PDE4B inhibitor and its uses

Abstract

The compound shown in formula I, its stereoisomers or pharmaceutically acceptable salts, or a pharmaceutical composition containing them, and their use in the manufacture of a therapeutic agent for treating related diseases as a PDE4B inhibitor, wherein each group shown in formula (I) is as defined in the specification. [Chemical formula 1] TIFF2025518257000169.tif37156

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceuticals, and particularly relates to a low-molecular compound having PDE4B selective inhibitory activity, its stereoisomer or pharmaceutically acceptable salt, and its use in the manufacture of pharmaceuticals for treating related diseases.

Background Art

[0002] PDE4 inhibitors produce an antidepressant effect in humans and animals by enhancing the cAMP signal in the brain. PDE4 inhibitors also play an important role in the treatment of other central nervous system diseases including Alzheimer's disease, Parkinson's disease, schizophrenia, stroke, and Huntington's disease.

[0003] In addition, the research and development of PDE4 inhibitors have also made great progress. In the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease, the research and development principle of such pharmaceuticals is derived from the action of PDE4 in inhibiting the functions of a series of inflammatory cells and resident cells, and is considered to be related to the pathogenesis of these diseases. A number of clinical studies have shown that cyclic adenosine monophosphate (cAMP) can block the proliferation and chemotaxis of inflammatory cells, inhibit the release of inflammation and cytotoxic mediators in the lung, and the content of PDE4 in immune cells, inflammatory cells and smooth muscle cells is particularly rich.

[0004] PDE4 inhibitors mainly inhibit the hydrolysis of PDE4, increase the cAMP level in the body, inhibit the release of inflammatory factors, promote the generation of anti-inflammatory mediators, and exert anti-inflammatory effects. Roflumilast is clinically used for the treatment of COPD, has significant anti-inflammatory effects, and can inhibit the release of inflammatory mediators such as TNF-α, interleukin, and chemokine from monocytes, macrophages, and T cells. However, such inhibitors generally have serious side effects such as nausea and vomiting, which limit the clinical application of PDE4 inhibitors. A number of studies have shown that in the human body, the subtype B of phosphodiesterase 4 (PDE4B) is related to the inflammatory response and is involved in the release of various inflammatory mediators in the body, while the subtype D is closely related to the occurrence of side effects such as nausea and vomiting. This provides a new idea for finding PDE4 inhibitors with low side effects, that is, designing PDE4B inhibitors may reduce the impact of side effects and promote further clinical application.

[0005] Phosphodiesterase 4 has a high selectivity for cAMP and has four subtypes: PDE4A, 4B, 4C, and 4D, with at least 25 splice variants. The protein sequences of the catalytic domains of the four subtypes of PDE4 have a high degree of homology, and inhibitors acting on the catalytic domain do not produce subtype selectivity. However, most of the reported classical PDE4 inhibitors act on the catalytic domain. The mode of action of the newly reported PDE4 inhibitors in recent years is that the inhibitor acts on the catalytic domain and the regulatory sequence at the same time, and the regulatory sequence can stabilize the closed three-dimensional structure of the protein and prevent the entry of cAMP. However, studies have shown that there are amino acid differences between PDE4B and 4D on this regulatory sequence, and it has been found that subtype selectivity can be generated by designing inhibitors based on this difference. Therefore, based on the difference in the two amino acids of PDE4B Leu674 / PDE4D Gln594 on the downstream regulatory sequence CR3 (Conserved Region 3), it is expected to achieve selectivity for subtype B, maintain activity, and reduce the side effects of the inhibitor at the same time.

[0006] A PDE4B inhibitor with good activity, high safety, low side effects and more excellent pharmacokinetics selectivity has been discovered, which has a promising future for good clinical development and can be used for the treatment of COPD or cancer or other proliferative or pathological conditions.

Summary of the Invention

Means for Solving the Problems

[0007] The present invention provides a low-molecular compound having PDE4B inhibitory activity, a stereoisomer thereof or a pharmaceutically acceptable salt, and the compound is as shown in formula (I),

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

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Chem.

Chem.

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Chem.

Chem.

Chemical formula

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[0008] According to a specific embodiment 1 of the present invention, a compound represented by formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0009] Furthermore, a compound represented by formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0010] According to Embodiment 2 of the present invention, it is the compound, stereoisomer or pharmaceutically acceptable salt described in Embodiment 1, each L 2 is independently selected from CO, O, NR L2 , C 1-4 an alkylene group, C 2-4 an alkenylene group, C 2-4 an alkynylene group,

Chemical formula

[0011] According to Option 3 of the present invention, it is a compound of Option 1 or 2, its stereoisomer or pharmaceutically acceptable salt, and the compound has the structure of Formula II as follows:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0012] According to Embodiment 4 of the present invention, a compound of Embodiment 1 or 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Cy is selected from a 5-membered monocyclic heteroaryl group, a 5-membered heteroaryl group-fused benzene ring, a 5-membered heteroaryl group-fused 5-membered heteroaryl group, a 5-membered heteroaryl group-fused 6-membered heteroaryl group, a 5-membered heteroaryl group-fused 4-membered cycloalkyl group, a 5-membered heteroaryl group-fused 5-membered cycloalkyl group, a 5-membered heteroaryl group-fused 6-membered cycloalkyl group, a 5-membered heteroaryl group-fused 4-membered heterocycloalkyl group, a 5-membered heteroaryl group-fused 5-membered heterocycloalkyl group, a 5-membered heteroaryl group-fused 6-membered heterocycloalkyl group, a 6-membered heteroaryl group-fused benzene ring, a 6-membered heteroaryl group-fused 5-membered heteroaryl group, a 6-membered heteroaryl group-fused 6-membered heteroaryl group, a 6-membered heteroaryl group-fused 4-membered cycloalkyl group, a 6-membered heteroaryl group-fused 5-membered cycloalkyl group, a 6-membered heteroaryl group-fused 6-membered cycloalkyl group, a 6-membered heteroaryl group-fused 4-membered heterocycloalkyl group, a 6-membered heteroaryl group-fused 5-membered heterocycloalkyl group, a 6-membered heteroaryl group-fused 6-membered heterocycloalkyl group, or Cy is optionally further substituted with 1 to 3 R's

Chemical formula

[0013] Furthermore, a compound of Embodiment 1 or 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Cy is selected from a 5-membered monocyclic heteroaryl group, a 5-membered heteroaryl group-fused benzene ring, a 5-membered heteroaryl group-fused 5-membered heteroaryl group, a 5-membered heteroaryl group-fused 6-membered heteroaryl group, a 5-membered heteroaryl group-fused 4-membered cycloalkyl group, a 5-membered heteroaryl group-fused 5-membered cycloalkyl group, a 5-membered heteroaryl group-fused 6-membered cycloalkyl group, a 5-membered heteroaryl group-fused 4-membered heterocycloalkyl group, a 5-membered heteroaryl group-fused 5-membered heterocycloalkyl group, a 5-membered heteroaryl group-fused 6-membered heterocycloalkyl group, a 6-membered heteroaryl group-fused benzene ring, a 6-membered heteroaryl group-fused 5-membered heteroaryl group, a 6-membered heteroaryl group-fused 6-membered heteroaryl group, a 6-membered heteroaryl group-fused 4-membered cycloalkyl group, a 6-membered heteroaryl group-fused 5-membered cycloalkyl group, a 6-membered heteroaryl group-fused 6-membered cycloalkyl group, a 6-membered heteroaryl group-fused 4-membered heterocycloalkyl group, a 6-membered heteroaryl group-fused 5-membered heterocycloalkyl group, a 6-membered heteroaryl group-fused 6-membered heterocycloalkyl group, or, [Chemical formula] is.

[0014] According to the fifth aspect of the present invention, a compound according to the third aspect, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, L is, [Chemical formula] selected from, X 1 X 2 are independently CR X1 or N, each R X1 is independently H, F, Cl, a methyl group, an ethyl group, or R X1 and R 3 and the atoms to which they are attached together form a C 5 cycloalkyl group, C 6A cycloalkyl group, a 5-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, or a 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O is formed, R 3 is H, F, Cl, =O, CN, C 1-3 is an alkyl group, each R is independently H, F, Cl, a methyl group, an ethyl group, acetylene, propyne, or two adjacent Rs and the atoms to which they are attached together form a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, or a cyclohexenyl group, and the cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, or cyclohexenyl group is optionally substituted with 1 to 3 groups selected from F, Cl, =O, CN, a methyl group, an ethyl group, a methoxy group, an ethoxy group, OH, and NH 2 and is substituted with 1 to 3 groups selected from Furthermore, a compound of Scheme 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is

Chemical formula

[0015] Furthermore, a compound of Scheme 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is [Chemical formula] selected from, X 1 X 2 is independently CR X1 or N, each R X1 is independently H, F, Cl, a methyl group, or an ethyl group, each R is independently H, F, Cl, a methyl group, an ethyl group, acetylene, propyne, or two adjacent Rs and the atoms to which they are attached together form a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, or a cyclohexenyl group, and the cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, or cyclohexenyl group is optionally substituted with 1 to 3 groups selected from F, Cl, =O, CN, a methyl group, an ethyl group, a methoxy group, an ethoxy group, OH, and NH 2 selected.

