Substituted pyrazolopyridines as 4th generation egfr inhibitors

Abstract

The present invention provides a compound as a fourth-generation EGFR inhibitor, which is a compound or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof. The present invention also provides a pharmaceutical composition comprising the compound, and use thereof in the treatment of cancer.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to EGFR inhibitors. Background Art

[0002] Lung cancer is one of the most common malignancies, with approximately 1.6 million new cases worldwide each year. Lung cancer is categorized into two types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for approximately 85% of all lung cancer cases (Nature Reviews Disease Primers, 2015, 1, 15009). Epidermal growth factor receptor (EGFR) is the most common driver gene in NSCLC, with a positive rate of 17% in all NSCLCs, nearly 30% to 40% in Chinese patients, and as high as approximately 60% in lung adenocarcinomas.

[0003] EGFR is a transmembrane glycoprotein that belongs to the ErbB family of tyrosine kinase receptors. EGFR is abnormally activated by various mechanisms, such as receptor overexpression, mutation, ligand-dependent receptor dimerization, and ligand-independent activation. Sustained activation of its kinase activity initiates downstream signaling pathways that promote cell proliferation, differentiation, and survival. Small molecule inhibitors of EGFR kinase can inhibit tyrosine kinase activation, leading to biological effects such as inhibiting tumor cell proliferation and promoting apoptosis, and are a hot area of ​​research for lung cancer.

[0004] Osimertinib is a drug developed to target first- and second-generation drug-resistant EGFR mutations (del19 or L858R) combined with the T790M mutation. While clinically effective, it can also develop resistance with continued treatment. In 2015 (Nature Medicine, 2015, 21, 560–562), data on resistance in 15 patients taking osimertinib were first reported. The EGFR C797S mutation was a major mechanism of resistance to osimertinib, accounting for approximately 40% of patients. Furthermore, recent literature reports indicate that 22–25% of patients who develop resistance after second-line osimertinib therapy harbor the C797S mutation (Nature Cancer, 2021, 377–391). Therefore, there is an urgent clinical need to develop new small molecule inhibitors targeting the C797S mutation to provide patients with safer and more effective fourth-generation EGFR inhibitors. Summary of the Invention

[0005] In this study, we used major clinically observed mutations, including del19 and del19 / T790M / C797S, to conduct cellular evaluations and validate them in engineered Ba / F3 cells. Ultimately, we discovered a series of novel chemical entities with strong biological activity and minimal inhibition against the wild-type, demonstrating high selectivity and safety.

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

[0007]

[0008] in,

[0009] X1 or X2 are independently selected from N or CH, and contain at least one N;

[0010] R1 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl or 4-12 membered heterocyclic group, wherein R1 may be optionally replaced by halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-7 cycloalkyl substitution;

[0011] R2 is selected from H, C 1-6 Alkyl or C 3-7 Cycloalkyl;

[0012] R3 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl or 4-12 membered heterocyclic group, said R3 may be optionally replaced by halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-7 cycloalkyl substitution;

[0013] R4 is selected from H, C 1-6 Alkyl or C 3-7 Cycloalkyl;

[0014] R5 is selected from 5-membered heteroaryl, 5-6-membered heterocyclyl or 9-12-membered heteroaryl; said R5 may be optionally replaced by 1, 2 or 3 R x replace;

[0015] R x Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-R a 、CN、-C(O)NH2、-S(O)2-Ra or C 3-7 Cycloalkyl;

[0016] R a Selected from C 1-6 Alkyl, C 3-7 Cycloalkyl, -OH, -OMe or -NH2.

[0017] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, and optionally a pharmaceutically acceptable excipient.

[0018] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, and further comprising another therapeutic agent.

[0019] In another aspect, the present invention provides use of a compound of the present invention in the preparation of a medicament for treating and / or preventing EGFR kinase-mediated diseases.

[0020] In another aspect, the present invention provides a method for treating and / or preventing an EGFR kinase-mediated disease in a subject, comprising administering to the subject a compound or composition of the present invention.

[0021] In another aspect, the present invention provides a compound of the present invention or a composition of the present invention for use in the treatment and / or prevention of EGFR kinase-mediated diseases.

[0022] In a specific embodiment, the EGFR kinase-mediated disease treated by the present invention is cancer, including cancer selected from the group consisting of lung cancer (including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), lung adenocarcinoma, and lung squamous cell carcinoma).

[0023] Other objects and advantages of the present invention will be apparent to those skilled in the art from the following detailed description, examples and claims.

[0024] definition

[0025] Chemical definition

[0026] Definitions of specific functional groups and chemical terms are described in more detail below.

[0027] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C 5-6 alkyl.

[0028] “C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl and C 1-2 Alkyl groups are preferred. 1-6 Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term “C 1-6 "Alkyl" also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0029] “C 1-6 "Alkylene" refers to the removal of C 1-6 In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3Alkylene is preferred. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylenes, for example, alkylenes substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0030] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0031] Therefore, “C 1-6 "Haloalkyl" refers to the above-mentioned "C 1-6 Alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-4 Halogenated alkyl is particularly preferred, more preferably C 1-2 Haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. The haloalkyl group can be substituted at any available point of attachment, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0032] “C 3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 4-10 Cycloalkyl, C 3-7 Cycloalkyl, C 3-6 Cycloalkyl and C 3-5 Cycloalkyl is particularly preferred, more preferably C 5-6Cycloalkyl. Cycloalkyl also includes a ring system in which the above-mentioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such a case, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyls include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), and the like. The cycloalkyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0033] "3-10 membered heterocyclyl" refers to a group of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. In some embodiments, a 4-9 membered heterocyclyl is preferably a 4-9 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, a 5-8 membered heterocyclyl is preferably a 5-8 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, a 3-8 membered heterocyclyl is preferably a 3-8 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; a 3-7 membered heterocyclyl is preferably a 3-7 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 4-7 membered heterocyclyl is preferably a 4-7 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 4-6 membered heterocyclyl is preferably a 4-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; and a 5-6 membered heterocyclyl is more preferably a 5-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes a ring system in which the above-mentioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or a ring system in which the above-mentioned heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such a case, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiorenyl. Exemplary 4-membered heterocyclyls containing one heteroatom include, but are not limited to, azetidinyl, oxetane, and thiidine. Exemplary 5-membered heterocyclyls containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thienyl.Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyl groups) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. The heterocyclyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0034] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 Aryl also includes ring systems in which an aryl ring as described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Aryl groups can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0035] "5-10 membered heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-9 membered heteroaryl is preferred, which is a 5-9 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryls are particularly preferred and are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryls containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryls containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryls containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryls containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azacycloheptatrienyl, oxepinyl, and thieptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. A heteroaryl group can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0036] Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, etc., as defined herein, are optionally substituted groups.

[0037] Exemplary substituents on carbon atoms include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2, -CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2, -SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa)3、-OSi(R aa )3、-C(=S)N(R bb )2, -C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa )2、-B(OR cc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0038] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa 、=NNR bb C(=O)OR aa 、=NNR bb S(=O)2R aa 、=NR bb or = NOR cc replace;

[0039] R aa Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R aa The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0040] R bb Each of the following is independently selected from: hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0041] R cc Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R cc The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0042] R ddEach of the is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee 、-ON(R ff )2、-N(R ff )2,、-N(R ff )3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2、-C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee 、-SO2N(R ff )2, -SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee )3、-OSi(R ee )3、-C(=S)N(R ff )2, -C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)2Ree 、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0043] R ee Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0044] R ff Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ff The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0045] R gg Each of the independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - 、-NH(C 1-6 Alkyl)2 + X - 、-NH2(C 1-6 alkyl) + X - 、-NH3 + X - 、-N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2、C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; wherein X - For the counter ion.

[0046] Exemplary substituents on nitrogen atoms include, but are not limited to, hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR bb )R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R attached to the nitrogen atom cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substituted, and wherein R aa 、R bb 、R cc and R dd As mentioned above.

[0047] Other definitions

[0048] As used herein, the term "pharmaceutically acceptable salt" refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention that are suitable for use in contact with patient tissues within the scope of sound medical judgment, do not produce undue toxicity, irritation, allergic response, etc., are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the present invention.

[0049] "Subjects" to be administered include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0050] "Disease," "disorder," and "condition" are used interchangeably herein.

[0051] Generally, an "effective amount" of a compound is an amount sufficient to elicit the desired biological response. As will be appreciated by those skilled in the art, the effective amount of a compound of the invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount includes both a therapeutically effective amount and a prophylactically effective amount.

