 。

[0300] Compound 5: 1 1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 6.63 (s, 1H), 6.33 (d, J = 1.2 Hz, 1H), 5.93 (s, 2H), 4.61 (br t, J = 11.6 Hz, 2H), 4.45 - 4.08 (m, 4H), 3.90 (br d, J = 10.8 Hz, 2H), 3.19 - 2.73 (m, 5H), 2.37 (br d, J = 1.8 Hz, 3H), 2.21 (br d, J = 13.6 Hz, 1H), 2.09 - 1.77 (m, 9H), 1.64 (br s, 2H). LC-MS (ESI) m / z: 634.3 (M+1) + 。

[0301] Compound 6: 1 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 6.63 (s, 1H), 6.33 (s, 1H), 5.92 (s, 2H), 4.54 (br t, J = 12.4 Hz, 2H), 4.17 - 3.93 (m, 4H), 3.81 (br t, J = 11.9 Hz, 2H), 3.10 - 2.95 (m, 3H), 2.80 (br dd, J = 5.8, 10.5 Hz, 1H), 2.74 - 2.66 (m, 1H), 2.37 (br d, J = 1.8 Hz, 3H), 2.17 - 2.07 (m, 1H), 1.97 - 1.75 (m, 9H), 1.62 - 1.49 (m, 2H). LC-MS (ESI) m / z: 634.3 (M+1) + 。

[0302] Example 2: Compound 7

[0303] first step:

[0304] Under nitrogen, a mixed solution of compound 3-3A (150 mg), compound 1-12 (162.10 mg), potassium phosphate (160.53 mg), and 1,1-di(tert-butylphosphino)ferrocenepalladium chloride (32.86 mg) in dioxane (3 ml) and water (1 ml) was heated to 90°C and stirred for 12 hours. Anhydrous sodium sulfate was added to the reaction solution, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 7-1. LC-MS (ESI) m / z: 754.4 (M+1) + .

[0305] Step 2:

[0306] To a solution of compound 7-1 (0.1 g) in ethyl acetate (2 ml) was added a hydrogen chloride / ethyl acetate solution (4 mol / L, 3 ml) at 25°C, and the mixture was stirred at 25°C for 0.5 hours. The reaction solution was concentrated at 20°C, and the residue was purified by preparative HPLC (column type: Phenomenex luna C18 150*25 mm*10 μm; mobile phase A: aqueous solution containing formic acid; mobile phase B: acetonitrile; gradient (B%): 9%-39%; 10 minutes) to obtain the formate salt of compound 7. 1 H NMR (400MHz, DMSO-d6) δ9.06(s,1H),8.20(br s,1H),6.89(d,J=2.0Hz,1H),6.47(d,J=2.0Hz,1H),6.33(s,2H),4.42(br d,J=12.2Hz,2H),4.25-4.13(m,2H),3.61(br s,4H),3.12-3.06(m,1H),3.01(ddd,J=9.5,6.2,3.5Hz,1H),2.72(d,J=11.9Hz,1H),2.54(br s,1H),2.12-2.03(m,1H),2.03-1.95(m,1H),1.90(br d,J=13.4Hz,1H),1.86-1.41(m,10H).LC-MS(ESI)m / z:654.3(M+1) + .

[0307] Example 3: Compound 8

[0308] To a solution of compound 3 (0.1 g) and triethylamine (23.95 mg) in dichloromethane (2 mL) at 0°C under nitrogen was added ethyl chloroformate (15.41 mg), and the mixture was allowed to react at 0°C for 1 hour. Water (5 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with dichloromethane (5 mL x 2). The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The crude product was purified by preparative HPLC (column type: Phenomenex luna C18 150*25 mm*10 μm; mobile phase A: aqueous solution containing formic acid; mobile phase B: acetonitrile; gradient (B%): 22%-52%; 10 minutes) to yield compound 8. 1 H NMR(400MHz,DMSO-d6)δ9.06(s,1H),6.62(s,1H),6.33(s,1H),5.89(s,2H),4.51(br s,2H),4.36(br s,2H),4.27-4.17(m,2H),4.13(q,J=7.1Hz,2H),3.64(br s,2H),3.12(br dd,J=6.5,11.6Hz,1H),3.07-3.00(m,1H),2.74(br d,J=11.9Hz,1H),2.60-2.54(m,1H),2.37(br s,3H),2.14-2.05(m,1H),2.04-1.96(m,1H),1.94-1.43(m,10H),1.24(t,J=7.1Hz,3H).LC-MS(ESI)m / z:706.3(M+1) + .

[0309] Example 4: Compound 9

[0310] To a solution of compound 7 (1.8 g) in dichloromethane (30 ml) were added compound 9-1 (1.64 g) and triethylamine (2.78 g) at 25° C., and the mixture was stirred at 25° C. for 12 hours. The reaction solution was concentrated at 20° C., and the resulting crude product was purified by preparative HPLC (column model: Kromasil Eternity XT 250*80 mm*10 um; mobile phase A: aqueous solution containing ammonium bicarbonate; mobile phase B: acetonitrile; gradient (B%): 60%-90%, 20 minutes) to give compound 9. 1H NMR (400MHz, DMSO-d6) δ9.07(s,1H),6.89(d,J=1.96Hz,1H),6.74(q,J=5.38Hz,1H),6.47(d,J=2.08Hz,1H),6.34(s,2H),4.61-4.44(m,2H),4.37(br s,2H),4.27-4.14(m,2H),3.69-3.61(m,1H),3.10(br dd,J=11.49,6.85Hz,1H),3.01(ddd,J=9.48,5.99,3.73Hz,1H),2.72(d,J=11.74Hz ,1H),2.57-2.53(m,2H),2.07(dd,J=13.45,5.62Hz,1H),2.02-1.96(m,1H),1.90(br d,J=13.57Hz,1H),1.87-1.78(m,3H),1.77-1.67(m,3H),1.65-1.52(m,2H),1.51-1.44(m,4H),1.10(br d,J=6.85Hz,7H).LC-MS(ESI)m / z:812.4(M+1) + .