[0016] According to Embodiment 6 of the present invention, it is a compound of Embodiment 1, a stereoisomer thereof, or a pharmaceutically acceptable salt, [Chemical formula] is [Chemical formula] selected from the structures of, or [Chemical formula] selected from.

[0017] According to Embodiment 7 of the present invention, the compound of the present invention is a compound selected from one of the structures in Table 1 below, a stereoisomer thereof, or a pharmaceutically acceptable salt.

[0018] [Table 1-1] [Table 1-2]

Table 1-3

Table 1-4

[0019] According to Scheme 8 of the present invention, the compound of the present invention is a compound selected from one of the structures in Table 2 below, its stereoisomer or a pharmaceutically acceptable salt thereof.

[0020]

Table 2-1

Table 2-2

Table 2-3

Table 2-4

[0021] The present invention further provides a composition or a pharmaceutical preparation, which contains the compound, its stereoisomer or a pharmaceutically acceptable salt thereof described in any one of the foregoing schemes, and a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical composition may be in the form of a unit dosage form (the unit dosage form is also called a "formulation specification").

[0022] Furthermore, the composition or pharmaceutical preparation of the present invention contains 1 to 1500 mg of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof described in any one of the foregoing schemes, and a pharmaceutically acceptable carrier and / or excipient.

[0023] The present invention further provides the use of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof described in any one of the foregoing schemes in the manufacture of a medicament for treating / preventing a PDE4B-mediated disease. Furthermore, the PDE4B-mediated disease is cancer, COPD, idiopathic pulmonary fibrosis or interstitial lung disease.

[0024] The present invention further provides a method for treating mammalian diseases, the method comprising administering to a subject a therapeutically effective amount of a compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof shown in any one of the foregoing embodiments, and the disease is preferably cancer or COPD, idiopathic pulmonary fibrosis, interstitial lung disease, and preferably, the therapeutically effective amount is 1 to 1500 mg. In some embodiments, the mammals described in the present invention include humans.

[0025] The "effective amount" or "therapeutically effective amount" described in this application includes administering a sufficient amount of the compounds disclosed in this application, which alleviates to some extent one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms or causes of the disease, or any other desirable change in the biological system. For example, the "effective amount" for therapeutic use is the amount of the composition containing the compounds disclosed in this application necessary to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts are 1 to 1500 mg, 1 to 1400 mg, 1 to 1300 mg, 1 to 1200 mg, 1 to 1000 mg, 1 to 900 mg, 1 to 800 mg, 1 to 700 mg, 1 to 600 mg, 1 to 500 mg, 1 to 400 mg, 1 to 300 mg, 1 to 250 mg, 1 to 200 mg, 1 to 150 mg, 1 to 125 mg, 1 to 100 mg, 1 to 80 mg, 1 to 60 mg, 1 to 50 mg, 1 to 40 mg, 1 to 25 mg, 1 to 20 mg, 5 to 1500 mg, 5 to 1000 mg, 5 to 900 mg, 5 to 800 mg, 5 to 700 mg, 5 to 600 mg, 5 to 500 mg, 5 to 400 mg, 5 to 300 mg, 5 to 250 mg, 5 to 200 mg, 5 to 150 mg, 5 to 125 mg, 5 to 100 mg, 5 to 90 mg, 5 to 70 mg, 5 to 80 mg, 5 to 60 mg, 5 to 50 mg, 5 to 40 mg, 5 to 30 mg, 5 to 25 mg, 5 to 20 mg, 10 to 1500 mg, 10 to 1000 mg, 10 to 900 mg, 10 to 800 mg, 10 to 700 mg, 10 to 600 mg, 10 to 500 mg, 10 to 450 mg, 10 to 400 mg, 10 to 300 mg, 10 to 250 mg, 10 to 200 mg, 10 to 150 mg, 10 to 125 mg, 10 to 100 mg, 10 to 90 mg, 10 to 80 mg, 10 to 70 mg, 10 to 60 mg, 10 to 50 mg, 10 to 40 mg, 10 to 30 mg, 10 to 20 mg, 20 to 1500 mg, 20 to 1000 mg, 20 to 900 mg, 20 to 800 mg, 20 to 700 mg, 20 to 600 mg, 20 to 500 mg, 20 to 400 mg, 20 to 350 mg, 20 to 300 mg, 20 to 250 mg, 20 to 200 mg, 20 to 150 mg, 20 to 125 mg, 20 to 100 mg, 20 to 90 mg, 20 to 80 mg, 20 to 70 mg, 20 to 60 mg, 20 to 50 mg, 20 to 40 mg, 20 to 30 mg, 50 to 1500 mg, 50 to 1000 mg,including, but not limited to, 50 to 900 mg, 50 to 800 mg, 50 to 700 mg, 50 to 600 mg, 50 to 500 mg, 50 to 400 mg, 50 to 300 mg, 50 to 250 mg, 50 to 200 mg, 50 to 150 mg, 50 to 125 mg, 50 to 100 mg, 100 to 1500 mg, 100 to 1000 mg, 100 to 900 mg, 100 to 800 mg, 100 to 700 mg, 100 to 600 mg, 100 to 500 mg, 100 to 400 mg, 100 to 300 mg, 100 to 250 mg, 100 to 200 mg In some embodiments, the pharmaceutical composition or formulation of the present invention contains the above-mentioned therapeutically effective amount of the compound of the present invention or its stereoisomer, solvate, or pharmaceutically acceptable salt. The present invention relates to a pharmaceutical composition or pharmaceutical formulation, which contains a therapeutically effective amount of the compound described in the present invention, its stereoisomer or pharmaceutically acceptable salt, and a carrier and / or excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in the unit dosage form is also referred to as the "formulation specification"). In some embodiments, the pharmaceutical composition contains 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg of the compound of the present invention, its stereoisomer or pharmaceutically acceptable salt, but not limited thereto.

[0026] A method for treating a mammalian disease, said method comprising administering to a subject a therapeutically effective amount of a compound of the present invention, its stereoisomer or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and said disease is preferably cancer, COPD, idiopathic pulmonary fibrosis or interstitial lung disease.

[0027] A method for treating a mammalian disease, said method comprising administering to a subject a compound of the present invention, its stereoisomer or a pharmaceutically acceptable salt, which is a pharmaceutical, and a pharmaceutically acceptable carrier and / or excipient, in a daily dose of 1 to 1500 mg / day, wherein said daily dose may be a single dose or a divided dose, and in some embodiments, the daily dose includes, but is not limited to, 10 to 1500 mg / day, 20 to 1500 mg / day, 25 to 1500 mg / day, 50 to 1500 mg / day, 75 to 1500 mg / day, 100 to 1500 mg / day, 200 to 1500 mg / day, 10 to 1000 mg / day, 20 to 1000 mg / day, 25 to 1000 mg / day, 50 to 1000 mg / day, 75 to 1000 mg / day, 100 to 1000 mg / day, 200 to 1000 mg / day, 25 to 800 mg / day, 50 to 800 mg / day, 100 to 800 mg / day, 200 to 800 mg / day, 25 to 400 mg / day, 50 to 400 mg / day, 100 to 400 mg / day, 200 to 400 mg / day, and in some embodiments, the daily dose includes, but is not limited to, 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, 1500 mg / day.

[0028] The present invention relates to a kit, which may include a composition in the form of a single dose or multiple doses, and the kit includes a compound of the present invention, its stereoisomer or a pharmaceutically acceptable salt, and the amount of the compound of the present invention, its stereoisomer or a pharmaceutically acceptable salt is the same as its amount in the above pharmaceutical composition.

[0029] In the present invention, the amount of the compound of the present invention, its stereoisomer or pharmaceutically acceptable salt is, in each case, converted in the form of the free base.

[0030] "Formulation specification" refers to the weight of the active ingredient contained in one unit formulation, one tablet unit formulation, or each other unit formulation.

[0031] Synthetic route Patent documents such as WO 2013026797A1 describe the production method of PDE4B inhibitors. Those skilled in the art can combine this document and known organic synthesis techniques to produce the compounds of the present invention, and the starting materials thereof are commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are those obtained from regular commercial sources, and the suppliers include companies such as Titan Technology, Energy Chemical, Shanghai Derm, Chengdu Kelong Chemical Industry, Shaoyuan Chemical Technology, Nanjing Pharmatech, WuXi AppTec, and Alfa Chemistry.

[0032] Known chemical substance indexes created by the Chemical Information Search Service of the American Chemical Society can be used to selectively identify specific and similar reactants, and these indexes are available in many public libraries, university libraries, and online. For chemicals that are known but not available in catalogs, optionally, a custom chemical synthesis contractor can be requested to manufacture them, and many of the standard chemical suppliers (for example, the companies listed above) provide custom synthesis services.

[0033] Terms Unless otherwise specified in the present invention, the terms of the present invention have the following meanings.

[0034] In this specification, "halogen" refers to F, Cl, Br, I, or their isotopes.

[0035] "Halogenation" or "halogen substitution" refers to the substitution of a hydrogen atom by one or more selected from F, Cl, Br, I, or their isotopes. The upper limit of the number of halogen substituents is equal to the sum of the replaceable hydrogens of the group to be substituted. Unless otherwise particularly limited, the number of halogen substituents is any integer between 1 and the upper limit. When the number of halogen substituents is greater than 1, they may be substituted with the same or different halogens.