[0052] "Combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and other therapeutic agents. For example, a compound of the invention can be administered simultaneously or sequentially with the other therapeutic agents in separate unit dosage forms, or can be administered simultaneously with the other therapeutic agents in a single unit dosage form. DETAILED DESCRIPTION

[0053] As used herein, the term "compound of the present invention" refers to the compound of the following formula (I) (including sub-general formulae, such as formula (II), (II) or (IV), etc.) or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and a mixture thereof.

[0054] In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0055]

[0056] in,

[0057] X1 or X2 are independently selected from N or CH, and contain at least one N;

[0058] R1 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl or 4-12 membered heterocyclic group, wherein R1 may be optionally replaced by halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-7 cycloalkyl substitution;

[0059] R2 is selected from H, C 1-6 Alkyl or C 3-7 Cycloalkyl;

[0060] R3 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl or 4-12 membered heterocyclic group, said R3 may be optionally replaced by halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-7 cycloalkyl substitution;

[0061] R4 is selected from H, C 1-6 Alkyl or C 3-7 Cycloalkyl;

[0062] R5 is selected from 5-membered heteroaryl, 5-6-membered heterocyclyl or 9-12-membered heteroaryl; said R5 may be optionally replaced by 1, 2 or 3 R x replace;

[0063] R x Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-R a 、CN、-C(O)NH2、-S(O)2-R a or C 3-7 Cycloalkyl;

[0064] R a Selected from C 1-6 Alkyl, C 3-7 Cycloalkyl, -OH, -OMe or -NH2.

[0065] In another embodiment, the present invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0066]

[0067] in,

[0068] X1 or X2 are independently selected from N or CH, and contain at least one N;

[0069] R1 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl or 4-12 membered heterocyclic group, wherein R1 may be optionally replaced by halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-7 cycloalkyl substitution;

[0070] R3 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl or 4-12 membered heterocyclic group, said R3 may be optionally replaced by halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-7 cycloalkyl substitution;

[0071] R5 is selected from 5-membered heteroaryl, 5-6-membered heterocyclyl or 9-12-membered heteroaryl; said R5 may be optionally replaced by 1, 2 or 3 R x replace;

[0072] R x Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-R a 、CN、-C(O)NH2、-S(O)2-R a or C 3-7 Cycloalkyl;

[0073] R a Selected from C 1-6 Alkyl, C 3-7 Cycloalkyl, -OH, -OMe or -NH2.

[0074] In another embodiment, the present invention is directed to a compound of formula (III), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0075]

[0076] in,

[0077] R1 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl or 4-12 membered heterocyclic group, wherein R1 may be optionally replaced by halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-7 cycloalkyl substitution;

[0078] R5 is selected from 5-membered heteroaryl, 5-6-membered heterocyclyl or 9-12-membered heteroaryl; said R5 may be optionally replaced by 1, 2 or 3 R x replace;

[0079] R x Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-R a 、CN、-C(O)NH2、-S(O)2-R a or C 3-7 Cycloalkyl;

[0080] R a Selected from C 1-6 Alkyl, C 3-7 Cycloalkyl, -OH, -OMe or -NH2.

[0081] n is selected from 0, 1, 2 or 3.

[0082] In another embodiment, the present invention is directed to a compound of formula (IV), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0083]

[0084] in,

[0085] R1 is selected from C 3-7 Cycloalkyl or 4-12 membered heterocyclic group, wherein R1 may be optionally replaced by halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-7 cycloalkyl substitution;

[0086] R x Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-R a 、CN、-C(O)NH2、-S(O)2-R a or C 3-7 Cycloalkyl;

[0087] R a Selected from C 1-6 Alkyl, C 3-7 Cycloalkyl, -OH, -OMe or -NH2.

[0088] In another embodiment, the present invention relates to a compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, selected from:

[0089]

[0090]

[0091] Example 1 Preparation of key intermediates

[0092] Notes on commonly used abbreviations:

[0093] Abbreviations: PE = petroleum ether; EA = ethyl acetate; MeOH = methanol; DCM = dichloromethane; DCE = dichloroethane; CH3CN = acetonitrile; 1,4-dioxane = 1,4-dioxane; DMSO = dimethyl sulfoxide; HFIP = hexafluoroisopropanol; DMF = N,N-dimethylformamide; THF = tetrahydrofuran; Hex = n-hexane; IPA = isopropanol; NMP = N-methylpyrrolidone; NMO = N-methylmorpholine-N-oxide; TEA = triethylamine; DIEA = diisopropylethylamine; CuI = cuprous iodide; CuCN = cuprous cyanide; triphosgene = triphosgene; p-TsOH = p-toluenesulfonic acid; T3P = 1-propylphosphoric acid cyclic anhydride; TsN3 = p-toluenesulfonyl azide; PPA = polyphosphoric acid; SEM-Cl = 2-(trimethylsilyl)ethoxymethyl chloride.

[0094] Synthesis of intermediate int 1

[0095]

[0096] Step 1: Int 1-1 (10 g, 0.055 mol) was added to a reaction flask. 100 mL of IPA and methylamine hydrochloride (22.3 g, 0.33 mol) were then added with stirring. The temperature was raised to 80°C and stirred for 4 hours. The reaction was complete after LC-MS analysis. The reaction was stopped, the solvent was concentrated to dryness, and 50 mL of ethanol was added to slurry at room temperature for 1 hour. The mixture was filtered and the filter cake was spin-dried and slurried with 40 mL of methyl tert-butyl ether for 1 hour. The mixture was filtered and rinsed with 10 mL of methyl tert-butyl ether. The solid was dried under reduced pressure to obtain the desired product, Int 1-2 (5.3 g, 0.03 mol), in a yield of 54.4%. LC-MS: ESI-MS (m / z): [M+H] + =177.

[0097] Step 2: Intermediate int 1-2 (5 g, 0.028 mol) and NIS (6.67 g, 0.029 mol) were added to a reaction flask, followed by 50 mL of CH3CN. Stirring was initiated, the atmosphere was replaced with nitrogen, and the temperature was raised to 80°C. Stirring was complete after LC-MS analysis. The reaction was stopped, cooled to room temperature, and slurried with 20 mL of water for 1 hour. The mixture was filtered, the filter cake was rinsed with 15 mL of water, and the solid was dried under reduced pressure to obtain intermediate int1-3 (6.3 g, 0.021 mol) in a yield of 74.3%. LC-MS: ESI-MS (m / z): [M+H] + =303.

[0098] Step 3: Dissolve chlorosulfonyl isocyanate (2.32 g, 0.016 mol) in 6 mL of 2-methyltetrahydrofuran (2-methyltetrahydrofuran) with stirring. Cool the mixture to -15°C, then add a solution of int 1-3 (6 g, 0.02 mol) in 2-methyltetrahydrofuran (30 mL) dropwise. Keep the temperature below -5°C during the addition. After completion, maintain the temperature at -10°C for 1 h. Then, add aqueous sodium hydroxide (2.0 M, 40 mL) while keeping the temperature below 18°C. After completion, cool the mixture to 0°C and continue stirring for 1 h. LC-MS analysis indicates that the reaction is complete. Stop the reaction, filter the mixture, rinse the solid with 40 mL of water, and dry under reduced pressure to obtain int 1-4 (3.5 g, 0.01 mol). Yield: 50%. LC-MS: ESI-MS (m / z): [M+H] + =346.

[0099] Step 4: Int 1-4 (3 g, 8.7 mmol), cuprous iodide (33 mg, 0.02 eq), and 1.10-phenanthroline (18 mg, 0.01 eq) were added to a reaction flask. Then, 30 mL of CH3CN and DIEA (2.2 g, 17.4 mmol) were added. Stirring was initiated, the atmosphere replaced with nitrogen, and the temperature was raised to 80°C. Stirring was continued for 18 h. LC-MS confirmed the reaction was complete. The reaction was stopped, cooled to room temperature, and filtered. The filter cake was slurried with CH3CN and 10% ammonium chloride at 40°C for 2 h, filtered, and dried under reduced pressure to obtain intermediate int 1-5 (1.5 g, 6.88 mmol) in a yield of 79%. LC-MS: ESI-MS (m / z): [M+H] + =219.