[0311] Example 5: Compound 10

[0312] first step:

[0313] To a solution of compound 3-3A (0.6 g) in ethyl acetate (5 ml) was added a hydrogen chloride / ethyl acetate solution (4 mol / L, 5 ml) and stirred at 20°C for 0.5 hours. Further hydrogen chloride / ethyl acetate solution (4 mol / L, 5 ml) was added to the reaction solution and stirred at 20°C for 1.5 hours. The reaction solution was concentrated to obtain the hydrochloride salt of compound 10-1. LC-MS (ESI) m / z: 495.2 (M+1) + .

[0314] Step 2:

[0315] At 20°C, sodium nitrite (136.34 mg) was added to an aqueous solution (7 mL) of the hydrochloride salt of compound 10-1 (0.7 g) and acetic acid (158.20 mg), and the mixture was stirred at 20°C for 0.5 hours. Saturated aqueous sodium carbonate solution (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL*2). The combined organic phases were washed with saturated brine (30 mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain compound 10-2. LC-MS (ESI) m / z: 524.2 (M+1)+ .

[0316] Step 3:

[0317] Under nitrogen protection, a mixed solution of compound 10-2 (0.2 g), compound 1-11 (225.91 mg), potassium phosphate (238.88 mg) and 1,1-di(tert-butylphosphino)ferrocenepalladium chloride (48.90 mg) in dioxane (3 ml) and water (1 ml) was heated to 90°C and stirred for 12 hours. Anhydrous sodium sulfate was added to the reaction solution, filtered, and the filtrate was concentrated. The residue was purified by preparative TLC (dichloromethane / methanol = 10 / 1) to obtain compound 10-3. LC-MS (ESI) m / z: 663.3 (M+1) + .

[0318] Step 4:

[0319] To a mixed solution of compound 10-3 (0.13 g) in acetic acid (0.5 ml) and water (0.5 ml) was added zinc powder (60 mg) at 20°C, and the mixture was stirred at 20°C for 1 hour. The reaction solution was filtered, and the filtrate was purified by preparative HPLC (column model: Phenomenex Luna C18 150*25 mm*10 um; mobile phase A: aqueous solution containing formic acid; mobile phase B: acetonitrile; gradient (B%): 7%-37% over 10 minutes) to obtain the formate salt of compound 10. 1 H NMR (400MHz, DMSO-d6) δ9.04(s,1H),8.18(s,1H),6.62(s,1H),6.33(d,J=1.6Hz,1H),5.89(br s,2H),4.51-4.32(m,2H),4.26-4.13(m,2H),3.76-3.63(m,3H),3.31(br s,2H),3.15-3.09(m,1H),3.02(ddd,J=9.3,5.9,3.6Hz,1H),2.72(d,J=11.9Hz,1H),2.59-2.54(m,1H),2.37(br d,J=1.9Hz,3H),2.12-1.67(m,8H),1.66-1.43(m,5H); LC-MS(ESI)m / z:649.4(M+1) + .

[0320] Example 6: Compound 11

[0321] first step:

[0322] At 20°C, zinc powder (211.76 mg) was added to a mixed solution of water (2 ml) and acetic acid (2 ml) of compound 10-2 (0.4 g) and stirred at 20°C for 1 hour. The reaction solution was filtered, the filtrate was adjusted to pH 8-9 with saturated aqueous sodium carbonate solution, and the aqueous phase was extracted with dichloromethane (10 ml * 2). The combined organic phase was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated. The crude product was purified by preparative TLC (dichloromethane / methanol = 10 / 1) to give compound 11-1. LC-MS (ESI) m / z: 510.1 (M+1) +

[0323] Step 2:

[0324] At 20°C, a solution of compound 11-1 (40 mg), aqueous formaldehyde solution (purity: 37%, 25.46 mg), and acetic acid (942.08 μg) in acetonitrile (2 ml) was stirred for 1 hour. Sodium cyanoborohydride (9.86 mg) was then added to the reaction mixture and stirred for 1 hour. The reaction mixture was purified by preparative TLC (dichloromethane / methanol = 10 / 1) to obtain compound 11-2. LC-MS (ESI) m / z: 538.3 (M+1) + .