[0036] "Deuteration" or "deuteride" refers to the situation where the hydrogen atoms in groups such as an alkyl group, cycloalkyl group, alkylene group, aryl group, heteroaryl group, mercapto group, heterocycloalkyl group, alkenyl group, alkynyl group, etc. are substituted with at least one isotope deuterium. The upper limit of the number of deuterations is equal to the sum of the replaceable hydrogens of the group to be substituted. Unless otherwise particularly limited, the number of deuterations is any integer between 1 and the upper limit, preferably 1 to 20 deuterium atom substitutions, more preferably 1 to 10 deuterium atom substitutions, more preferably 1 to 6 deuterium atom substitutions, and even more preferably 1 to 3 deuterium atom substitutions.

[0037] "Alkyl group" refers to a monovalent straight-chain or branched-chain saturated aliphatic hydrocarbon group. Unless otherwise specified, it is an alkyl group having 1 to 20 carbon atoms, preferably an alkyl group having 1 to 8 carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms, even more preferably an alkyl group having 1 to 4 carbon atoms, and even more preferably an alkyl group having 1 to 2 carbon atoms. Non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, neobutyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group and various branched-chain isomers thereof.

[0038] "Alkylene group" refers to a divalent straight-chain and branched-chain saturated alkyl group. Examples of alkylene groups include, but are not limited to, methylene group, ethylene group, propylene group, and butylene group.

[0039] "Cycloalkyl group" refers to a monovalent non-aromatic, partially unsaturated or fully saturated, substituted or unsubstituted carbocyclic hydrocarbon group. Unless otherwise specified, it generally has 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 6 carbon atoms, and even more preferably 3 to 4 carbon atoms. Non-limiting examples include cyclopropylene group, cyclobutyl group, cyclopentyl group, cyclohexyl group, [Chemical formula] cycloheptyl group, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group or cyclohexenyl group, etc.

[0040] "Cycloalkylene group" refers to a divalent group of "cycloalkyl group". Non-limiting examples include cyclopropylene group, cyclobutylene group, etc.

[0041] The term "heterocyclic ring" or "heterocyclic ring group" refers to a substituted or unsubstituted aromatic ring, a substituted or unsubstituted, saturated or partially unsaturated non-aromatic ring. When there is no particular limitation, it contains 1 to 3 heteroatoms selected from N, O, or S, and includes monocyclic heterocyclic rings, bicyclic bridged heterocyclic rings, bicyclic fused heterocyclic rings, and bicyclic spiro heterocyclic rings, etc. When not particularly limited, it is a 3- to 12-membered heterocyclic ring, more preferably a 4- to 12-membered heterocyclic ring, still more preferably a 4- to 10-membered heterocyclic ring, and even more preferably a 4- to 7-membered heterocyclic ring. Its definition includes heterocycloalkyl groups and heteroaryl groups. N and S in the heterocyclic ring group can be oxidized to various oxidation states. The heterocyclic ring group may be linked on a heteroatom or a carbon atom. Non-limiting examples include oxiranyl group, azacyclopropyl group, oxetanyl group, azetidinyl group, 1,3-dioxolanyl group, 1,4-dioxolanyl group, 1,3-dioxanyl group, azacycloheptyl group, pyridyl group, furyl group, thienyl group, pyranyl group, N-alkylpyrrolyl group, pyrimidinyl group, pyrazinyl group, pyrazolyl group, pyridazinyl group, imidazolyl group, piperidinyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, 1,3-dithianyl group, dihydrofuryl group, dihydropyranyl group, dithiolanyl group, tetrahydrofuryl group, tetrahydropyrrolyl group, tetrahydroimidazolyl group, oxazolyl group, dihydrooxazolyl group, tetrahydrooxazolyl group, tetrahydrothiazolyl group, tetrahydropyranyl group, benzimidazolyl group, benzopyridyl group, pyrrolopyridyl group, benzodihydrofuryl group, azabicyclo[3.2.1]octyl group, azabicyclo[5.2.0]nonyl group, oxatricyclo[5.3.1.1]dodecyl group, azadamantyl group, and oxaspiro[3.3]heptyl group,

Chemical formula

[0042] The term "heterocyclylene group" refers to a divalent group corresponding to the "heterocyclic ring group", and non-limiting examples include imidazolinylene group, piperidinediyl group, aziridylene group, etc.

[0043] "Carbon ring" or "carbon ring group" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic carbon ring group, including monocyclic carbon rings, bicyclic bridged rings, bicyclic fused rings, and bicyclic spiro rings, etc. Unless otherwise specified, it has 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 6 carbon atoms. Its definition includes cycloalkyl groups and aryl groups. In non-limiting examples, monocyclic carbon rings include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group or phenyl group,

Chem.

Chem.

Chem.

Chem.

[0044] "Aryl group" refers to a carbon ring having aromaticity. Non-limiting examples include phenyl group, naphthyl group, etc.

[0045] "Alkynyl group" refers to a straight-chain or branched-chain monovalent unsaturated hydrocarbon group containing one or more carbon-carbon triple bonds. Unless otherwise specified, the alkynyl group contains 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. Non-limiting examples are ethynyl group, propynyl group, propargyl group, etc.

[0046] "Alkenyl group" refers to a linear or branched monovalent unsaturated hydrocarbon group containing one or more carbon-carbon double bonds. Unless otherwise specified, the alkynyl group contains 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. Non-limiting examples include vinyl group, propenyl group, allyl group, 2-butenyl group, 1-butenyl group, etc.

[0047] "Alkoxy group" or "alkyloxy group" refers to an -O-alkyl group. In the absence of specific limitations, it is -O-C 1-8 alkyl group, preferably -O-C 1-6 alkyl group, more preferably -O-C 1-4 alkyl group, even more preferably -O-C 1-2 alkyl group. Non-limiting examples include methoxy group, ethoxy group, n-propoxy group, sopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, n-hexyloxy group, cyclopropoxy group, and cyclobutoxy group, etc.

[0048] "Halogenated alkoxy group" refers to an -O-haloalkyl group. In the absence of specific limitations, it is -O-halogenated C 1-8 alkyl group, preferably -O-halogenated C 1-6 alkyl group, more preferably -O-halogenated C 1-4 alkyl group, even more preferably -O-halogenated C 1-2 alkyl group. Non-limiting examples include monofluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, difluoroethyloxy group, etc.

[0049] "C 1-4 alkylacyl group" refers to C 1-4 alkyl-C(O)-. Non-limiting examples include formyl group, acetyl group, propionyl group.

[0050] "C 1-4 alkylsulfonyl group" refers to C 1-4 alkyl-S(O) 2- refers to. Non-limiting examples include a methanesulfonyl group, an ethanesulfonyl group, and a propylsulfonyl group.

[0051] The term "heteroaryl ring" or "heteroaryl group" refers to a heterocyclic ring having aromaticity. Non-limiting examples include a pyrazolyl group, a pyrimidine group, a thiazolyl group, a pyridine group, a furyl group, and the like.

[0052] The term "heterocycloalkyl group" refers to a non-aromatic, partially unsaturated or fully saturated heterocyclic ring, which generally has 4 to 12 ring members, preferably 4 to 10 ring members, more preferably 4 to 7 ring members, and even more preferably 5 or 6 ring members. In addition to carbon atoms, the heterocycloalkyl group further contains 1 to 3 heteroatoms selected from N, S, and O as ring members. Non-limiting examples include an azetidinyl group, a morpholino group, a piperazinyl group, a piperidinyl group, a tetrahydropyranyl group, an oxetanyl group, and the like.

[0053] The term "alkylamino group" or "alkylamino group" refers to an amino group substituted with one or two alkyl groups, -N-(alkyl) 2 or -NH-alkyl group, which is also written as a monoalkylamino group. Non-limiting examples include a dimethylamino group, a monomethylamino group, a diethylamino group, a monoethylamino group, and the like.

[0054] The term "optional" or "optionally" means that the event or circumstance described thereafter may occur, but does not necessarily occur, and the description includes both the case where the event or circumstance occurs and the case where it does not occur. For example, the term "alkyl group optionally substituted by F" means that the alkyl group may be substituted by F, but does not necessarily have to be substituted by F, indicating that it includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.

[0055] "Pharmaceutically acceptable salt" refers to a salt obtained by the reaction of a compound of the present invention with a non-toxic inorganic base or organic base for the free acid, or a non-toxic inorganic acid or organic acid for the free base, while maintaining the biological effectiveness and properties of the free acid or free base of the compound of the present invention.

[0056] "Pharmaceutical composition" represents one or more of the compounds described herein or their stereoisomers, solvates, pharmaceutically acceptable salts or co-crystals, mixtures with other components, where the other components include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0057] "Carrier" refers to a system that does not significantly stimulate the living body, does not eliminate the biological activity and properties of the given compound, and changes the administration form and in vivo distribution of the drug to the human body, controls the drug release rate, and can deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0058] "Excipient" refers to a substance that is not a therapeutic agent itself but is added to a pharmaceutical composition as a diluent, adjuvant, adhesive, and / or vehicle, thereby improving its handling and storage properties, or allowing or facilitating the compound or pharmaceutical composition to form a dosage form for administration. As is known to those skilled in the art, pharmaceutical excipients can provide various functions and may be described as wetting agents, buffers, suspending aids, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, coloring agents, flavoring agents, and sweeteners. Examples of pharmaceutical excipients include, but are not limited to, the following: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and cross-linked carboxymethyl cellulose (e.g., sodium cross-linked carboxymethyl cellulose); (4) tragacanth gum powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, castor oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) water for endotoxin testing; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solutions; (21) polyesters, polycarbonates, and / or polyanhydrides; and (22) other non-toxic and compatible substances used in pharmaceutical formulations.