[0100] Step 5: Int 1-5 (1.5 g, 6.88 mmol) was added to the reaction flask, followed by 15 mL of phosphorus oxychloride and 3 mL of DIEA. Stirring was initiated, and the temperature was raised to 100°C and stirred for 1 h. LC-MS confirmed the reaction was complete. The reaction was stopped, concentrated, extracted with EA, and purified by column chromatography to afford the intermediate int 1-6 (1.0 g, 4.24 mmol) in a 57% yield. LC-MS: ESI-MS (m / z): [M+H] + =236.

[0101] Step 6: Intermediate int 1-6 (1.0 g, 4.24 mmol), (R)-octahydropyrrolo[1,2-a]pyrazine (0.641 g, 5.1 mmol), and potassium carbonate (1.2 g, 8.48 mmol) were added to a reaction flask. 10 mL of CH3CN was added and the mixture was microwaved at 85°C for 3 h. The reaction was complete as determined by LC-MS. The mixture was concentrated, extracted with EA, and purified by column chromatography to afford intermediate int 1-7 (1.0 g, 3.07 mmol) in a yield of 72.4%. LC-MS: ESI-MS (m / z): [M+H] + =326.

[0102] Step 7: Intermediate int 1-7 (0.5 g, 1.53 mmol), (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (10.0 eq, 2.0 g), and potassium carbonate (13.0 eq, 2.7 g) were added to a reaction flask. 5 mL of DMF was added and the mixture was microwaved at 140°C for 3.5 h. The reaction was complete as determined by LC-MS. The mixture was extracted with EA, concentrated, and the crude product was purified by silica gel column chromatography to afford int 1 (0.44 g, 1.13 mmol) in a yield of 73.9%. LC-MS: ESI-MS (m / z): [M+H] + =389.

[0103] Synthesis of intermediate int 2 / int 2a

[0104]

[0105] Step 1: Dissolve int 2-1 (12.4 g, 65.3 mmol) in N,N-dimethylacetamide (125 mL). Add hydrazine hydrate (19.6 g, 392 mmol) with stirring in an ice bath. After addition, heat to 75°C and react for 5 h. TLC confirms complete reaction of the starting material, and cool to room temperature. Pour the reaction solution into ice water and extract twice with EA (250 mL*2). Combine the organic phases, wash with water and brine, dry over anhydrous sodium sulfate, filter, and concentrate. The crude product is purified by silica gel column chromatography to obtain the intermediate int 2-2 (10.5 g). LC-MS: ESI-MS (m / z): [M+H] + =168.

[0106] Step 2: Add the intermediate int 2-2 (10.5 g, 62.8 mmol) and THF (105 mL) to a 250 mL reaction flask, and add TEA (19.1 g, 188.6 mmol) and di-tert-butyl dicarbonate (20.6 g, 94.2 mmol) in sequence with stirring. Stir at room temperature for 18 h. The reaction is complete as determined by LC-MS. Water (100 mL) and 200 mL of EA are added to the reaction system, and the liquids are separated. The organic phase is washed with water and brine, dried, filtered, and concentrated. The crude product is purified by silica gel column chromatography to obtain the product int 2 (16.5 g, 61.6 mmol). LC-MS: ESI-MS (m / z): [M+H] + =268.

[0107] Intermediate int 2-2 (9 g, 48.6 mmol) was dissolved in 80 mL of anhydrous DMF under nitrogen. Sodium hydride (60%) (2.4 g, 60 mmol) was added at 0°C and stirred for 15 minutes. PMBCl (9.4 g, 60 mmol) was then added dropwise to the reaction system. The reaction was stirred at room temperature for 2 hours. LC-MS confirmed complete consumption of the starting material. The reaction was quenched with water and extracted three times with EA. The combined organic phases were concentrated and the crude product was purified by column chromatography to yield 13 g of compound int 2a. LC-MS: ESI-MS (m / z): [M+H] + =288.

[0108] Synthesis of intermediate int 3

[0109]

[0110] Step 1: Dissolve compound int 3-1 (231.0 mg, 1.21 mmol) in 4 mL of anhydrous THF under nitrogen. Add 0.68 mL of n-butyl lithium (1.70 mmol, 2.5 M in THF) dropwise at -78°C. Stir for 1 hour. Add isopropoxyboronic acid pinacol ester (315.0 mg, 1.69 mmol). After addition, move to room temperature and react for 1 hour. LC-MS confirms complete reaction. Quench with saturated ammonium chloride, extract three times with EA, dry over anhydrous sodium sulfate, and concentrate to obtain 269.0 mg of crude int 3-2, which is used directly in the next step. LCMS: ESI-MS (m / z): [M+H] + =239.

[0111] Step 2: Dissolve compound int 3-2 (197.0 mg, 0.83 mmol), compound int 2-5 (243.7 mg, 0.91 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (107.9 mg, 0.17 mmol), and cesium carbonate (539.1 mg, 1.65 mmol) in a mixture of 2 mL of 1,4-dioxane and 0.4 mL of water. Heat to 115°C in a microwave reactor under nitrogen for 4 h. LC-MS confirmed complete consumption of the starting material. Dilute with water, extract three times with EA, dry over anhydrous sodium sulfate, and concentrate. The crude product was purified by silica gel column chromatography (PE / EA = 20-30%) to obtain 32.0 mg of compound int 3, in a yield of 15.8%. LCMS: ESI-MS (m / z): [M+H] + =244.

[0112] Synthesis of intermediate int 4

[0113]

[0114] Step 1: Dissolve compound int 4-1 (1 g, 6.6 mmol) in 10 mL of DMF under nitrogen. Add cesium carbonate (6.4 g, 19.8 mmol) at 0°C and stir for 15 minutes. Add dimethylpropylene oxide (1.4 g, 19.8 mmol) dropwise to the reaction system. Stir at room temperature overnight. LC-MS confirms complete consumption of the starting material. Quench with water, extract three times with EA, combine the organic phases, and concentrate. The crude product is purified by silica gel column chromatography to yield 1 g of compound int 4-2 in a 60.6% yield. LCMS: ESI-MS (m / z): [M+H] + =249.

[0115] Step 2: Dissolve compound int 4-2 (1 g, 4.0 mmol) in 20 mL of THF. Under nitrogen, add TEA (800 mg, 8.0 mmol). Cool to 0°C and slowly add tert-butyldimethylsilyl trifluoromethanesulfonate (2.1 g, 8.0 mmol) dropwise. Stir for 1 hour. LC-MS confirms complete consumption of the starting material. Dilute with water and extract three times with EA. The organic phases are combined and concentrated. The crude product is purified by silica gel column chromatography to obtain 850 mg of compound int 4-3 in a 58.5% yield. LCMS: ESI-MS (m / z): [M+H] + =363.

[0116] Step 3: Dissolve compound int 4-3 (850 mg, 2.3 mmol) in 20 mL of THF, cool to -78°C under nitrogen, and add 2 mL of n-butyllithium (2 M in THF) dropwise. Stir for 20 min. Add triisopropyl borate (564 mg, 3.0 mmol) in THF dropwise at low temperature. LC-MS confirms the reaction is complete. Quench with saturated ammonium chloride, extract three times with EA, combine the organic phases, wash once with saturated sodium chloride solution, concentrate, and purify the crude product by silica gel column chromatography to obtain 820 mg of compound int 4-4, in a yield of 87.0%. LCMS: ESI-MS (m / z): [M+H] + =411.

[0117] Step 4: Dissolve compound int 4-4 (820 mg, 2.0 mmol), compound int 2 (587 mg, 2.2 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (100 mg), and cesium carbonate (1.3 g, 4 mmol) in a mixture of 10 mL of 1,4-dioxane and 2 mL of water. Heat to 90°C in a microwave reactor under nitrogen for 2 h. LC-MS confirmed complete consumption of the starting material. Dilute with water and extract three times with EA. The organic phase was concentrated to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 400 mg of compound int 4 in a yield of 48.2%. LCMS: ESI-MS (m / z): [M+H] + =416.

[0118] Synthesis of intermediate int 5

[0119]

[0120] Step 1: Dissolve compound int 5-1 (8.00 g, 29.48 mmol) in 80 mL of anhydrous THF under nitrogen. Add 24.95 mL of isopropylmagnesium chloride lithium chloride complex (32.44 mmol, 1.3N in THF) dropwise at 0°C and stir at 0°C for 0.5 h. Dissolve cuprous bromide (4.65 g, 32.42 mmol) and lithium bromide (5.63 g, 64.82 mmol) in 80 mL of THF, mix thoroughly, and add dropwise to the reaction mixture. Stir for 5 minutes before adding ethyl oxalyl chloride (4.43 g, 32.45 mmol). Add dropwise until addition is complete and allow to stir at room temperature for 1 h. LC-MS confirms complete consumption of the starting material. Quench the mixture with saturated ammonium chloride and extract three times with EA. The combined organic phases are washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-15% PE / EA) to obtain 4.83 g of compound int 5-2, with a yield of 56.0%. LCMS: ESI-MS (m / z): [M+H] + =292,294.