[0325] Step 3:

[0326] Under nitrogen, a mixture of compound 11-2 (25 mg), compound 1-11 (27.98 mg), 1,1-di(tert-butylphosphino)ferrocenepalladium chloride (6.06 mg), and potassium phosphate (29.59 mg) in dioxane (1.2 mL) and water (0.4 mL) was heated to 90°C and stirred for 2 hours. Anhydrous sodium sulfate was added to the reaction solution, filtered, and the filtrate concentrated. The residue was purified first by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 10 / 1) and then by preparative HPLC (column model: Phenomenex luna C18 150*25 mm*10 μm; mobile phase A: aqueous solution containing formic acid; mobile phase B: acetonitrile; gradient (B%): 9%-39% over 10 minutes) to obtain compound 11. 1H NMR (400MHz, DMSO-d6) δ9.07(s,1H),6.62(s,1H),6.33(d,J=1.6Hz,1H),5.88(s,2H),4.33(br d,J=11.6Hz,2H),4.25-4.10(m,2H),3.79(br d,J=11.5Hz,2H),3.69(br s,2H),3.10(br dd,J=11.9,6.6Hz,1H),3.02(dt,J=6.2,3.0Hz,1H),2.72(d,J=12.0Hz,1H),2.57-2.53(m,1H),2.41-2.32(m,9H),2.07(br dd,J=13.6,5.7Hz,1H),2.03-1.94(m,1H),1.89(br d,J=13.4Hz,1H),1.86-1.69(m,4H),1.64-1.44(m,5H).LC-MS(ESI)m / z:677.4(M+1) + .

[0327] Example 7: Compound 12

[0328] first step:

[0329] Compound 12-1 (59.14 mg) was added to a solution of compound 7 (0.2 g) and triethylamine (61.89 mg) in dichloromethane (4 ml) at 0°C under nitrogen protection, and the mixture was allowed to react at 0°C for 0.5 hours. The reaction solution was quenched with water (5 ml), and after separation, the aqueous phase was extracted with dichloromethane (5 ml). The combined organic phases were washed with saturated brine (10 ml) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by preparative TLC (dichloromethane / methanol = 10 / 1) to obtain compound 12-2. LC-MS (ESI) m / z: 746.1 (M+1) + .

[0330] Step 2:

[0331] A solution of compound 12-2 (70 mg) and potassium acetate (46.01 mg) in N,N-dimethylformamide (1 mL) was stirred at 20°C for 0.5 hours. Potassium acetate (18.41 mg) was added to the reaction mixture, and the mixture was stirred at 20°C for 0.5 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL x 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was first purified by preparative HPLC (column model: Phenomenex luna C18 150*25mm*10um; mobile phase A: aqueous solution containing formic acid; mobile phase B: acetonitrile; gradient (B%): 26%-56%; 10 minutes). The crude product was further purified by preparative HPLC (column model: Welch Ultimate XB-CN 250*50*10um; mobile phase A: n-hexane; mobile phase B: ethanol; gradient (B%): 20%-60%; 15 minutes) to obtain compound 12. 1 H NMR (400MHz, DMSO-d6) δ9.07(s,1H),6.89(d,J=1.8Hz,1H),6.47(d,J=2.1Hz,1H),6.3 5(s,2H),5.74(s,2H),4.66-4.45(m,2H),4.44-4.33(m,2H),4.28-4.17(m,2H),3.76-3 .52(m,2H),3.17-2.98(m,2H),2.81-2.69(m,1H),2.60-2.54(m,1H),2.14-2.05(m,4H) ,2.04-1.95(m,1H),1.95-1.68(m,7H),1.67-1.40(m,3H).LC-MS(ESI)m / z:770.3(M+1) + .

[0332] Example 8: Compound 13

[0333] first step:

[0334] To a solution of compound 13-1 (5 g) in N,N-dimethylformamide (50 ml) was added iodosuccinimide (6.22 g). The reaction solution was reacted at 20°C for 16 hours. Iodosuccinimide (5.18 g) was added to the reaction solution and the reaction was continued at 20°C for 3 hours. 200 ml of water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (200 ml). The combined organic phases were washed with water (300 ml) and saturated brine (300 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by rapid silica gel column (silica gel column: 40 g Silica Flash Column, eluent: 0-20% ethyl acetate / petroleum ether, flow rate: 100 ml / min) to obtain compound 13-2. 1 H NMR (400MHz, CDCl3-d) δ7.17 (d, J 2.7Hz, 1H), 6.86 (d, J = 2.7Hz, 1H), 4.07 (br s, 2H). LC-MS (ESI) m / z: 344.9 (M+3) + .

[0335] Step 2:

[0336] A solution of compound 13-2 (6.2 g) in acetic anhydride (32.70 g) was reacted at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was stirred with dichloromethane (10 ml) and water (10 ml) for 1 hour, filtered, and the filter cake was dried under reduced pressure to obtain compound 13-3. LC-MS (ESI) m / z: 382.7, 384.7 (M-1) - .

[0337] Step 3:

[0338] Under a nitrogen atmosphere, methyl fluorosulfonyl difluoroacetate (13.72 g), cuprous iodide (13.61 g) and hexamethylphosphoric triamide (12.80 g) were added to a solution of compound 13-3 (5.5 g) in N-methylpyrrolidone (50 ml) and reacted at 60°C for 14 hours. Water (200 ml) and aqueous ammonia (100 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate (200 ml * 3). The combined organic phases were washed with water (300 ml) and saturated brine (300 ml) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 13-4. LC-MS (ESI) m / z: 324.8 (M-1) - .

[0339] Step 4:

[0340] Iron powder (3.24 g) and ammonium chloride (3.11 g) were added to a mixed solution of compound 13-4 (3.8 g) in ethanol (40 ml) and water (20 ml), and the reaction solution was reacted at 90°C for 1 hour. The reaction solution was filtered, the filter cake was washed with methanol (50 ml), and the filtrate was concentrated under reduced pressure. Water (50 ml) was added to the residue, extracted with ethyl acetate (50 ml * 3), and the combined organic phase was concentrated under reduced pressure. The residue was purified by a flash silica gel column (silica gel column: 40 g Silica Flash Column, eluent: 0-25% ethyl acetate / petroleum ether, flow rate: 100 ml / min) to obtain compound 13-5. LC-MS (ESI) m / z: 294.8 (M-1) - .