[0059] "Stereoisomer" refers to an isomer that results from different spatial arrangements of atoms in a molecule and includes cis-trans isomers, enantiomers, and conformational isomers.

[0060] "Solvate" refers to a substance formed by the intermolecular non-covalent bonding of a compound of the present invention or a salt thereof with a stoichiometric or non-stoichiometric solvent. When the solvent is water, it becomes a hydrate.

[0061] "Co-crystal" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonding or other non-covalent bonds, where the pure states of API and CCF are both solids at room temperature, and there is a fixed stoichiometric ratio between the components. Co-crystals are multi-component crystals, including not only two-component co-crystals formed between two neutral solids, but also multi-component co-crystals formed between a neutral solid and a salt or a solvate.

Embodiments for Carrying out the Invention

[0062] Hereinafter, the content of the present invention will be described in detail with reference to examples. When specific conditions are not specified in the examples, they were carried out according to the experimental methods under general conditions. It should be understood that the examples given are for better explaining the content of the present invention, and the content of the present invention is not limited to the examples given. Non-essential improvements and adjustments made by those skilled in the art to the embodiments based on the above invention content still fall within the protection scope of the present invention.

[0063] Dess-Martin reagent, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one DIPEA: N,N-diisopropylethylamine NMP; N-methylpyrrolidone TBDMSCl: tert-butyldimethylchlorosilane DMAP: 4-dimethylaminopyridine HATU: 2-(7-azabenzotriazole)-N,N,N’,N’-tetramethyluronium hexafluorophosphate T 3 P: tricyclic anhydride propyl phosphate

[0064] Example 1:

Chemical formula

[0065] Step 1: Substrate 1A (5.0 g, 26.11 mmol) was added to a 250 mL single-necked flask, dissolved in dioxane (40 mL), and sodium carbonate solution (2 M, 40 mL), 1B (9.7 g, 31.33 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (2.1 g, 2.61 mmol) were added. The mixture was stirred at 100 °C overnight under nitrogen gas protection. The reaction solution was diluted with water (40 mL), suction filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate (2 × 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to obtain the title compound 1C (7.2 g, 94%).

[0066] LC-MS (ESI): m / z = 238.1 [M - 56 + H] + 。

[0067] Step 2: Substrate 1C (0.6 g, 2.04 mmol), methanol (5 mL), and dioxane hydrochloride (4 M, 5 mL) were added to a 50 mL single-necked flask and dissolved. The mixture was stirred at room temperature for 3 h, and the reaction solution was concentrated to obtain the title compound 1D (0.47 g, 100%).

[0068] LC-MS (ESI): m / z = 194.1 [M + H] + 。

[0069] Step 3: Substrate 1E (0.15 g, 0.52 mmol) (Compound 1E is synthesized according to the method of Patent WO2013026797) and dioxane (10 mL) were added to a 50 mL single-necked flask and dissolved. 1C (0.14 g, 0.62 mmol) and diisopropylethylamine (0.2 g, 1.55 mmol) were added, and the mixture was reacted at 100 °C overnight. The reaction solution was concentrated, purified by HPLC, and lyophilized to obtain the title compound 1 (120 mg, 52%).

[0070] Fractionation method: Instrument: Waters 2767 preparative liquid phase, chromatographic column: SunFire@Prep C18 (19 mm × 250 mm). Dissolve the sample in DMF, filter it through a 0.45 μm filter to prepare the sample solution. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 5 mM aqueous ammonia); b. Gradient elution, the content of mobile phase A is 30% - 80%; c. Flow rate is 15 mL / min; d. Elution time is 15 min, retention time: 7.0 min.

[0071] 1 H NMR (400 MHz, DMSO-d6) δ 7.49 - 7.46 (m, 2H), 7.42 - 7.37 (m, 2H), 7.35 (s, 1H), 6.31 (t, 1H), 4.83 (t, 1H), 4.35 (s, 2H), 3.97 (t, 2H), 3.75 (d, 2H), 3.45 - 3.39 (m, 1H), 3.26 - 3.16 (m, 1H), 2.99 - 2.81 (m, 2H), 2.51 - 2.49 (m, 2H), 2.43 - 2.27 (m, 2H), 2.23 - 2.16 (m, 2H), 1.87 - 1.71 (m, 2H).

[0072] LC-MS (ESI): m / z = 445.2 [M + H] + 。

[0073] Example 2

Chemical formula

[0074] Step 1: Sodium borohydride (1.9 g, 51.05 mmol) and anhydrous tetrahydrofuran (50 mL) were added to a 500 mL single-necked flask. Boron trifluoride ethyl etherate (7.25 g, 51.05 mmol) was added dropwise in an ice bath. After the addition was complete, the mixture was stirred in the ice bath for 0.5 h. A solution of 2A (5.0 g, 17.02 mmol) in tetrahydrofuran (20 mL) was continuously added dropwise in the ice bath, and the temperature was allowed to rise naturally to room temperature and stirred overnight. Water (19 mL), ethanol (19 mL), and sodium hydroxide solution (10%, 103 mL) were sequentially added to the reaction solution. Finally, hydrogen peroxide (9.4 mL, 51.05 mmol) was added, and the mixture was stirred at 70 °C overnight. The reaction solution was adjusted to pH = 5 - 6 with HCl (2 M), extracted with dichloromethane (3 × 100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the title compound ±2B (± represents a racemic mixture of the indicated configurations) (4.0 g, 75%) was obtained by column chromatography (petroleum ether:ethyl acetate (v / v) = 4:1).

[0075] LC-MS(ESI): m / z = 256.1[M - 56 + H] + 。

[0076] Step 2: ±2B (1.9 g, 6.09 mmol) was added to a 100 mL single-necked flask, dissolved in anhydrous dichloromethane (20 mL), and bis(2-methoxyethyl)aminosulfur trifluoride (1.48 g, 6.67 mmol) was added dropwise in an ice bath. The temperature was slowly raised to room temperature and stirred overnight. The reaction solution was washed with saturated sodium bicarbonate solution (20 mL), the aqueous phase was extracted with dichloromethane (2 × 20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the title compound ±2C (1.56 g, 82%) was obtained by column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1).

[0077] LC-MS(ESI): m / z = 258.1[M - 56 + H] + 。

[0078] Step 3: Add ±2C (1.56 g, 4.97 mmol) and anhydrous methanol (10 mL) to a 100 mL single-necked flask and dissolve. Then add dioxane hydrochloride (10 mL), stir at room temperature for 2 h, and concentrate to obtain the title compound ±2D (1.24 g, 100%).

[0079] LC-MS (ESI): m / z = 214.1 [M+H] + 。

[0080] Step 4: Add 1E (0.30 g, 1.04 mmol) and dioxane (10 mL) to a 50 mL single-necked flask and dissolve. Then add ±2D (0.32 g, 1.26 mmol) and diisopropylethylamine (0.4 g, 3.14 mmol), and react at 100 °C overnight. Concentrate the reaction solution, and obtain a mixture by column chromatography (dichloromethane:methanol = 20:1 - 8:1). Then obtain the title compound 2 (0.11 g, 23%) and the title compound 3 (90 mg, 19%) by chiral separation.

[0081] Chiral separation method: Instrument: Waters 150MGM, Chromatographic column: Chiralpak Column, Mobile phase: A: carbon dioxide and B: methanol (0.1% aqueous ammonia), Isocratic elution: 30% mobile phase B, Flow rate: 100 mL / min, Back pressure: 100 bar, Column temperature: 25 °C, Wavelength: 220 nm, Elution time: 2.9 min.

[0082] Compound 2, retention time 1.94 min, 1 H NMR (400 MHz, DMSO-d6) δ 7.43 (s, 1H), 7.40 - 7.33 (m, 4H), 5.04 - 5.01 (d, 1H), 4.82 (t, 1H), 4.71 - 4.63 (m, 1H), 4.57 - 4.51 (m, 1H), 3.77 - 3.66 (m, 2H), 3.47 - 3.39 (m, 1H), 3.27 - 3.19 (m, 1H), 3.09 - 2.81 (m, 5H), 2.46 - 2.25 (m, 2H), 2.20 - 2.14 (m, 2H), 1.91 - 1.55 (m, 4H).

[0083] Compound 3, retention time 2.23 min, 1 H NMR (400 MHz, DMSO-d6) δ 7.43 (s, 1H), 7.39 - 7.34 (m, 4H), 5.05 - 5.02 (m, 1H), 4.82 (t, 1H), 4.69 - 4.52 (m, 2H), 3.71 (d, 2H), 3.48 - 3.39 (m, 1H), 3.27 - 3.19 (m, 1H), 3.08 - 2.81 (m, 5H), 2.41 - 2.29 (m, 2H), 2.21 - 2.10 (m, 2H), 1.89 - 1.55 (m, 4H).

[0084] LC-MS (ESI): m / z = 465.2 [M + H] + .