[0121] Step 2: Dissolve methyltriphenylphosphonium bromide (6.49 g, 18.17 mmol) in 48 mL of anhydrous THF under nitrogen. Add potassium tert-butoxide (2.04 g, 18.18 mmol) at 0°C. After complete addition, stir at room temperature for 1 hour. Dissolve compound int 5-2 (4.83 g, 16.51 mmol) in 20 mL of anhydrous THF and add it to the reaction system. Stir at room temperature for 1 hour. LC-MS indicates complete consumption of the starting material. Quench with water, extract three times with EA, combine the organic phases, and concentrate. The crude product is purified by silica gel column chromatography (5% PE / EA) to obtain 4.01 g of compound int 5-3, in an 83.8% yield. LCMS: ESI-MS (m / z): [M+H] + =290,292.

[0122] Step 3: Dissolve trimethylsulfoxide iodide (3.35 g, 15.22 mmol) in anhydrous THF under nitrogen. Add potassium tert-butoxide (1.71 g, 15.24 mmol) at 0°C. After 0.5 h, compound int 5-3 (4.01 g, 13.83 mmol) in 20 mL of anhydrous THF was added to the reaction system. After complete addition, the mixture was allowed to react at room temperature for 1 h. LC-MS confirmed the reaction was complete. Quench with water, extract three times with EA, combine the organic phases, concentrate, and purify the crude product by silica gel column chromatography (5% EA / PE) to obtain 1.09 g of compound int 5-4 as a white solid in a yield of 25.9%. LCMS: ESI-MS (m / z): [M+H] + =304,306.

[0123] Step 4: Dissolve compound int 5-4 (1.09 g, 3.58 mmol) in 10 mL of anhydrous THF under nitrogen. Add 10.7 mL of diisobutylaluminum hydride (10.70 mmol, 1N in Toluene) dropwise at 0°C. After addition, warm the mixture to room temperature and stir for 15 hours. LC-MS confirmed complete reaction. Add 0.43 mL of water, 0.43 mL of 15% sodium hydroxide solution, and 1.07 mL of water sequentially. Stir for 0.5 hour, then add anhydrous magnesium sulfate and continue stirring for 1 hour. Filter and concentrate. The crude product is purified by silica gel column chromatography (20-40% EA / PE) to obtain 0.67 g of compound int 5-5 as a white solid in a yield of 71.3%. LCMS: ESI-MS (m / z): [M+H] + =262,264.

[0124] Step 5: Dissolve compound int 5-5 (400.0 mg, 1.52 mmol) in 40 mL of anhydrous 1,4-dioxane. Add potassium tert-butoxide (239.8 mg, 2.14 mmol) under nitrogen. After addition, heat to 100°C and react for 8 hours. LC-MS confirms complete consumption of the starting material. Cool to room temperature, filter, and concentrate. The crude product is purified by silica gel column chromatography (20-30% EA / PE) to obtain 290 mg of compound int 5-6, in an 84.6% yield. LCMS: ESI-MS (m / z): [M+H] + =226,228.

[0125] Step 6: Dissolve compound int 5-6 (197.0 mg, 0.87 mmol), tetrakistriphenylphosphine palladium (201.4 mg, 0.17 mmol), and hexamethyltin (428.4 mg, 1.31 mmol) in 6 mL of anhydrous 1,4-dioxane. Heat to 100°C under nitrogen for 13 hours. LC-MS confirmed complete reaction. Cool to room temperature, concentrate the reaction solution, and purify the crude product by silica gel column chromatography (5% MeOH / DCM) to obtain 250.3 mg of compound int 5-7, in a 92.7% yield. LCMS: ESI-MS (m / z): [M+H] + =310,312.

[0126] Step 7: Dissolve compound int 5-7 (31.0 mg, 0.10 mmol), compound int 2a (28.8 mg, 0.10 mmol), tetrakistriphenylphosphine palladium (11.6 mmol, 0.01 mmol), cuprous iodide (3.8 mg, 0.02 mmol), and cesium fluoride (38.1 mg, 0.20 mmol) in 2 mL of anhydrous 1,4-dioxane. Heat to 110°C under nitrogen for 14 h. LC-MS confirmed complete consumption of the starting material. Cool to room temperature, concentrate the reaction solution, and purify the crude product by preparative thin-layer chromatography (5% MeOH / DCM) to afford 25.0 mg of compound int 5-8, in a 62.8% yield. LCMS: ESI-MS (m / z): [M+H] + =399.

[0127] Step 8: Compound int 5-8 (59.0 mg, 0.15 mmol) was dissolved in a mixture of 2 mL of trifluoroacetic acid and 0.4 mL of trifluoromethanesulfonic acid. The mixture was stirred at room temperature for 13 h. LC-MS confirmed complete reaction. The reaction mixture was concentrated, and the residue was adjusted to pH 10 with saturated sodium carbonate solution. The mixture was extracted three times with EA. The organic phases were combined and concentrated. The crude product was purified by preparative thin-layer chromatography (5% MeOH / DCM) to afford 28.0 mg of compound int 5, in a yield of 68.0%. LCMS: ESI-MS (m / z): [M+H] + =279.

[0128] Synthesis of intermediate int 6

[0129]

[0130] Step 1: Thionyl chloride (30 mL) was added to compound int 6-1 (2.05 g, 8.87 mmol). The mixture was heated to 80°C and stirred for 2 h. The reaction was complete by TLC. The reaction mixture was cooled to room temperature and concentrated in vacuo to afford a crude product (1.53 g). The crude product was dissolved in CH3CN (19 mL), and TEA (2.28 g, 22.57 mmol) was added at 0°C. The mixture was stirred for 5 min. α,α-Dimethylbenzylamine (1.87 g, 7.54 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 1 h. The reaction was complete by LC-MS. The reaction mixture was concentrated and purified by silica gel column chromatography (PE:EA = 8:1) to afford int 6-2 (1.66 g, 63%) as a white solid. LC-MS: ESI-MS (m / z): [M+H] + =349.

[0131] Step 2: Dissolve compound int 6-2 (1.66 g, 4.77 mmol), pinacol diboronate (2.42 g, 9.54 mmol), and potassium acetate (935 mg, 9.54 mmol) in 1,4-dioxane (17 mL). Add Pd(dppf)Cl2 (346 mg, 0.48 mmol). Heat to 90°C and stir overnight under nitrogen. LC-MS analysis confirmed the reaction was complete. The reaction solution was cooled to room temperature, filtered through celite, extracted with water and EA, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography (MeOH / DCM = 10%) to afford int 6-3 (700 mg, 47% yield) as a white solid. LC-MS: ESI-MS (m / z): [M+H] + =315.

[0132] Step 3: Compound int 6-3 (300 mg, 0.95 mmol), int 2 (232 mg, 0.87 mmol), and cesium carbonate (849 mg, 2.61 mmol) were added to toluene (8 mL), followed by [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (63 mg, 0.09 mmol). Under nitrogen, the mixture was heated to 110°C and stirred overnight. LC-MS confirmed the reaction was complete. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was extracted with water and EA. The mixture was concentrated in vacuo, and the crude product was purified by silica gel column chromatography (PE:EA = 3:1) to afford int 6-4 (240 mg, 38%) as a white solid. LC-MS: ESI-MS (m / z): [M+H] + =502.

[0133] Step 4: Add HCl-dioxane (2M, 10 mL) to compound int 6-4 (240 mg, 0.48 mmol) and stir at room temperature for 2 h. LC-MS confirmed the reaction was complete. The reaction solution was concentrated in vacuo to obtain a white solid crude product, int 6 (160 mg), which was used directly in the next step. LC-MS: ESI-MS (m / z): [M+H] + =402.