[0341] Step 5:

[0342] To a solution of compound 13-5 (3 g) in acetonitrile (60 ml) was added cuprous bromide (4.35 g) and isopropyl nitrite (3.55 g), and the mixture was reacted at 60°C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column (silica gel column: 40 g Silica Flash Column, eluent: 0-25% ethyl acetate / petroleum ether, flow rate: 100 ml / min) to obtain compound 13-6. LC-MS (ESI) m / z: 357.8, 359.9 (M-1) - .

[0343] Step 6:

[0344] Concentrated sulfuric acid (27.60 g) was added to a mixed solution of compound 13-6 (7.1 g) in ethanol (60 ml) and water (15 ml), and the mixture was reacted at 80°C for 1.5 hours. The reaction solution was concentrated under reduced pressure to remove the ethanol in the reaction solution, and water (100 ml) was added to the residue, and the mixture was extracted with ethyl acetate (100 ml * 3). The combined organic phase was concentrated under reduced pressure. The residue was purified by flash silica gel column (silica gel column: 80 g Silica Flash Column, eluent: 0-10% ethyl acetate / petroleum ether, flow rate: 100 ml / min) to obtain compound 13-7. LC-MS (ESI) m / z: 315.8, 317.8 (M-1) - .

[0345] Step 7:

[0346] To a solution of compound 13-7 (1.5 g) and Boc anhydride (3.08 g) in ethyl acetate (30 ml) were added 4-dimethylaminopyridine (57.46 mg) and N,N-diisopropylethylamine (1.82 g), and the mixture was reacted at 70°C for 0.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash silica gel column (silica gel column: 40 g The residue was purified by silica flash column, eluent: 0-5% ethyl acetate / petroleum ether, flow rate: 100 ml / min) to obtain compound 13-8. 1H NMR (400MHz, CDCl3-d) δ7.55 (s, 2H), 1.49 (s, 18H).

[0347] Step 8:

[0348] To a solution of compound 13-8 (0.4 g) in tetrahydrofuran (8 mL) under a nitrogen atmosphere at 0°C was added trimethylsilyl chloride (418.54 mg). Then, n-butyllithium (2.5 mol / L, 678.03 μL) was added dropwise to the reaction solution, and the mixture was allowed to react at 20°C for 16 hours. The reaction solution was added dropwise to water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to provide compound 13-9.

[0349] Step 9:

[0350] To a solution of compound 13-9 (0.45 g) in ethyl acetate (2 ml) was added hydrogen chloride / ethyl acetate (4 mol / L, 5.40 ml) and the mixture was reacted at 20°C for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was purified by flash silica gel column (silica gel column: 25 g Silica Flash Column, eluent: 0-15% ethyl acetate / petroleum ether, flow rate: 80 ml / min) to obtain compound 13-10. LC-MS (ESI) m / z: 312.1, 314.1 (M+1) + .

[0351] Step 10:

[0352] Under a nitrogen atmosphere, to a solution of compound 13-10 (60 mg) and bis(pinacol boronate) (146.41 mg) in dioxane (2 mL) were added [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (14.06 mg) and potassium acetate (56.58 mg). The reaction mixture was reacted at 110°C for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 13-11. LC-MS (ESI) m / z: 360.3 (M+1) + .

[0353] Step 11:

[0354] Under a nitrogen atmosphere, to a mixed solution of compound 3-3A (45 mg) and compound 13-11 (31.04 mg) in dioxane (0.8 ml) and water (0.2 ml) were added [1,1-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (9.38 mg) and potassium phosphate (45.85 mg), and the mixture was reacted at 85°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative TLC (dichloromethane / methanol = 10 / 1) to obtain compound 13-12. LC-MS (ESI) m / z: 792.4 (M+1) + .

[0355] Step 12:

[0356] To a solution of compound 13-12 (40 mg) in ethyl acetate (1 mL) was added a hydrogen chloride / ethyl acetate solution (4 mol / L, 1 mL). The reaction mixture was allowed to react at 20°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure at 25°C, and the residue was purified by preparative HPLC (column type: Phenomenex luna C18 150*25 mm*10 μm, mobile phase A: aqueous solution containing formic acid; mobile phase B: acetonitrile, gradient (B%): 18%-48% over 9 minutes) to obtain the formate salt of compound 13. 1 H NMR (400MHz, DMSO-d6) δ9.03 (s, 1H), 8.23 ​​(br s, 1H), 7.03 (s, 1H), 6.50 (d, J = 1.5Hz, 1H), 5.94 (br s, 2H), 4.41 (br d,J=11.9Hz,2H),4.23-4.12(m,1H),4.13-4.12(m,1H),3.61(br d,J=11.0Hz,5H),3.09(br dd,J=11.9,6.7Hz,1H),3.00(ddd,J=9.3,5.9,3.7Hz,1H),2.71(br d,J=11.9Hz,1H),2.07(br dd,J=13.3,5.7Hz,1H),2.02-1.94(m,1H),1.89(br d,J=13.2Hz,1H),1.84-1.77(m,1H),1.76-1.51(m,7H),1.46(ddd,J=12.4,8.3,3.9Hz,1H),1.16(dd,J=14.1,5.6Hz,1H),0.31(s,9H). LC-MS(ESI)m / z:692.4(M+1) + .