[0085] Example 3

Chemical Structure

[0086] Step 1: Add 4A (2.0 g, 9.38 mmol) and anhydrous tetrahydrofuran (10 mL) to a 100 mL single-necked flask and dissolve. Dropwise add 4B (10.3 mL, 1 M, 10.32 mmol) in an ice bath, warm up to room temperature, stir for 3 h, quench with saturated ammonium chloride solution (30 mL), extract with ethyl acetate (2 × 20 mL), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and obtain the title compound 4C (2.6 g, 85%) by column chromatography (petroleum ether:ethyl acetate (v / v) = 4:1).

[0087] LC-MS (ESI): m / z = 252.1 [M - 56 - 18 + H] + .

[0088] Step 2: Substrate 4C (1.0 g, 3.07 mmol) and dichloromethane (10 mL) were added to a 50 mL single-necked flask and dissolved. Trifluoroacetic acid (5 mL) was added, and the mixture was stirred overnight at room temperature. The pH was adjusted to 8 - 9 with NaOH (2 M) solution, and then extracted with dichloromethane (2 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a mixture of the title compounds 4D and 4E (0.6 g, 94%).

[0089] LC-MS (ESI): m / z = 208.1 [M+H] + 。

[0090] Step 3: 1E (0.20 g, 0.69 mmol) was added to a 50 mL single-necked flask and dissolved in dioxane (5 mL). A mixture of 4D and 4E (0.21 g, 1.01 mmol) and diisopropylethylamine (0.26 g, 2.05 mmol) were added, and the reaction was carried out overnight at 100 °C. The reaction solution was concentrated and separated by column chromatography (dichloromethane:methanol = 20:1 - 10:1) to obtain 0.5 g of the crude product, which was purified by HPLC to obtain the title compound 4 (0.13 g, 42%) and the title compound 5 (50 mg, 16%).

[0091] Fractionation method: Instrument: Waters 2767 preparative liquid phase, chromatographic column: SunFire@Prep C18 (19 mm × 250 mm). The sample was dissolved in DMF, filtered through a 0.45 μm filter to prepare the sample solution. Conditions for preparative chromatography: a. Regarding the composition of mobile phases A and B, mobile phase A: acetonitrile, mobile phase B: water (containing 5 mM aqueous ammonia); b. Gradient elution, the content of mobile phase A is 35% - 70%; c. Flow rate is 15 mL / min; d. Elution time is 15 min, retention times: compound 4, 4.0 min and compound 5, 7.0 min.

[0092] Compound 4, 11H NMR (400 MHz, DMSO-d6) δ 7.33 (brs, 4H), 7.24 (s, 1H), 6.17 (t, 1H), 4.82 (t, 1H), 4.30 - 4.32 (m, 2H), 4.09 - 3.85 (m, 2H), 3.71 (d, 2H), 3.44 - 3.36 (m, 1H), 3.24 - 3.16 (m, 1H), 2.98 - 2.78 (m, 2H), 2.66 - 2.56 (m, 2H), 2.44 - 2.27 (m, 2H), 2.17 (brs, 2H), 1.93 - 1.69 (m, 4H).

[0093] Compound 5 1 1H NMR (400 MHz, DMSO-d6) δ 7.34 (brs, 4H), 7.25 (s, 1H), 6.03 (t, 1H), 4.82 (t, 1H), 4.05 - 3.80 (m, 4H), 3.72 (d, 2H), 3.45 - 3.37 (m, 1H), 3.24 - 3.15 (m, 1H), 2.98 - 2.80 (m, 2H), 2.77 - 2.65 (m, 2H), 2.53 - 2.45 (m, 2H), 2.42 - 2.25 (m, 2H), 2.20 - 2.07 (m, 2H), 1.82 - 1.68 (m, 2H).

[0094] LC-MS (ESI): m / z = 459.1 [M + H] + .

[0095] Example 4 [Chem.]

[0096] Step 1: (3aR,6aS)-Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (2.12 g, 10 mmol), 1-chloro-4-iodobenzene (2.61 g, 11 mmol), Pd 2 (dba) 3(915 mg, 1 mmol), Xphos (952 mg, 2 mmol) and sodium tert-butoxide (1.15 g, 12 mmol) were weighed into a 250 mL three-necked flask, toluene (50 mL) and tert-butyl alcohol (10 mL) were added, and after purging with nitrogen gas, the reaction was carried out at 100 °C for 16 h. After monitoring the complete reaction by LCMS, the system was cooled to room temperature, filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated and then separated by silica gel column chromatography (PE:EA = 20:1~5:1) to obtain the target compound 6A (2.76 g, 85.2%).

[0097] LC-MS (ESI): m / z = 323.2 [M+H] + 。

[0098] Step 2: 6A (2.76 g, 0.85 mmol) was dissolved in methanol (30 mL), a solution of dioxane hydrochloride (5 mL, 4 M) was added, and the reaction was carried out at room temperature for four hours, and then spin-dried to obtain the title compound 6B (2.56 g, crude product).

[0099] LC-MS (ESI): m / z = 223.2 [M+H] + 。

[0100] Step 3: 1E (287 mg, 1 mmol), 6B (300 mg) were dissolved in 1,4-dioxane (20 mL), DIPEA (1 mL) was added, and the mixture was left overnight at 90 °C. After detecting the complete reaction of the starting materials by LCMS, the system was concentrated, water (20 mL) was added, and extraction was carried out with a mixed solution of DCM:MeOH = 20:1 (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and then passed through a column (DCM:MeOH = 1:0~0:1) to obtain compound 6 (289 mg, 60.9%).

[0101] 1 H NMR (400 MHz, DMSO-d 6) δ 7.33 - 7.07 (m, 3H), 6.66 - 6.38 (m, 2H), 4.85 - 4.76 (m, 1H), 3.82 - 3.74 (m, 2H), 3.74 - 3.67 (m, 2H), 3.52 - 3.34 (m, 5H), 3.26 - 3.13 (m, 3H), 3.13 - 3.04 (m, 2H), 2.96 - 2.79 (m, 2H), 2.43 - 2.27 (m, 2H), 2.19 - 2.09 (m, 2H), 1.86 - 1.65 (m, 2H).

[0102] LC-MS (ESI): m / z = 474.2[M + H] + .

[0103] Example 5 [Chemical formula]

[0104] Step 1: Dissolve compound 7A (1 g, 4.2 mmol) in 50 mL of tetrahydrofuran under a nitrogen gas atmosphere, and cool the system to 0 °C. Slowly add dropwise 4.6 mL of 4-chlorophenylmagnesium bromide (1 M in THF), warm the temperature to room temperature, and then react for 3 h. Add saturated aqueous ammonium chloride solution to quench the reaction, concentrate the reaction system, extract three times with 50 mL of ethyl acetate, and dry over anhydrous sodium sulfate. Concentrate the organic phase to obtain the crude product of compound 7B, which was directly used in the next step.

[0105] LCMS m / z = 296.1[M - 55] + .

[0106] Step 2: Dissolve the crude product of compound 7B in a mixed solvent (DCM:TFA = 50 mL:4 mL), and react at room temperature for 2 h. After the reaction is completed, concentrate the system to obtain the crude product of compound 7C, which was directly used in the next step.

[0107] LCMS m / z = 234.2[M + 1] + .

[0108] Step 3: The crude product of Compound 7C was dissolved in 50 mL of methanol, 300 mg of palladium carbon (10%) was added, and the reaction was carried out overnight under a hydrogen gas atmosphere. The solid residue was removed from the system by suction filtration, and the filtrate was concentrated to obtain the crude product of Compound 7D, which was directly used in the reaction of the next step.

[0109] LCMS m / z=236.1[M+1] + 。

[0110] Step 4: Under a nitrogen gas atmosphere, the crude product of Compound 7D, Compound 1E (150 mg, 0.52 mmol) and DIPEA (0.86 mL, 5.2 mmol) were dissolved in 30 mL of 1,4-dioxane, heated to 100 °C, and reacted for 18 h. After concentrating the reaction system, it was separated by thin layer chromatography to obtain Compound 7 (98 mg, 38%).

[0111] LCMS m / z=487.1[M+1] + 。

[0112] 1 H NMR (400MHz, DMSO-d6) δ 7.34 - 7.26 (m, 5H), 4.87 - 4.84 (m, 1H), 3.85 - 3.59 (m, 6H), 3.44 - 3.34 (m, 1H), 3.26 - 3.15 (m, 1H), 2.95 - 2.81 (m, 2H), 2.54 - 2.46 (m, 1H), 2.41 - 2.27 (m, 2H), 2.15 (s, 2H), 1.99 - 1.93 (m, 2H), 1.86 - 1.68 (m, 4H), 1.64 - 1.57 (m, 2H), 1.50 - 1.41 (m, 2H).

[0113] Example 6

Chemical Structure

[0114] Step 1: After weighing Compound 8A (2.00 g, 10.91 mmol) and Compound 1B (3.31 g, 10.91 mmol) into a 100 mL single-neck flask, 1,4-dioxane (15 mL) was added and dissolved. Then, sodium carbonate solution (2N, 15 mL) and Pd(dppf)Cl 2 (0.66 g, 1.1 mmol) were added. After the addition was complete, the mixture was stirred at 100 °C for 4 h. When the TLC spotting plate (petroleum ether:ethyl acetate = 5:1) showed complete reaction, water (20 mL) was added to the reaction solution, and the mixture was stirred for 5 min. Then, ethyl acetate (20 mL) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure and purified by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain the target compound 8B (2.50 g, 80%).