[0134] Synthesis of intermediate int 7

[0135]

[0136] The first step: Compound int 7-1 (1.60 g, 4.86 mmol), int 7-2 (1.06 g, 4.86 mmol), tris(dibenzylideneacetone)dipalladium (445.5 mg, 0.49 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (563.0 mg, 0.97 mmol), N,N-diisopropylethylamine (1.26 g, 9.73 mmol) were dissolved in 16 mL of anhydrous dioxane and the temperature was raised to 80 ° C under nitrogen protection for reaction. After 3 h, LC-MS controlled the complete conversion of the raw material. The mixture was cooled to room temperature, filtered, and the filter cake was washed with EA, diluted with water, extracted three times with EA, and the organic phases were combined and concentrated. The crude product was purified by silica gel column chromatography (10-20% EA / PE) to obtain 1.88 g of compound int 7-3. Yield: 92.2%, LC-MS: ESI-MS (m / z): [M+H] + =419,421.

[0137] Step 2: Compound int 7-3 (1.78 g, 4.24 mmol) was dissolved in a mixture of 20 mL of THF and 2 mL of ethanol. Sodium ethoxide (346.0 mg, 5.09 mmol) was added and stirred at room temperature. After 0.5 h, LC-MS indicated complete hydrolysis of the starting material. 4 mL of formic acid and 8 mL of triethyl orthoformate were added to the reaction mixture. After addition, the mixture was heated to 80°C and reacted for 1 h. LC-MS indicated complete conversion of the intermediate. After cooling to room temperature, the reaction mixture was poured into a protective sodium bicarbonate solution and extracted twice with EA. The organic phases were combined and concentrated. The crude product was purified by silica gel column chromatography (3% MeOH / DCM) to obtain 0.91 g of compound int 7-4 in an 87.6% yield. LC-MS: ESI-MS (m / z): [M+H] + =245,247.

[0138] Step 3: Dissolve compound int 7-4 (200.0 mg, 0.82 mmol), tetrakistriphenylphosphine palladium (94.1 mg, 0.081 mmol), and hexamethyltin (401.0 mg, 1.26 mmol) in 6 mL of anhydrous 1,4-dioxane. Heat to 100°C under nitrogen for 20 h. LC-MS confirmed complete reaction. Cool to room temperature, concentrate the reaction solution, and purify the crude product by silica gel column chromatography (3% MeOH / DCM) to obtain 168.7 mg of compound int 7-5, in a yield of 62.5%. LC-MS: ESI-MS (m / z): [M+H] + =329,331.

[0139] Step 4: Dissolve compound int 7-5 (125.7 mg, 0.38 mmol), compound int 2 (102.3 mg, 0.38 mmol), tetrakistriphenylphosphine palladium (132.5 mmol, 0.11 mmol), and cuprous iodide (21.8 mg, 0.11 mmol) in 4 mL of anhydrous 1,4-dioxane. Heat to 115°C under nitrogen for 20 h. LC-MS confirmed complete consumption of the starting material. Cool to room temperature and concentrate the reaction solution to obtain 354.0 mg of crude int 7-6, which was used directly in the next step without purification. LC-MS: ESI-MS (m / z): [M+H] + =398.

[0140] Step 5: Compound int 7-6 (354.0 mg) was dissolved in a mixture of 1.5 mL of trifluoroacetic acid and 4 mL of DCM. The reaction was stirred at room temperature for 1 hour. LC-MS confirmed the complete reaction. The reaction solution was concentrated and diluted with water. The aqueous phase was extracted twice with EA. The pH of the aqueous phase was adjusted to 10 with saturated potassium carbonate and the aqueous phase was extracted three more times with EA. The organic phase was concentrated and the crude product was purified by silica gel column chromatography (5-10% MeOH / DCM) to obtain 14.0 mg of compound int 7, a two-step yield of 12.4%. LC-MS: ESI-MS (m / z): [M+H] + =298.

[0141] Synthesis of intermediate int 8

[0142]

[0143] Step 1: Dissolve compound int 2 (500.0 mg, 1.87 mmol), compound int 8-1 (410 mg, 2.24 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (120.8 mg, 0.18 mmol), and cesium carbonate (1.52 g, 4.67 mmol) in a mixture of 10 mL of 1,4-dioxane and 2 mL of water. Heat to 100°C under nitrogen for 2 h. LC-MS confirmed complete consumption of the starting material. Cool to room temperature, dilute with water, and extract three times with EA. The crude product was purified by silica gel column chromatography (5% MeOH / DCM) to afford compound int 8-2 (510 mg, 1.37 mmol) in a yield of 73.7%. LC-MS: ESI-MS (m / z): [M+H] + =371.

[0144] Step 2: Dissolve compound int 8-2 (500 mg, 1.35 mmol) in 20 mL of DCM. Add 2 mL of trifluoroacetic acid to the reaction system and react at room temperature for 5 h. LC-MS monitors the complete consumption of the starting material. Add saturated sodium bicarbonate aqueous solution to the reaction system, adjust the pH to 8, and dilute with water. Extract three times with EA, dry over anhydrous sodium sulfate, and concentrate. The crude product is purified by silica gel column chromatography (10-20% EA / PE) to obtain compound int 8 (335 mg, 1.24 mmol) in a yield of 91.8%. LC-MS: ESI-MS (m / z): [M+H] + =271.

[0145] Synthesis of intermediate int 9

[0146]

[0147] Step 1: Dissolve 1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]boronic acid (10.8 g, 47.6 mmol), compound int 2a (10.0 g, 36.6 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (500 mg), and cesium carbonate (23.8 g, 73.2 mmol) in a mixture of 100 mL of 1,4-dioxane and 20 mL of water. Heat to 90°C under nitrogen for 12 h. LC-MS confirmed complete consumption of the starting material. Dilute with water, extract three times with EA, and concentrate the organic phase under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 10.4 g of compound int 9-1 in a yield of 65.3%. LC-MS: ESI-MS (m / z): [M+H] + =435.

[0148] Step 2: Dissolve compound int 9-1 (5.0 g, 11.5 mmol) in 20 mL of 1,4-dioxane. Under nitrogen, add 15 mL of dioxane hydrochloride solution (60.0 mmol, 4N in THF) dropwise. Stir for 1 hour after addition. LC-MS confirms complete reaction. Quench with saturated sodium carbonate and extract three times with EA. The combined organic phases are washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 5 g of crude int 9-2. LC-MS: ESI-MS (m / z): [M+H] + =335.

[0149] Step 3: Dissolve crude int 9-2 (5 g, 11.5 mmol) in 40 mL of DCM. Under nitrogen, add TEA (2.02 g, 20 mmol). Cool to 0°C and slowly add methylsulfonyl chloride (1.72 g, 15 mmol) dropwise. Stir for 1 hour. LC-MS confirms complete consumption of the starting material. Dilute with water and extract three times with EA. The organic phase is concentrated under reduced pressure. The crude product is purified by silica gel column chromatography to obtain 2.9 g of compound int 9-3. LC-MS: ESI-MS (m / z): [M+H] + =413.

[0150] Step 4: Dissolve compound int 9-3 (2.9 g, 7.0 mmol) in 20 mL of trifluoroacetic acid and heat to 90°C under nitrogen for 2 hours. LC-MS confirmed complete reaction. Cool to room temperature, concentrate the reaction mixture, quench with saturated sodium carbonate, and extract three times with EA. The combined organic phases were washed once with saturated sodium chloride and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 1.6 g of compound int 9, in a yield of 78.0%. LC-MS: ESI-MS (m / z): [M+H] + =293.

[0151] Synthesis of intermediate int 10

[0152]

[0153] Step 1: Dissolve compound int 9-1 (5 g, 11.5 mmol) in 50 mL of MeOH, add 500 mg of Pd / C (10%), and heat to 45°C under a hydrogen balloon for 8 h. LC-MS confirmed complete consumption of the starting material. Filter and concentrate to obtain 5 g of compound int 10-1 in a 65.3% yield. LC-MS: ESI-MS (m / z): [M+H] + =437.

[0154] Step 2: Dissolve compound int 10-1 (5.0 g, 11.5 mmol) in 20 mL of 1,4-dioxane under nitrogen. Add 15 mL of dioxane hydrochloride solution (60.0 mmol, 4N in THF) dropwise and stir for 1 hour. LC-MS confirms the reaction is complete. Quench with saturated sodium carbonate and extract three times with EA. The combined organic phases are washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 5 g of crude int 10-2. LC-MS: ESI-MS (m / z): [M+H] + =337.