[0357] Example 9: Compound 14

[0358] first step:

[0359] Referring to the synthesis method of compound 10-3, compound 1-12 was used instead of compound 1-11 to synthesize compound 14-1. LC-MS (ESI) m / z: 683.1 (M+1) + .

[0360] Step 2:

[0361] Referring to the synthesis method of the formate salt of compound 10, compound 14-1 was used instead of compound 10-3 to synthesize the formate salt of compound 14. 1 H NMR (400MHz, DMSO-d6) δ9.05(s,1H),8.16(s,1H),6.88(d,J=1.7Hz,1H),6.47(d,J=2.1 Hz,1H),6.32(s,2H),4.50-4.33(m,2H),4.24-4.14(m,2H),3.74-3.61(m,4H),3.31(br s,2H),3.10(br dd,J=6.8,11.9Hz,1H),3.01(ddd,J=3.7,6.1,9.4Hz,1H),2.72(d,J=12.0Hz,1H),2.57-2.52 (m,1H),2.12-2.03(m,1H),2.03-1.66(m,6H),1.65-1.42(m,5H).LC-MS(ESI)m / z:669.2(M+1) + .

[0362] Experimental Example 1: GP2D cell proliferation assay

[0363] Purpose of the experiment:

[0364] This experiment aims to verify the inhibitory effect of the disclosed compounds on the proliferation of GP2D cells with KRAS G12D mutation.

[0365] Experimental Materials:

[0366] DMEM medium, penicillin / streptomycin antibiotics were purchased from Gibco, and fetal bovine serum was purchased from Hyclone. 3D CellTiter-Glo (a chemiluminescent cell viability assay) reagent was purchased from Promega. GP2D cell line (DMEM + 10% FBS + 1% penicillin / streptomycin) was purchased from ECACC, and the Envision multi-label analyzer was purchased from PerkinElmer.

[0367] Experimental methods:

[0368] Cells were seeded in ultra-low attachment 96-well U-shaped plates, with 80 μL of cell suspension per well, containing 1000 cells. The plates were incubated overnight in a CO2 incubator.

[0369] The compound to be tested was diluted 5-fold into 8 concentrations using a dispenser, i.e., from 2mM to 25.6nM, and a double-well experiment was set up. 78μL of culture medium was added to the middle plate, and then 2μL of the gradient diluted compound per well was transferred to the middle plate according to the corresponding position. After mixing, 20μL of each well was transferred to the cell plate. The concentration range of the compound transferred to the cell plate was 10μM to 0.128nM. The cell plate was placed in a carbon dioxide incubator and cultured for 5 days. Prepare another cell plate and read the signal value on the day of drug addition as the maximum value (Max value in the equation below) for data analysis.

[0370] Add 100 μL of cell viability chemiluminescent detection reagent to the cell plate and incubate at room temperature for 30 minutes to allow the luminescent signal to stabilize. Read the results using a multi-label analyzer.

[0371] Data Analysis:

[0372] The raw data were converted into inhibition rate, IC, using the equation (Sample-Min) / (Max-Min)*100%. 50 The value can be obtained by four-parameter curve fitting (obtained in "log(inhibitor)vs.response--Variable slope" mode in GraphPad Prism).

[0373] Experimental results:

[0374] The anti-proliferative activity of the disclosed compounds on GP2D cells with KRAS G12D mutation IC 50 The data are shown in Table 1.

[0375] Table 1. Effects of Compounds on KRAS G12D Antiproliferative activity of mutant GP2D cells

[0376] Note: A stands for IC 50 ≤10nM.

[0377] Experimental conclusion: The disclosed compounds showed higher anti-proliferative activity against GP2D cells with KRAS G12D mutation.

[0378] Experimental Example 2: Pharmacokinetic Evaluation Experiment in Mice

[0379] Purpose of the experiment:

[0380] Male CD-1 (ICR) mice were used as test animals. LC-MS / MS was used to determine the plasma concentrations of the test compound at different times after intravenous and oral administration. The pharmacokinetic behavior of the test compound in mice was studied and its pharmacokinetic characteristics were evaluated.

[0381] Experimental plan:

[0382] Experimental animals: Five healthy adult male CD-1 (ICR) mice were divided into two groups according to the principle of similar weight: IV group (1 group) with 2 mice in each group and PO group (1 group) with 3 mice in each group. Animals were purchased from Beijing Weitonglihua Experimental Animal Co., Ltd.

[0383] Drug preparation:

[0384] Group IV: Weigh an appropriate amount of sample and add appropriate amounts of Solutol (polyethylene glycol-15 hydroxystearate), SLS (sodium lauryl sulfate), and water in the volume ratio of 10:0.5:89.5. Stir at room temperature until the solution reaches a clear state of 1.50 mg / mL.

[0385] PO group: Weigh an appropriate amount of sample, add appropriate amounts of Solutol (polyethylene glycol-15 hydroxystearate), SLS (sodium lauryl sulfate) and water in the volume ratio of 10:0.5:89.5, and stir at room temperature until the solution reaches a clear state of 2.0 mg / mL.

[0386] Administration: After fasting overnight, the IV group received intravenous administration with a volume of 2 mL / kg and a dose of 3 mg / kg; the PO group received oral administration with a volume of 10 mL / kg and a dose of 20 mg / kg.