[0115] LCMS m / z = 286.1 [M+1] + 。

[0116] Step 2: After weighing Compound 8B (1.00 g, 3.50 mmol) into a 100 mL single-neck flask, ethyl acetate (20 mL) was added and dissolved. Then, palladium on carbon (0.19 g, 1.74 mmol) was added to the reaction solution. After the addition was complete, the mixture was stirred under hydrogen gas conditions for 1 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound 8C (1.00 g, 99%).

[0117] LCMS m / z = 288.1 [M+1] + 。

[0118] Step 3: After weighing Compound 8C (1.00 g, 3.48 mmol) into a 100 mL single-neck flask, methanol (20 mL) was added and dissolved. Then, dioxane hydrochloride solution (4N, 20 mL) was added, and the mixture was stirred for 2 h after the addition was complete. The organic phase was concentrated under reduced pressure to obtain the target compound 8D (0.60 g, yield: 92%).

[0119] LCMS m / z = 188.2 [M+1] + 。

[0120] Step 4: Add compound 8D (0.20 g, 1.04 mmol) to a 100 mL single-neck flask. Dissolve compound 1E (0.30 g, 1.04 mmol) in 1,4-dioxane (10 mL), and finally add N,N-diisopropylethylamine (0.40 g, 3.12 mmol). After the addition is complete, protect the system with nitrogen gas, stir at 100 °C for 16 h, concentrate the reaction solution under reduced pressure to obtain the crude product of the target compound, and obtain the title compound 8 (190 mg, 62%) by preparative HPLC.

[0121] Preparative method: Instrument: Waters 2767 preparative liquid phase, chromatographic column: SunFire@Prep C18 (19 mm × 250 mm). Dissolve the sample in DMF, filter it through a 0.45 μm filter to prepare the sample solution. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 5 mM aqueous ammonia); b. Gradient elution, the content of mobile phase A is 40% - 80%; c. Flow rate is 15 mL / min; d. Elution time is 20 min, retention time: 10.38 min.

[0122] LCMS m / z = 439.2 [M + 1] + 。

[0123] 1 1H NMR (400 MHz, DMSO-d6) δ 7.26 (s, 1H), 7.02 - 7.04 (m, 1H), 6.94 - 6.97 (m, 1H), 4.75 - 4.82 (m, 3H), 3.71 (d, 3H), 3.36 - 3.45 (m, 1H), 3.17 - 3.25 (m, 1H), 3.07 (s, 4H), 2.74 - 2.96 (m, 5H), 2.27 - 2.41 (m, 2H), 2.12 - 2.19 (m, 2H), 1.70 - 1.80 (m, 4H), 1.44 - 1.54 (m, 2H).

[0124] Example 7

Chemical formula

[0125] Step 1: After weighing Compound 9A (2.00 g, 10.05 mmol) and Compound 1B (3.11 g, 10.05 mmol) into a 100 mL single-necked flask, 1,4-dioxane (15 mL) was added and dissolved. Then, a sodium carbonate solution (2N, 15 mL) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.66 g, 1.01 mmol) were added to the reaction solution. After the addition was complete, the mixture was stirred at 100 °C for 4 h, and the complete reaction was monitored by TLC (petroleum ether:ethyl acetate = 5:1). Water (20 mL) was added to the reaction solution, and the mixture was stirred for 5 min. Then, ethyl acetate (20 mL) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure and purified by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain the target compound 9B (2.50 g, 80%).

[0126] LCMS m / z=300.1[M+1] + 。

[0127] Step 2: After weighing Compound 9B (3.00 g, 9.95 mmol) into a 100 mL single-necked flask, ethyl acetate (20 mL) was added and dissolved. Then, palladium on carbon (0.50 g, 4.97 mmol) was added to the reaction solution. After the addition was complete, the mixture was stirred under hydrogen gas conditions for 1 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure until the liquid stopped dripping to obtain the target compound 9C (3.00 g, 99%).

[0128] LCMS m / z=302.1[M+1] + 。

[0129] Step 3: After weighing Compound 9C (3.00 g, 9.89 mmol) into a 100 mL single-necked flask, methanol (20 mL) was added and dissolved. Then, a dioxane hydrochloride solution (4N, 20 mL) was added, and the mixture was stirred for 2 h after the addition was complete. The organic phase was concentrated under reduced pressure to obtain the target compound 9D (2.00 g, 99%).

[0130] LCMS m / z=202.2[M+1] + 。

[0131] Step 4: To a 100 mL single-neck flask, add Compound 9D (0.20 g, 1.03 mmol) and Compound 1E (0.29 g, 1.03 mmol), then add 1,4-dioxane (10 mL) to dissolve them, and finally add N,N-diisopropylethylamine (0.26 g, 2.05 mmol). After the addition is complete, protect the system with nitrogen gas, stir at 100 °C for 16 h, concentrate the reaction solution under reduced pressure to obtain the crude product of the target compound, and obtain the title compound 9 (190 mg, 64%) by preparative HPLC.

[0132] Preparative method: Instrument: Waters 2767 preparative liquid phase, chromatographic column: SunFire@Prep C18 (19 mm × 250 mm). Dissolve the sample in DMF, filter it through a 0.45 μm filter to prepare the sample solution. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 5 mM aqueous ammonia); b. Gradient elution, the content of mobile phase A is 45% - 80%; c. Flow rate is 20 mL / min; d. Elution time is 20 min, retention time: 8.11 min.

[0133] LCMS m / z = 453.2 [M + 1] + 。

[0134] 1 1H NMR (400 MHz, DMSO-d6) δ 7.26 (s, 1H), 7.07 - 7.12 (m, 2H), 6.96 - 6.97 (m, 1H), 4.75 - 4.82 (m, 3H), 3.72 (d, 2H), 3.36 - 3.45 (m, 1H), 3.18 - 3.25 (m, 1H), 2.75 - 2.97 (m, 9H), 2.28 - 2.41 (m, 2H), 2.11 - 2.20 (m, 2H), 1.93 - 2.01 (m, 2H), 1.72 - 1.80 (m, 4H), 1.44 - 1.54 (m, 2H).

[0135] Example 8

Chemical Structure

[0136] Step 1: After weighing 10A (2.00 g, 9.47 mmol) into a 100 mL single-neck flask, add tetrahydrofuran (30 mL) to dissolve it. Then add 4-chlorophenylmagnesium chloride (18.94 mL, 18.94 mmol) to the reaction solution. After the addition is complete, stir at room temperature for 4 h. When the TLC spotting plate (petroleum ether:ethyl acetate = 3:1) indicates complete reaction, add water (20 mL) to the reaction solution, stir for 5 min, then add ethyl acetate (20 mL) for extraction. Separate the organic phase, dry the organic phase over anhydrous sodium sulfate, concentrate the crude product under reduced pressure, and purify it by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain the target compound 10B (1.50 g, 48%).

[0137] LCMS m / z = 324.1 [M+1] + 。

[0138] Step 2: After weighing 10B (0.50 g, 1.54 mmol) into a 100 mL single-neck flask, add dichloromethane (15 mL) to dissolve it. Then add trifluoroacetic acid (5 mL) to the reaction solution. After the addition is complete, stir at room temperature for 16 h. After the reaction is complete, concentrate the filtrate under reduced pressure to obtain the target compound 10C (0.40 g, crude product).

[0139] LCMS m / z = 206.1 [M+1] + 。

[0140] Step 3: After weighing 10C (0.40 g, 1.94 mmol) into a 100 mL single-neck flask, add methanol (20 mL) to dissolve it. Then add palladium on carbon (0.10 g, 0.97 mmol). After the addition is complete, stir for 2 h. After the reaction is complete, filter the reaction solution and concentrate the organic phase under reduced pressure to obtain the target compound 10D (0.40 g, crude product).

[0141] LCMS m / z = 208.2 [M+1] + 。

[0142] Step 4: To a 100 mL single-necked flask, add compound 10D (0.40 g, 1.91 mmol) and compound 1E (0.55 g, 1.91 mmol), add 1,4-dioxane (10 mL) to dissolve, and finally add N,N-diisopropylethylamine (0.74 g, 5.73 mmol). After the addition is complete, protect the system with nitrogen gas, stir at 100 °C for 16 h, concentrate the reaction solution under reduced pressure to obtain a crude product of the target compound, and obtain the title compound 10 (25 mg, 4%) by preparative HPLC.

[0143] Preparative method: Instrument: Waters 2767 preparative liquid phase, chromatographic column: SunFire@Prep C18 (19 mm × 250 mm), dissolve the sample in DMF, filter with a 0.45 μm filter to prepare the sample solution. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 5 mM aqueous ammonia); b. Gradient elution, the content of mobile phase A is 50% - 90%; c. Flow rate is 15 mL / min; d. Elution time is 20 min, retention time: 6.45 min.

[0144] LCMS m / z = 459.2 [M + 1] + 。

[0145] 1 1H NMR (400 MHz, DMSO-d6) δ 7.34 - 7.36 (m, 2H), 7.25 - 7.30 (m, 3H), 4.86 (t, 1H), 4.14 (s, 2H), 3.92 (s, 2H), 3.70 (d, 2H), 3.35 - 3.44 (m, 2H), 3.17 - 3.24 (m, 1H), 2.82 - 2.95 (m, 2H), 2.54 - 2.61 (m, 2H), 2.24 - 2.34 (m, 4H), 2.10 - 2.16 (m, 2H), 1.69 - 1.85 (m, 2H).