[0155] Step 3: Dissolve the crude product of compound int 10-2 (5 g, 11.5 mmol) in 40 mL of DCM. Under nitrogen, add TEA (2.02 g, 20 mmol). Cool to 0°C and slowly add methylsulfonyl chloride (1.72 g, 15 mmol) dropwise. Stir for 1 hour. LC-MS confirms complete consumption of the starting material. Dilute with water and extract three times with EA. The organic phase is concentrated under reduced pressure. The crude product is purified by silica gel column chromatography to obtain 2.9 g of compound int 10-3. LC-MS: ESI-MS (m / z): [M+H] + =415.

[0156] Step 4: Dissolve compound int 10-3 (2.9 g, 7.0 mmol) in 20 mL of trifluoroacetic acid and heat to 90°C under nitrogen for 2 hours. LC-MS confirmed complete reaction. Cool to room temperature, concentrate the reaction mixture, quench with saturated sodium carbonate, and extract three times with EA. The combined organic phases were washed once with saturated sodium chloride and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 1.6 g of compound int 10, in a yield of 78.0%. LC-MS: ESI-MS (m / z): [M+H] + =295.

[0157] Synthesis of intermediate int 11

[0158]

[0159] Step 1: To the intermediate int 11-1 (7.1 g, 22.7 mmol) was added ethanol (100 mL), followed by selenium dioxide (5.1 g, 34.0 mmol) and water (3 drops). The temperature was raised to 70°C and stirred for 1 hour. TLC indicated the reaction was complete. The reaction solution was cooled to room temperature and filtered. The filter cake was rinsed with DCM and concentrated to afford the crude product. This was stirred in a mixed solvent (PE:EA = 5:1) for 1 hour and filtered to afford the pale yellow solid product int 11-2 (1.5 g, 3.8 mmol) in a yield of 16.7%. LC-MS: ESI-MS (m / z): [M+H] + =391,393.

[0160] Step 2: The raw intermediate int 11-2 (1.5 g, 3.8 mmol) and dimethyl sulfate (1.2 mL, 38 mmol) were heated to 130°C and stirred for 1 hour. LC-MS confirmed the complete reaction. The reaction solution was cooled to room temperature and ether was added. A yellow solid was precipitated by stirring. After filtration and drying, the product intermediate int 11-3 (1.5 g, 3.7 mmol) was obtained in a yield of 97.7%. LC-MS: ESI-MS (m / z): [M+H] + =405,407.

[0161] Step 3: Add intermediate int 11-3 (1.3 g, 3.22 mmol) to a 100 mL single-necked flask, add sodium hydroxide solution, and stir at room temperature for 2 h. After the reaction is complete, extract with DCM, dry the organic phase over anhydrous sodium sulfate, and concentrate. The crude product is purified by silica gel column chromatography (40% EA / PE) to obtain intermediate int 11-4 (700 mg, 2.15 mmol) in a yield of 66.7%. LC-MS: ESI-MS (m / z): [M+H] + =327,329.

[0162] Step 4: Add intermediate int 11-4 (700 mg, 2.15 mmol) to a 100 mL single-necked flask, add 10 mL of DCE solvent, and then add triphosgene (960 mg, 3.22 mmol). Stir at room temperature overnight. LC-MS showed the reaction was complete. The reaction solution was quenched with water and extracted with DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 50%) to obtain intermediate int 11-5 (400 mg, 1.14 mmol) in a yield of 52.9%. LC-MS: ESI-MS (m / z): [M+H] + =353,355.

[0163] Step 5: Dissolve compound int 11-5 (80.0 mg, 0.23 mmol) in 3 mL of phosphorus oxychloride and heat to 100°C for 2 h. LC-MS confirmed complete consumption of the starting material. Cool to room temperature, concentrate the reaction solution, and purify the crude product by silica gel column chromatography (10-15% EA / PE) to obtain 73.0 mg of compound int 11-6 in an 86.7% yield. LC-MS: ESI-MS (m / z): [M+H] + =371,373.

[0164] Step 6: Dissolve compound int 11-6 (73.0 mg, 0.20 mmol) and (R)-octahydropyrrolo[1,2-a]pyrazine (99.2 mg, 0.79 mmol) in 2 mL of CH3CN and heat to 100°C in a microwave reactor for 2 h. LC-MS confirmed complete conversion of the starting material. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (4% MeOH / DCM) to obtain 71.0 mg of compound int 11-7 in a yield of 78.3%. LC-MS: ESI-MS (m / z): [M+H] + =461,463.

[0165] Step 7: Dissolve compound int 11-7 (77.0 mg, 0.17 mmol), (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (24.9 mg, 0.18 mmol), methanesulfonic acid [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2'-amino-1,1'-biphenyl]palladium(II) DCM adduct (31.6 mg, 0.033 mmol), and sodium tert-butoxide (48.1 mg, 0.50 mmol) in 3 mL of anhydrous 1,4-dioxane. Heat to 90°C under nitrogen for 7 h. LC-MS confirmed complete consumption of the starting material. Cool to room temperature, dilute with water, and extract three times with DCM. The combined organic phases were concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (3% MeOH / DCM) to obtain 63.0 mg of the desired product, int 11, in an 87.3% yield. LC-MS:ESI-MS(m / z):[M+H] + =432,434.

[0166] Synthesis of intermediate int 12

[0167]

[0168] Step 1: Dissolve compound int 12-1 (1.97 g, 7.21 mmol) in 40 mL of anhydrous THF under nitrogen. Slowly add a 1 mol / L solution of methylmagnesium bromide in THF (10.8 mL, 10.80 mmol) dropwise at -70°C. After addition, warm to room temperature and react. After 2 hours, LC-MS confirms complete reaction. Add saturated ammonium chloride to quench the reaction, extract three times with EA, and combine the organic phases, concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (10-15% EA / PE) to afford 1.30 g of compound int 12-2, in a yield of 71.4%. LC-MS: ESI-MS (m / z): [M+H] + =253.

[0169] Step 2: Dissolve compound int 12-2 (500.0 mg, 1.98 mmol), (4-methoxypyridin-3-yl)boronic acid (363.1 mg, 2.37 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (127.8 mg, 0.20 mmol), and cesium carbonate (1.61 g, 4.95 mmol) in a mixture of 10 mL of 1,4-dioxane and 2 mL of water. Heat to 100°C under nitrogen for 2 h. LC-MS confirmed complete consumption of the starting material. Cool to room temperature, dilute with water, and extract three times with EA. The combined organic phases were concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (3% MeOH / DCM) to obtain 442.0 mg of compound int 12-3, in a yield of 68.6%. LC-MS: ESI-MS (m / z): [M+H] + =326.

[0170] Step 3: Dissolve compound int 12-3 (442.0 mg, 1.36 mmol) in 4 mL of isopropanol and add 4 mL of a 4 mol / L solution of hydrogen chloride in dioxane. Stir the mixture at room temperature for 3 hours. LC-MS confirms complete reaction. The reaction mixture is concentrated, and the residue is neutralized with saturated sodium carbonate. The mixture is extracted three times with EA. The organic phase is concentrated under reduced pressure, and the crude product is purified by silica gel column chromatography (4% MeOH / DCM) to yield 200.0 mg of compound int 12, in a yield of 61.0%. LC-MS: ESI-MS (m / z): [M+H] + =242.

[0171] Synthesis of intermediate int 13

[0172]

[0173] Compound int 13-1 (779.3 mg, 2.80 mmol), compound int 2 (500.0 mg, 1.87 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (120.6 mg, 0.19 mmol), and cesium carbonate (1.52 g, 4.67 mmol) were dissolved in a mixture of 10 mL of 1,4-dioxane and 2 mL of water. The mixture was heated to 100°C under nitrogen for 16 hours. LC-MS confirmed complete consumption of the starting material. The mixture was diluted with water and extracted three times with EA. The combined organic phases were concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (2-4% MeOH / DCM) to obtain 144.0 mg of compound int 13 in a yield of 27.2%. LC-MS: ESI-MS (m / z): [M+H] + =284.

[0174] Synthesis of intermediate int 14

[0175]

[0176] Step 1: Compound int 14-1 (630 mg, 3.86 mmol), int 2 (1.55 g, 5.79 mmol), potassium carbonate (1.06 g, 7.72 mmol), and Pd(dppf)Cl2 (280 mg, 0.386 mmol) were added to a mixture of 1,4-dioxane and water (10 mL:2 mL). The atmosphere was replaced with nitrogen three times and the mixture was refluxed at 90°C for 4 h. TLC (PE:EA = 1:1) confirmed the complete reaction. The mixture was cooled, quenched with water, extracted with EA, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) to obtain int 14-2 (160 mg, 11.84% yield) as a brown solid. LC-MS: ESI-MS (m / z): [M+H] + =351.