[0387] Experimental operation:

[0388] Male CD-1 (ICR) mice were intravenously administered with the test compound. Approximately 25 μl of blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, and placed in commercial anticoagulant tubes pre-coated with EDTA-K2. For the oral administration group, approximately 25 μl of blood was collected at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, and placed in commercial anticoagulant tubes pre-coated with EDTA-K2 (ethylenediaminetetraacetic acid dipotassium). The tubes were centrifuged for 10 minutes to separate plasma and stored at -60°C. Four hours after administration, the animals were allowed to eat. Plasma levels of the test compound were determined by LC-MS / MS following intravenous and oral administration. The linear range of the method was 2.00 to 2000 nmol / L. Plasma samples were analyzed after protein precipitation with acetonitrile.

[0389] Experimental results:

[0390] The pharmacokinetic results of the disclosed compounds are shown in Table 2.

[0391] Table 2. Pharmacokinetic results of the disclosed compounds

[0392] Note: Cl: clearance rate; V d : Volume of distribution; AUC 0-last : exposure dose; T 1 / 2 : half-life; C max : Maximum compound concentration after oral administration; T max : Reach C max time; F: bioavailability.

[0393] Experimental conclusion: The disclosed compounds have good pharmacokinetic properties, showing high oral absorption exposure and oral bioavailability.

[0394] Experimental Example 3: GP2D in vivo efficacy experiment

[0395] Purpose of the experiment:

[0396] The in vivo efficacy of the test compounds was evaluated in a colorectal cancer GP2D cell subcutaneous xenograft tumor model in BALB / c nude mice.

[0397] Experimental operation:

[0398] BALB / c nude mice, female, 6 weeks old. A total of 36 mice were required. They were provided by Beijing Weitonglihua Laboratory Animal Co., Ltd. GP2D cells were inoculated subcutaneously in mice at a seeding rate of 2 × 10 6 / 0.2mL, and the average tumor volume reached about 130mm 3 Randomization and drug administration began at 1:00 pm. The frequency and dosage of oral administration are shown in Table 3. Tumor diameter was measured with a vernier caliper twice a week. Tumor volume was calculated as: V = 0.5a × b 2 , a and b represent the major and minor diameters of the tumor, respectively. The anti-tumor efficacy of a compound was evaluated using the TGI (%). TGI (%) reflects the rate of tumor growth inhibition. TGI (%) is calculated as follows: TGI (%) = [(1 - (mean tumor volume at the end of treatment in a given treatment group - mean tumor volume at the start of treatment in that treatment group) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the start of treatment in the solvent control group)] × 100%.

[0399] Experimental results: The experimental results are shown in Table 3.

[0400] Table 3. Effects of the test substances on animals in the colorectal cancer GP2D cell subcutaneous xenograft tumor model of BALB / c nude mice

[0401] Experimental conclusion: The disclosed compounds exhibited good in vivo efficacy in the colorectal cancer GP2D subcutaneous xenograft tumor model, had significant tumor inhibition and even tumor shrinkage effects, and were well tolerated by animals.

[0402] Experimental Example 4: In vivo efficacy study of PK59

[0403] Purpose of the experiment:

[0404] The in vivo efficacy of the test compounds was evaluated in a pancreatic cancer PK59 cell subcutaneous xenograft tumor model in BALB / c nude mice.

[0405] Experimental operation:

[0406] BALB / c nude mice, female, 5 weeks old. A total of 36 mice were required. They were provided by Beijing Weitonglihua Laboratory Animal Co., Ltd. PK59 cells were inoculated subcutaneously in mice at a seeding rate of 1×10 6 / 0.2mL, and the average tumor volume reached about 110mm 3 Randomization and drug administration began at 1:00 pm. The frequency and dosage of oral administration are shown in Table 4. Tumor diameter was measured with a vernier caliper twice a week. The tumor volume was calculated as: V = 0.5a × b 2 , a and b represent the major and minor diameters of the tumor, respectively. The anti-tumor efficacy of a compound was evaluated using the TGI (%). TGI (%) reflects the rate of tumor growth inhibition. TGI (%) is calculated as follows: TGI (%) = [(1 - (mean tumor volume at the end of treatment in a given treatment group - mean tumor volume at the start of treatment in that treatment group) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the start of treatment in the solvent control group)] × 100%.

[0407] Experimental results: The experimental results are shown in Table 4.

[0408] Table 4. Effects of the test substances on animals in the pancreatic cancer PK59 cell subcutaneous xenograft tumor model in BALB / c nude mice

[0409] Experimental conclusion: The disclosed compound exhibited good in vivo efficacy in a pancreatic cancer subcutaneous xenograft tumor model, had a significant tumor-suppressing effect, and was well tolerated by animals.