[0146] Example 9

Chemical Structure

[0147] Step 1: Weigh Compound 11A (2.00 g, 7.78 mmol) and Compound 1B (2.89 g, 9.34 mmol) into a 100 mL single-neck flask. Then add 1,4-dioxane (15 mL) and dissolve. Add sodium carbonate solution (2N, 15 mL) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.57 g, 0.78 mmol) to the reaction solution. After the addition is complete, stir at 100 °C for 4 h. When the TLC spotting plate (petroleum ether:ethyl acetate = 5:1) indicates complete reaction, add water (20 mL) to the reaction solution, stir for 5 min, add ethyl acetate (20 mL) for extraction, separate the organic phase, dry the organic phase over anhydrous sodium sulfate, concentrate the crude product under reduced pressure, and purify by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain the target compound 11B (2.60 g, 93%).

[0148] LCMS m / z = 360.1 [M+1] + 。

[0149] Step 2: Weigh Compound 11B (0.50 g, 1.39 mmol) into a 100 mL single-neck flask. Then add ethanol (20 mL) and dissolve. Add palladium on carbon (0.15 g, 1.39 mmol) to the reaction solution. After the addition is complete, stir under hydrogen gas conditions for 16 h. After the reaction is completed, filter the reaction solution and concentrate the filtrate under reduced pressure to obtain the target compound 11C (0.50 g, 99%).

[0150] LCMS m / z = 362.1 [M+1] + 。

[0151] Step 3: Weigh Compound 11C (0.50 g, 1.38 mmol) into a 100 mL single-neck flask. Then add methanol (20 mL) and dissolve. Add dioxane hydrochloride solution (4N, 20 mL). After the addition is complete, stir for 2 h. Concentrate the organic phase under reduced pressure to obtain the target compound 11D (0.40 g, crude product).

[0152] LCMS m / z = 262.2 [M+1] + 。

[0153] Step 4: To a 100 mL single-necked flask, add Compound 11D (0.20 g, 0.76 mmol) and Compound 1E (0.22 g, 0.76 mmol), add 1,4-dioxane (10 mL) to dissolve, and finally add N,N-diisopropylethylamine (0.29 g, 2.28 mmol). After the addition is complete, protect the system with nitrogen gas, stir at 100 °C for 16 h, concentrate the reaction solution under reduced pressure to obtain a crude product of the target compound, and obtain the title compound 11 (240 mg, 61%) by preparative HPLC.

[0154] Preparative method: Instrument: Waters 2767 preparative liquid phase, chromatographic column: SunFire@Prep C18 (19 mm × 250 mm), dissolve the sample in DMF, filter with a 0.45 μm filter to prepare the sample solution. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 5 mM aqueous ammonia), b. Gradient elution, the content of mobile phase A is 30% - 70%, c. Flow rate is 15 mL / min. d. Elution time is 20 min, retention time: 12.08 min.

[0155] LCMS m / z = 513.2 [M + 1] + 。

[0156] 1 1H NMR (400 MHz, DMSO-d6) δ 7.62 (d, 2H), 7.43 (d, 2H), 7.29 (s, 1H), 4.77 - 4.84 (m, 3H), 3.71 (d, 2H), 3.37 - 3.45 (m, 1H), 3.18 - 3.26 (m, 1H), 2.82 - 2.98 (m, 5H), 2.28 - 2.41 (m, 2H), 2.12 - 2.19 (m, 2H), 1.70 - 1.85 (m, 4H), 1.48 - 1.58 (m, 2H).

[0157] Example 10

Chemical Structure

[0158] Step 1: (4-Bromophenyl)sulfur pentafluoride (1.0 g, 3.55 mmol) and N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (12A, 1.65 g, 5.33 mmol) were dissolved in 1,4-dioxane (10 mL), an aqueous sodium carbonate solution (2 mol / L, 10 mL), and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (200 mg) were added, and the mixture was refluxed for 4 hours under the protection of nitrogen gas. It was extracted with ethyl acetate (30 mL × 2), dried over anhydrous sodium sulfate, concentrated, and then purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 100:10) to obtain the product (12B) (700 mg, yield 51%).

[0159] LCMS m / z = 330.1 [M + 1 - 56] + 。

[0160] Step 2: Compound 12B (700 mg, 1.8 mmol) was dissolved in methanol (10 mL), palladium carbon (100 mg) was added, and the mixture was hydrogenated at room temperature for 3 hours. It was filtered, and after concentrating the filtrate, the crude product (12C) (700 mg, yield 100%) was obtained.

[0161] LCMS m / z = 332.1 [M + 1 - 56] + 。

[0162] Step 3: Hydrogen chloride - dioxane (10 mL) was added to compound 12C (700 mg, 1.8 mmol), and the mixture was reacted at room temperature for 1 hour. After concentration, the crude product (12D) (400 mg, yield 72%) was obtained.

[0163] LCMS m / z = 288.1 [M + 1] + 。

[0164] Step 4: Dissolve Compound 12D (0.1 g, 0.31 mmol) and Intermediate 1E (89 mg, 0.31 mmol) in 1,4-dioxane (10 mL), add N,N-diisopropylethylamine (120 mg, 0.93 mmol), reflux and stir, react overnight, concentrate, and then separate and purify directly by liquid-phase preparative column (liquid-phase preparative conditions: C18 reverse-phase preparative column, the mobile phase is deionized water (A) containing 0.1% aqueous ammonia and acetonitrile (B), gradient elution, B content = 5% - 50%, elution time 15 min, flow rate 12 mL / min, column temperature: 30 °C), to obtain the title compound 12 (50 mg, yield 29%, retention time is about 9.0 min).

[0165] 1 H NMR (400MHz,DMSO-d 6 ) δ7.79 (d,2H),7.50 (d,2H),7.30 (s,1H),4.91-4.72 (m,3H),3.72 (d,2H),3.47-3.36 (m,1H),3.27-3.17 (m,1H),3.02-2.80 (m,5H),2.44-2.26 (m,2H),2.22-2.09 (m,2H),1.87-1.69 (m,4H),1.60-1.47 (m,2H).

[0166] MS M / Z(ESI):m / z=539.1[M+1] + 。

[0167] Example 11

Chemical Structure

[0168] Step 1: p-Chloroiodobenzene (5.82 g, 24.41 mmol) and anhydrous tetrahydrofuran (50 mL) were added to a 250 mL three-necked flask, replaced with nitrogen gas, n-butyllithium (39 mmol, 11.5 mL) was added dropwise at -78 °C, reacted at -78 °C for 2 h, and then a tetrahydrofuran solution (20 mL) of 12A (5 g, 22.19 mmol) was added dropwise, maintained at -78 °C and reacted for 1 h. Water (100 mL) and ethyl acetate were added for extraction (50 mL × 2), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and then separated and purified by silica gel column chromatography (eluent EA / PE = 0 - 35%) to obtain the target compound 13B (4 g, 53.36%).

[0169] LC-MS (ESI): m / z=338.1[M+H] + 。

[0170] Step 2: 13B (4 g, 11.84 mmol) was added to a mixed system of dichloromethane (45 mL) and trifluoroacetic acid (15 mL), and reacted at room temperature for 3 h. The reaction solution was directly concentrated under reduced pressure and then put into the reaction of the next step.

[0171] LC-MS (ESI): m / z=220.1[M+H] + 。

[0172] Step 3: 13C (4 g, 11.99 mmol), methanol (50 mL) and 10% palladium on carbon (0.8 g) were added to a 100 mL single-necked flask, and reacted at room temperature for 1 h while replacing with hydrogen gas. After filtration and concentration of the filtrate under reduced pressure, it was separated and purified by HPLC to obtain the target compound 13D (1.5 g, 37.26%).

[0173] LC-MS (ESI): m / z=222.1[M+H] + 。

[0174] Separation method by preparative HPLC: 1. Instrument: Waters 2767 preparative liquid phase, chromatographic column: SunFire@Prep C18 (19 mm×250 mm). 2. The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution. 3. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% acetic acid). b. Gradient elution, the content of mobile phase A is 5% - 40%. c. Flow rate is 12 mL / min. d. Elution time is 20 min.

[0175] Step 4: To a 50 mL single-necked flask, compound 1E (0.15 g, 0.52 mmol), 13D (0.21 g, 0.63 mmol), dioxane (5 mL) and DIPEA (0.27 g, 2.05 mmol) were sequentially added, and the reaction was carried out at 100 °C for 5 h. After cooling the temperature to room temperature, the reaction solution was directly concentrated under reduced pressure and then separated and purified by silica gel column chromatography (eluent MeOH / DCM = 0 - 10%) to obtain 220 mg of the mixture.

[0176] The title compound 13 (0.14 g, 56%, retention time: 0.787 min) and the title compound 14 (20 mg, 8%, retention time: 0.995 min) were obtained by chiral preparative separation. Chiral preparative separation method: Instrument: Waters 150MGM, chromatographic column: Chiralpak Column, mobile phases: A: carbon dioxide and B: methanol (0.1% aqueous ammonia), isocratic elution: 30% mobile phase B, flow rate: 120 mL / min, back pressure: 100 bar, column temperature: 25 °C, wavelength: 220 nm, elution time: 5.5 min.