[0177] Step 2: The raw material int 14-2 (160 mg, 0.457 mmol) was dissolved in DCM (5 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 3 h. LC-MS showed that the reaction was complete. The reaction solution was added with sodium bicarbonate aqueous solution to adjust the pH to 8, extracted with DCM, and the organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by preparative thin-layer chromatography (MeOH:DCM=1:20) to obtain the pale yellow solid product int 14 (70 mg, 61.2%). LC-MS: ESI-MS (m / z): [M+H] + =251.

[0178] Synthesis of intermediate int 15

[0179]

[0180] Step 1: To the intermediate int 15-1 (500 mg, 1.94 mmol) was added 1,4-dioxane 5 mL and water 1 mL, followed by the addition of the intermediate int 2 (777 mg, 2.91 mmol), potassium carbonate (803 mg, 5.82 mmol) and Pd(dppf)Cl2 (285 mg, 0.388 mmol), and stirred at 90 ° C for 2 h. LC-MS showed that the reaction was complete. After the reaction solution was cooled to room temperature, the reaction solution was added to water and extracted with DCM. The organic phase was dried and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 50%) to obtain the intermediate int 15-2 (150 mg, 0.413 mmol) with a yield of 21.4%. LC-MS: ESI-MS (m / z): [M+H] + =364.

[0181] Step 2: Add 5 mL of 4N hydrogen chloride solution in dioxane to the intermediate int 15-2 (150 mg, 0.413 mmol) and stir at room temperature for 1 h. LC-MS showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure to remove the solvent to obtain the crude intermediate int 15 (100 mg, 0.381 mmol) in a yield of 92.6%. LC-MS: ESI-MS (m / z): [M+H] + =264.

[0182] Synthesis of intermediate int 16

[0183]

[0184] Step 1: Under nitrogen, intermediate int 16-1 (1.10 g, 4.45 mmol) was dissolved in 10 mL of DMSO. Potassium acetate (1.30 g, 13.35 mmol), pinacol diboron (1.25 g, 4.90 mmol), and 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (0.32 g, 0.45 mmol) were added. The reaction system was heated to 80°C for 3 hours. Completion was monitored by LC-MS. After cooling to room temperature, the reaction system was diluted with water and extracted three times with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain intermediate int 16-2 (800 mg) in a 60% yield. LC-MS: ESI-MS (m / z): [M+H] + =295.

[0185] Step 2: Under nitrogen, intermediate int 16-2 (200 mg, 0.68 mmol) was dissolved in a mixture of 5 mL of 1,4-dioxane and 1 mL of water. Intermediate int 2 (182 mg, 0.68 mmol), 1,1'-bis(diphenylphosphinoferrocenepalladium) dichloride (51 mg, 0.07 mmol), and potassium carbonate (282 mg, 2.04 mmol) were added. The reaction mixture was heated to 100°C in a microwave reactor for 1 h. LC-MS monitored the complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to afford intermediate int 16-3 (100 mg) in a 40% yield. LC-MS: ESI-MS (m / z): [M+H] + =400.

[0186] Step 3: Dissolve the intermediate int 16-3 (100 mg, 0.25 mmol) in 4 mL of DCM and add trifluoroacetic acid (42 mg, 0.5 mmol). After addition, react at room temperature for 2 h. LC-MS monitors the complete consumption of the starting material. Quench with saturated aqueous NaHCO₃ solution and extract three times with DCM. The organic phase is concentrated to yield 70 mg of crude int 16, which is used directly in the next step. LC-MS: ESI-MS (m / z): [M+H] + =300.

[0187] Example 2 Preparation of target molecule P1

[0188]

[0189] Compound int 3 (30.0 mg, 0.12 mmol), compound int 1 (48.0 mg, 0.12 mmol), trisdibenzylideneacetone dipalladium (22.6 mg, 0.024 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (21.0 mg, 0.048 mmol), and sodium tert-butoxide (23.7 mg, 0.24 mmol) were dissolved in 1.5 mL of anhydrous 1,4-dioxane and heated to 125°C in a microwave reactor under nitrogen for 1 hour. LC-MS confirmed complete consumption of the starting material. The mixture was cooled to room temperature, diluted with water, and extracted three times with DCM. The combined organic phases were concentrated, and the crude product was purified by preparative thin-layer chromatography (5% MeOH / DCM) to obtain 15.0 mg of the desired product P1 as a yellow solid in a yield of 21.0%. LC-MS: ESI-MS (m / z): [M+H] + =596.

[0190] 1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.58(s,1H),7.82(s,1H),7.29(s,1H),4.78(s,1H),3.95(s,3H),3.9 0(d,J=8.0Hz,1H),3.89(s,2H),3.79(d,J=8.0Hz,1H),3.75(s,3H),3.65(s,3H),3.64(d,J=12.0Hz,1H),3. 53(d,J=12.0Hz,1H),3.12-2.99(m,3H),2.82(s,3H),2.79-2.68(m,1H),2.45-2.34(m,1H),2.27-2.12(m, 2H),2.07(d,J=8.0Hz,1H),1.98(d,J=9.2Hz,1H),1.90-1.81(m,1H),1.79-1.66(m,3H),1.47-1.33(m,1H).

[0191] Referring to the synthetic route of compound P1, similar intermediate structures and methods were used to synthesize the following target molecules or key intermediates:

[0192]

[0193]

[0194]

[0195] Preparation of target molecule P2

[0196]

[0197] Compound int 20 (260 mg, 0.34 mmol) was dissolved in 5 mL of THF under nitrogen. Tetrabutylammonium fluoride (177 mg, 0.68 mmol) was added and stirred for 2 h. LC-MS confirmed the reaction was complete. Saturated sodium carbonate was added to quench the reaction, and the mixture was extracted three times with EA. The combined organic phases were washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 500 mg of crude product. The crude product was purified on a silica gel column to yield 50 mg of the target compound P2 in a 22.5% yield. LC-MS: ESI-MS (m / z): [M+H] + =654.

[0198] 1H NMR(400MHz,DMSO-d6)δ8.59(s,1H),8.50(s,1H),8.12(s,1H),7.22(s,1H),5.93(s,1H),4.78(s,2H),3.97(s ,3H),3.90(d,J=8.0Hz,1H),3.89(s,2H),3.79(d,J=8.0Hz,1H),3.62(s,3H),3.64(d,J=12.0Hz,1H),3.53(d,J =12.0Hz,1H),3.12-2.99(m,3H),2.79-2.75(m,1H),2.74(s,3H),,2.45-2.34(m,1H),2.27-2.12(m,2H),2.07 (d,J=8.0Hz,1H),1.98(d,J=9.2Hz,1H),1.90-1.81(m,1H),1.79-1.66(m,3H),1.47-1.33(m,2H),1.12(s,6H).

[0199] Preparation of target molecules P4 / P5

[0200]

[0201] Preparation of P5: Int 17 (80 mg, 0.11 mmol) was dissolved in DCM (10 mL). Trifluoroacetic acid (5 mL) was added, and the reaction mixture was heated to 80°C and stirred for 2 h. TLC (PE:EA = 1:1) confirmed the reaction was complete. The reaction system was cooled to room temperature, concentrated under reduced pressure, neutralized with saturated aqueous sodium bicarbonate, extracted with DCM, and the organic phase concentrated to yield the crude product. The crude product was purified by preparative thin-layer chromatography (PE:EA = 1:1) to yield 40 mg of P5 as a yellow solid. LC-MS: ESI-MS (m / z): [M+H] + =636.

[0202] 1 H NMR(400MHz,DMSO-d6)δ8.93(s,1H),8.88(s,1H),8.65(s,1H),8.18(s,1H),7.84(s,1H),7.73(s,1H),7.30(s,1H),4.03(s,3H),3.82- 3.75(m,6H),3.65(s,3H),3.60-3.50(m,2H),3.30-3.20(m,6H),2.85(s,3H),2.03-1.94(m,4H),1.90-1.75(s,2H),1.75-1.45(m,1H).