Claims

1. A compound of formula (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, n is selected from 0, 1, 2, 3, 4, or 5; m is selected from 0, 1, 2, 3, 4, 5, or 6; R6 is selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 alkoxy; R7 is selected from H, -NR 7a R 7b 、-C(O)R 7b 、-C(O)OR 7b 、-C(O)OC 1-6 Alkylene OC(O)R 7b 、-C(O)OC 1-6 Alkylene NR 7a C(O)R 7b 、-C(O)NR 7a R 7b 、-C(O)NR 7a C 1-6 Alkylene NR 7a C(O)R 7b , or -C(O)NR 7a C 1-6 Alkylene OC(O)R 7b ; R 7a Independently selected from H, or C 1-6 alkyl; R 7b independently selected from H, or optionally substituted by one or more R 7c Substituted with the following groups: C 1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, 3-12 membered cycloalkyl C 1-6 Alkylene, or 3-12 membered heterocyclic group C 1-6 alkylene; Each R 7c independently selected from deuterium, oxo, halogen, -OH, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1- 4-alkylamino, di-C 1-4 Alkylamino, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, halo C 1-4 Alkylamino, or halogenated di-C 1-4 Alkylamino; Each R8 is independently selected from halogen, -CN, -OH, -NH2, or optionally substituted by one or more R 8a Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, tri-C 1-6 Alkylsilyl, C 1-3 Alkoxy C 1-3 Alkylene, C 1-3 Alkylthio C 1-3 Alkylene, C 1-3 Alkylamino C 1-3 Alkylene, di-C 1-3 Alkylamino C 1-3 Alkylene, or tri-C 1-3 Alkylsilyl C 1-3 alkylene; Each R 8a independently selected from deuterium, oxo, halogen, -OH, -NH2, or -CN; Each R9 is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, or optionally substituted by one or more R 9a Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, or di-C 1-6 Alkylamino; Each R 9a independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, or di-C 1-4 Alkylamino.

2. The compound of formula (III) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R6 is selected from H, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 alkoxy; Alternatively, R6 is selected from H, halogen, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl or halogenated C 1-3 alkoxy; Alternatively, the R6 is selected from H, -F, -Cl, -Br, -I, -CN, methyl, methoxy, difluoromethyl, trifluoromethyl, or trifluoromethoxy; Alternatively, said R6 is selected from H and halogen.

3. The compound of formula (III) according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein Said R7 is independently selected from H, -NR 7a R 7b 、-C(O)R 7b 、-C(O)OR 7b 、-C(O)OC 1-4 Alkylene OC(O)R 7b 、-C(O)OC 1-4 Alkylene NR 7a C(O)R 7b 、-C(O)NR 7a R 7b 、-C(O)NR 7a C 1-4 Alkylene NR 7a C(O)R 7b , or -C(O)NR 7a C 1-4 Alkylene OC(O)R 7b ; Alternatively, said R7 is independently selected from H, -NR 7a R 7b 、-C(O)R 7b 、-C(O)OR 7b , or -C(O)OC 1-4 Alkylene OC(O)R 7b ; Alternatively, said R7 is independently selected from H, -NR 7a R 7b 、-C(O)OR 7b , or -C(O)OC 1-4 Alkylene OC(O)R 7b ; Alternatively, said R7 is independently selected from H, -NH2, -N(CH3)2, 4. The compound of formula (III) according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The R 7a Independently selected from H, or C 1-4 alkyl; Alternatively, the R 7a Independently selected from H, or C1-3 alkyl; Alternatively, the R 7a independently selected from H, methyl, ethyl, or isopropyl; Alternatively, the R 7b independently selected from H, or optionally substituted by one or more R 7c Substituted with the following groups: C 1-6 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocyclic group, 3-6 membered cycloalkyl C 1-3 Alkylene, or 4-6 membered heterocyclic group C 1-3 alkylene; Alternatively, the R 7b independently selected from optionally one or more R 7c Substituted with the following groups: C 1-6 Alkyl, 3-6 membered cycloalkyl, or 3-6 membered cycloalkyl C 1-3 alkylene; Alternatively, the R 7b independently selected from H, or optionally substituted by one or more R 7c Substituted groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, dioxolyl, cyclopropyl, C 1-3 Alkylene, cyclobutyl C 1-3 Alkylene, cyclopentyl C 1-3 Alkylene, cyclohexyl C 1-3 Alkylene, azetidinyl C 1-3 Alkylene, oxetane C 1-3 Alkylene, pyrrolidyl C 1-3 Alkylene, tetrahydrofuranyl C 1-3 Alkylene, piperidinyl C 1-3 Alkylene, tetrahydropyranyl C 1-3 Alkylene, piperazinyl C 1-3 Alkylene, morpholinyl C 1-3 Alkylene, or dioxolyl C 1-3 alkylene; Alternatively, the R 7b independently selected from H, or optionally substituted by one or more R 7c Substituted groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclopentylmethylene, Alternatively, the R 7b Independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, Cyclopentyl, cyclopentylmethylene, Alternatively, each of the R 7c independently selected from deuterium, oxo, halogen, -OH, -CN, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylthio, halo C 1-3 Alkylamino, or halogenated di-C 1-3 Alkylamino; Alternatively, each of the R 7c independently selected from deuterium, oxo, -F, -Cl, -Br, -I, -OH, -CN, -NH2, methyl, ethyl, isopropyl, methoxy, methylthio, methylamino, dimethylamino, diethylamino, fluoromethyl, or fluoromethoxy; Alternatively, each of the R 7c Independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, methyl, methoxy, methylthio, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.

5. The compound of formula (III) according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Each R8 is independently selected from halogen, -CN, -OH, -NH2, or optionally substituted by one or more R 8a Substituted with the following groups: C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, di-C 1-4 Alkylamino, tri-C 1-4 Alkylsilyl, C 1-2 Alkoxy C 1-2 Alkylene, C 1-2 Alkylthio C 1-2 Alkylene, C 1-2 Alkylamino C 1-2 Alkylene, di-C 1-2 Alkylamino C 1-2 Alkylene, or tri-C 1-2 Alkylsilyl C 1-2 alkylene; Alternatively, each R8 is independently selected from halogen, -CN, -OH, -NH2, or optionally substituted by one or more R 8a Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, tri-C 1-4 Alkylsilyl, C 1-2 Alkylthio C 1-2 Alkylene, di-C 1-2 Alkylamino C 1-2 Alkylene, or tri-C 1-2 Alkylsilyl C 1-2 alkylene; Alternatively, each R8 is independently selected from halogen, -CN, -OH, -NH2, or optionally substituted by one or more R 8a Substituted with the following groups: C 1-4 Alkyl or C 1-4 alkoxy; Alternatively, each R8 is independently selected from -F, -Cl, -Br, -I, -CN, -OH, -NH2, or optionally substituted by one or more R 8a Substituted groups as follows: methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, isopropoxy, methylthio, methylamino, dimethylamino, trimethylsilyl, methoxymethylene, methylthiomethylene, methylaminomethylene, dimethylaminomethylene, trimethylsilylmethylene; Alternatively, each R8 is independently selected from -F, -Cl, -Br, -I, -CN, -OH, -NH2, or optionally substituted by one or more R 8a Substituted groups: methyl, ethyl, methoxy, trimethylsilyl, methylthiomethylene, dimethylaminomethylene, trimethylsilylmethylene; Alternatively, each R8 is independently selected from -F, -Cl, -Br, -I, -CN, -OH, -NH2, methyl, ethyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, trimethylsilyl, 6. The compound of formula (III) according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Each R 8a independently selected from deuterium, -F, -Cl, -Br, -OH, -NH2, or -CN; Alternatively, each of the R 8a Independently selected from -F, -Cl, -Br, or methyl.

7. The compound of formula (III) according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Each R9 is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, or optionally substituted by one or more R 9a Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, or di-C 1-4 Alkylamino; Alternatively, each R9 is independently selected from deuterium, oxo, -F, -Cl, -Br, -I, -OH, -NH2, -CN, or optionally substituted by one or more R 9a Substituted groups such as methyl, ethyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, ethylamino, or dimethylamino; Alternatively, each R9 is independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, trifluoromethoxy, or dimethylaminomethylene; Alternatively, each R9 is independently selected from halogen.

8. The compound of formula (III) according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Each R 9a independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, or di-C 1-3 Alkylamino; Alternatively, each of the R 9a independently selected from deuterium, oxo, -F, -Cl, -Br, -I, -OH, -NH2, -CN, methoxy, ethoxy, methylthio, methylamino, ethylamino, dimethylamino, or diethylamino; Alternatively, each of the R 9a Independently selected from -F or -Cl.

9. The compound of formula (III) according to any one of claims 1 to 8, its stereoisomers or pharmaceutically acceptable salts thereof, which is selected from the compound of formula (II), its stereoisomers or pharmaceutically acceptable salts thereof, in, R1, R2 and R3 are as defined in any one of claims 1 to 8; R4, R5 are as defined in any one of claims 1 to 8; R6 and R7 are as defined in any one of claims 1 to 8.

10. The compound of formula (III) according to any one of claims 1 to 9, its stereoisomer or a pharmaceutically acceptable salt thereof, which is selected from the compound of formula (II), its stereoisomer or a pharmaceutically acceptable salt thereof, in, R1 and R2 are independently selected from -NH2, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, The C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl and C 2-4 Alkynyl is optionally substituted with 1, 2, 3, and 4 halogens; R3 is selected from -NH2; R4 and R5 are independently selected from H, halogen, C 1-4 Alkyl and C 1-4 Alkoxy, the C 1-4 Alkyl and C 1-4 Alkoxy is optionally substituted with 1, 2, 3, and 4 halogens; R6 is selected from halogen; R7 is selected from H, -N(R 10 )2, -C(=O)OC 1-4 Alkyl and -C(=O)OC 1-4 Alkylene-OC(=O)C 1-4 Alkyl, the C 1-4 Alkyl is optionally substituted with 1, 2, 3, and 4 halogens; Each R 10 Each independently selected from H and C 1-4 alkyl.

11. The compound of formula (II) according to claim 10, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R1 selects -NH2, -F, -Cl, -Br, -I, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH(CH3)2, -CF3, -OCF3, Alternatively, R1 is selected from -CF3, -OCF3, and -NH2; Alternatively, R2 is selected from -NH2, -F, -Cl, -Br, -I, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH(CH3)2, -CF3, -OCF3, Alternatively, R2 is selected from -CF3, -OCF3, and -NH2; Alternatively, R4 is selected from H, -F, -Cl, -Br, -I, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH(CH3)2, -CF3, and -OCF3; Alternatively, R4 is selected from H and -F; Alternatively, R5 is selected from H, -F, -Cl, -Br, -I, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH(CH3)2, -CF3, and -OCF3; Alternatively, R5 is selected from H and -F; Alternatively, R7 is selected from H, -NH2, -C(=O)OCH2CH3, -C(=O)OCH(CH3)OC(=O)CH(CH3)2 and -C(=O)OCH2OC(=O)CH3.

12. The compound according to any one of claims 1 to 11, its stereoisomer or a pharmaceutically acceptable salt thereof, which is selected from the following compounds, its stereoisomer or a pharmaceutically acceptable salt thereof:

13. The compound according to any one of claims 1 to 12, its stereoisomer or a pharmaceutically acceptable salt thereof, which is selected from the following compounds, its stereoisomer or a pharmaceutically acceptable salt thereof: 14 . A pharmaceutical composition comprising the compound according to claim 1 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

15. Use of the compound according to any one of claims 1 to 13, its stereoisomer, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 14 in the preparation of a medicament for treating a disease.

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