[0203] Preparation of P4: Compound P5 (30 mg, 0.06 mmol) was dissolved in DCM (10 mL), and Burgess reagent (30 mg) was added. The mixture was stirred at room temperature for 2 h. The reaction was completed by TLC. The mixture was quenched with water and extracted with DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was separated and purified by silica gel column chromatography (PE:EA = 5:1) to obtain the product P4 (10 mg) as a light yellow solid. LC-MS:ESI-MS (m / z): [M+H] + =618.

[0204] 1 H NMR (400MHz, CDCl3) δ8.87(s,2H),8.36(s,1H),7.37(s,1H),7.23(s,1H),4.08(d,J=8.0Hz,2H),4.02(s,3H),3.97(s,1H),3.92-3. 90(m,4H),3.8-3.73(s,5H),3.66(s,1H),3.65(s,3H),3.40-3.30(m,2H),3.05(s,3H),2.39(s,2H),2.24-2.22(m,2H),2.04(s,2H).

[0205] Preparation of target molecules P7 / P8

[0206]

[0207] Preparation of P8: Compound int 18 (400 mg, 0.64 mmol) was dissolved in 10 mL of DCM. Pyridine hydrobromide (2.10 g, 1.28 mmol) was added to the reaction system. After complete addition, the system was heated to 100°C and reacted for 3 h. LC-MS confirmed complete consumption of the starting material. The reaction system was diluted with water and extracted three times with DCM. The combined organic phases were concentrated, and the crude product was purified by silica gel column chromatography (2-5% MeOH / DCM) to obtain the desired product P8 (314 mg) in a yield of 79.6%. LC-MS: ESI-MS (m / z): [M+H] + =609.

[0208] 1H NMR (400MHz, CDCl3) δ8.83(s,1H),8.23(s,1H),7.19(s,1H),7.09(s,1H),7.07(s,1H),5.84(s,1H ),5.30(s,1H),4.72(s,1H),4.13-3.78(m,5H),3.70(s,3H),3.62(s,3H),3.60-3.17(m,6H),3.03 -2.71(m,4H),2.39-1.88(m,5H),1.57-1.28(m,2H).

[0209] Preparation of P7: Compound P8 (100 mg, 0.16 mmol) was dissolved in THF (10 mL). Sodium tert-butoxide (17 mg, 0.16 mmol) was added to the reaction system. 2 mL of a THF solution of iodomethane (23 mg, 0.16 mmol) was added dropwise while cooling in an ice bath. The mixture was reacted at 20°C for 1 h. LC-MS confirmed complete consumption of the starting material. The reaction system was diluted with water and extracted three times with DCM. The combined organic phases were concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (5% MeOH / DCM) to afford 20 mg of the product, P7, as a pale yellow solid, in a 20.0% yield. LC-MS: ESI-MS (m / z): [M+H] + =623.

[0210] 1 H NMR (400MHz, DMSO-d6) δ8.85(s,1H),8.68(s,1H),7.54(s,1H),7.33(s,1H),6.78(s,1H),4.73(s,1H),4.02-3.90(m,2H),3. 86-3.74(m,8H),3.73-3.65(m,8H),3.55-3.46(m,6H),2.84(s,3H),2.14-1.90(m,3H),1.74-1.59(m,1H),1.57-1.39(m,1H).

[0211] Preparation of target molecule P12

[0212]

[0213] Step 1: Dissolve compound int 19 (26.0 mg, 0.041 mmol) in a mixture of 1.5 mL of 4N hydrogen chloride in dioxane and 1.5 mL of IPA. Stir the reaction at room temperature for 2 h. LC-MS confirmed complete reaction. The reaction solution was concentrated under reduced pressure, and the residue was neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted three times with EA, and the organic phase was concentrated under reduced pressure to yield 22.8 mg of a brown solid, P12-1. The crude product was used directly in the next step without purification. LC-MS: ESI-MS (m / z): [M+H] + =552.

[0214] Step 2: Compound P12-1 (22.8 mg, 0.041 mmol) was dissolved in 3 mL of anhydrous THF under nitrogen. Sodium hydride (3.3 mg, 0.082 mmol) was added at 0°C and stirred for 5 minutes. Cyclopropylsulfonyl chloride (10.5 mg, 0.074 mmol) was then added. After complete addition, the mixture was warmed to room temperature and reacted for 1 hour. LC-MS confirmed the reaction was complete. Water was added to quench the reaction, and the mixture was extracted three times with EA. The combined organic phases were concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography to obtain 3.0 mg of the desired product P12 as a white solid in an 11.2% yield. LC-MS: ESI-MS (m / z): [M+H] + =656.

[0215] 1 H NMR(400MHz,DMSO-d6)δ8.74(s,1H),8.63(s,1H),8.60(s,1H),8.41(s,1H),8.31(s,1H),5.88(s,1H),4.75( s,1H),3.98(d,J=9.6Hz,1H),3.92-3.78(m,4H),3.63(s,3H),3.62(d,J=11.2Hz,1H),3.51(d,J=12.0Hz,1H) ,3.11-2.96(m,3H),2.86-2.77(m,3H),2.77-2.66(m,1H),2.44-2.31(m,1H),2.25-2.10(m,2H),2.06(d,J=9 .2Hz,1H),1.97(d,J=9.6Hz,1H),1.87-1.78(m,1H),1.77-1.64(m,2H),1.42-1.31(m,3H),1.30-1.19(m,2H).

[0216] Example 3

[0217] Promega CellTiter-Glo reagent was used to detect the effects of small molecule inhibitors on the proliferation of three Ba / F3 cell lines (Ba / F3-EGFR-del19, Ba / F3-FL-EGFR, Ba / F3-EGFR-del19-T790M-C797S).

[0218] (Ba / F3-EGFR-del19, Ba / F3-EGFR-del19-T790M-C797S) culture medium: 1640 medium, 10% FBS, Glutamax and penicillin-streptomycin.

[0219] (Ba / F3-FL-EGFR) culture medium: 1640 medium, 10% FBS, Glutamax, 100 ng / mL EGF and penicillin-streptomycin.

[0220] The cell lines were cultured in an incubator at 37°C and 5% CO2. Cells were passaged regularly and cells in the logarithmic growth phase were used for plating. 95 μL of cell suspension was added to each well of the cell plate, and culture medium without cells (containing 0.1% DMSO) was added to the Min control wells. Compound detection cell plate dosing: 5 μL of 20× compound working solution was added to the cell culture plate. 5 μL of DMSO-cell culture medium mixture was added to the Max control, and the final DMSO concentration was 0.1%. 5 μL of DMSO-cell culture medium mixture was added to the Max control. The final DMSO concentration was 0.1%.

[0221] The culture plates were incubated in a 37°C, 5% CO2 incubator for 72 hours. Cell viability was determined using the CellTiter-Glo luminescence assay. Data analysis:

[0222] The cell proliferation inhibition rate (Inhibition Rate) data were processed using the following formula:

[0223] Inhibition Rate(Inh%)=100-(RLU Drug -RLU Min ) / (RLU Max -RLU Min )*100%.

[0224] Of which: RLU Drug Indicates the relative luminescence unit of cells with added drugs, RLU Min Indicates the luminescence unit of the culture medium, RLU Max The relative luminescence units of cells added with DMSO are shown.

[0225] The inhibition rates corresponding to different concentrations of compounds were calculated in EXCEL, and then the inhibition rate curve was plotted using GraphPad Prism software and related parameters were calculated, including the maximum and minimum inhibition rates of cells, IC 50 value.

[0226] Table 1: Antiproliferative effects of representative compounds on BaF3 cells transfected with wild-type EGFR (wt), mutant EGFR (del19) and mutant EGFR (del19 / T790M / C797S)

[0227]

[0228] The above results show that some molecules of the present invention have a good anti-proliferative effect on osimertinib-resistant cell lines (containing the C797S mutation), demonstrating the effectiveness of the present invention in resolving osimertinib-resistant tumors. They also have a good inhibitory effect on primary cell lines with EGFR mutants (EGFR del19), and have weaker inhibition on wild-type cells, demonstrating the high selectivity of the molecules of the present invention.

Claims

1. A compound, or a pharmaceutically acceptable salt or tautomer thereof, wherein the compound is selected from: 。 2. A pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt or tautomer thereof.

3. Use of the compound according to claim 1, or a pharmaceutically acceptable salt or tautomer thereof, in the preparation of a medicament for treating and / or preventing EGFR kinase-mediated diseases.

4. The use according to claim 3, wherein the EGFR kinase-mediated disease is cancer, and the cancer is selected from lung cancer.

5. The use according to claim 4, wherein the lung cancer is selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma.

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