[0177] Compound 13 11H NMR (400 MHz, DMSO-d6) δ 7.34 - 7.25 (m, 4H), 7.22 (s, 1H), 4.83 (t, 1H), 3.73 (d, 2H), 3.66 - 3.62 (m, 2H), 3.52 - 3.50 (m, 2H), 3.45 - 3.33 (m, 1H), 3.25 - 3.08 (m, 2H), 2.97 - 2.74 (m, 4H), 2.44 - 2.23 (m, 4H), 2.17 - 2.13 (m, 2H), 1.84 - 1.67 (m, 2H), 1.45 - 1.38 (m, 2H).

[0178] LC-MS (ESI): m / z = 473.2 [M + H] + 。

[0179] Compound 14 1 1H NMR (400 MHz, DMSO-d6) δ 7.35 - 7.28 (m, 4H), 7.22 (s, 1H), 4.84 (t, 1H), 3.84 - 3.80 (m, 2H), 3.74 (d, 2H), 3.45 - 3.33 (m, 3H), 3.24 - 3.17 (m, 2H), 2.95 - 2.82 (m, 4H), 2.42 - 2.30 (m, 2H), 2.18 - 2.13 (m, 2H), 1.94 - 1.72 (m, 6H).

[0180] LC-MS (ESI): m / z = 473.2 [M + H] + 。

[0181] Example 12

Chemical Structure

[0182] Step 1: Dissolve compound 15A (5 g, 45 mmol) in 200 mL of dichloromethane, add triethylamine (17 mL, 122 mmol) and di-tert-butyl dicarbonate (11.5 mL, 50 mmol), react at room temperature for 5 h. After the raw materials disappeared, add saturated ammonium chloride aqueous solution to quench, extract three times with 200 mL of dichloromethane, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain compound 15B (8 g, 95%).

[0183] LCMS m / z = 127.2[M - 55] + 。

[0184] Step 2: Under a nitrogen gas atmosphere, dissolve compound 15C (15 g, 53.2 mmol) in 200 mL of tetrahydrofuran, cool the system to 0 °C, and slowly add borane tetrahydrofuran solution (133 mL, 1 M in THF). After warming to room temperature, heat to reflux for 3 h, cool to 0 °C, add 1 N hydrochloric acid to quench the reaction. After concentrating the system, add 200 mL of ethyl acetate to extract three times, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain 15 g of crude compound 15D, which was directly used in the next step of the reaction.

[0185] 1 H NMR (400MHz,CDCl 3 ) δ 7.82 - 7.81 (m,1H),7.41 - 7.33 (m,2H),4.64 (s,2H),1.92 (s,1H).

[0186] Step 3: Triphenylphosphine (22 g, 83.8 mmol) was dissolved in 250 mL of dichloromethane, and the system was cooled to 0 °C. Bromine (4.5 mL, 83.5 mmol) was slowly added. After stirring for 10 min, imidazole (7.6 g, 111 mmol) and 15 g of the crude product of Compound 15D were added. The temperature was raised to room temperature and the reaction was carried out for 3 h. Sodium thiosulfate was added to quench the reaction, and then it was extracted with 200 mL of dichloromethane, dried over anhydrous sodium sulfate, and the organic phase was concentrated and separated by column chromatography to obtain Compound 15E (12 g, 68%).

[0187] 1 H NMR (400MHz,CDCl 3 ) δ 7.86-7.84 (m,1H),7.42-7.29 (m,2H),4.55 (s,2H).

[0188] Step 4: Under a nitrogen gas atmosphere, Compound 15B (2 g, 11 mmol) was dissolved in 100 mL of tetrahydrofuran, cooled to -40 °C, and sodium bis(trimethylsilyl)amide (11 mL, 2 M in THF) was added and stirred for 30 min. Compound 15E (3.6 g, 10.8 mmol) was dissolved in a small amount of tetrahydrofuran and then added to the system. The reaction was carried out at -40 °C for 2 h. After the reaction was complete, saturated aqueous ammonium chloride solution was added to quench the reaction, the temperature was raised to room temperature, 100 mL of ethyl acetate was added and extracted 3 times, dried over anhydrous sodium sulfate, and the organic phase was concentrated and separated by column chromatography to obtain Compound 15F (2 g, 41%).

[0189] LCMS m / z=376.9[M-55] + .

[0190] Step 5: Under nitrogen gas, dissolve compound 15F (1.9 g, 4.4 mmol) in 20 mL of tetrahydrofuran, cool the system to -78 °C, slowly add n-butyllithium (9.5 mL, 2.5 M), maintain the temperature at -78 °C and react for 15 min. After the raw material disappeared, add saturated aqueous ammonium chloride solution to quench the reaction, add 50 mL of ethyl acetate and extract three times, dry over anhydrous sodium sulfate, concentrate the organic phase, and separate by column chromatography to obtain compound 15G (800 mg, 59%).

[0191] LCMS m / z=252.0[M-55] + 。

[0192] Step 6: Under a nitrogen gas atmosphere, dissolve compound 15G (400 mg, 1.3 mmol) in 20 mL of dichloromethane, add boron trifluoride ethyl etherate (1.5 mL, 11.4 mmol) and triethylsilane (3 mL, 23 mmol), heat the temperature to 45 °C and react for 10 h. After the raw material disappeared, cool the reaction system to room temperature, pour it into saturated aqueous sodium bicarbonate solution, add 50 mL of dichloromethane for extraction, dry over anhydrous sodium sulfate, and then concentrate the organic phase to obtain 280 mg of the crude product of compound 15H, which was directly charged into the reaction of the next step.

[0193] LCMS m / z=194.1[M+H] + 。

[0194] Step 7: Under a nitrogen gas atmosphere, dissolve 280 mg of the crude product of compound 15H, compound 1E (150 mg, 0.52 mmol) and DIPEA (0.86 mL, 5.2 mmol) in 30 mL of 1,4-dioxane, heat the temperature to 100 °C and react for 18 h. After concentrating the reaction system, separate by thin layer chromatography to obtain compound 15 (71 mg, 31%).

[0195] LCMS m / z=445.1[M+H] + 。

[0196] 11H NMR (400 MHz, DMSO-d6) δ 7.33 - 7.17 (m, 4H), 4.85 - 4.81 (m, 1H), 3.95 (s, 4H), 3.74 - 3.61 (m, 2H), 3.44 - 3.34 (m, 1H), 3.26 - 3.10 (m, 5H), 2.97 - 2.81 (m, 2H), 2.40 - 2.25 (m, 2H), 2.16 - 2.06 (m, 2H), 1.83 - 1.63 (m, 2H).

[0197] Example 13

Chemical Structure

[0198] Step 1: 4C (0.5 g, 1.53 mmol) and dichloromethane (10 mL) were added to a 50 mL single-necked flask and dissolved. Triethylsilane (0.53 g, 4.59 mmol) was added, and boron trifluoride ethyl etherate (0.43 g, 3.06 mmol) was added dropwise in an ice bath, followed by stirring overnight at room temperature. The reaction solution was washed with saturated sodium bicarbonate solution (20 mL), extracted with dichloromethane (2 × 20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 16A (0.35 g, crude product).

[0199] LC-MS (ESI): m / z = 210.1 [M + H] + .

[0200] Step 2: 1E (0.40 g, 1.39 mmol) and dioxane (10 mL) were added to a 50 mL single-necked flask and dissolved. 16A (0.35 g, 1.67 mmol) and diisopropylethylamine (0.54 g, 4.18 mmol) were added, and the reaction was carried out overnight at 100 °C. The reaction solution was concentrated and separated by column chromatography (dichloromethane:methanol = 20:1 - 10:1) to obtain 0.2 g of a crude product, and the title compound 16 (40 mg, 6%) and the title compound 17 (35 mg, 5%) were obtained by chiral preparative separation.

[0201] Chiral separation method: Instrument: Waters 150MGM, Chromatographic column: Chiralpak Column, Mobile phase: A: carbon dioxide and B: isopropyl alcohol (0.1% aqueous ammonia), Isocratic elution: 25% mobile phase B, Flow rate: 100 mL / min, Back pressure: 100 bar, Column temperature: 25 °C, Wavelength: 220 nm, Elution time: 2.8 min.

[0202] Compound 16, retention time 2.16 min, 1 H NMR (400 MHz, DMSO-d6) δ 7.29 (d, 2H), 7.22 (d, 2H), 7.16 (s, 1H), 4.85 - 4.74 (m, 1H), 4.09 - 3.87 (m, 2H), 3.73 - 3.61 (m, 3H), 3.45 - 3.36 (m, 2H), 3.26 - 3.19 (m, 1H), 3.00~2.77 (m, 2H), 2.71 - 2.62 (m, 1H), 2.42 - 2.34 (m, 2H), 2.15 - 2.10 (m, 2H), 1.98 - 1.91 (m, 2H), 1.75 - 1.60 (m, 6H).

[0203] Compound 17, retention time 2.47 min, 1 H NMR (400 MHz, DMSO-d6) δ 7.32 - 7.27 (m, 2H), 7.25 - 7.13 (m, 3H), 4.86 - 4.76 (m, 1H), 4.06 - 3.96 (m, 1H), 3.83 - 3.64 (m, 4H), 3.58 - 3.55 (m, 1H), 3.50 - 3.36 (m, 1H), 3.26 - 3.18 (m, 1H), 2.98 - 2.80 (m, 2H), 2.69 - 2.66 (m, 1H), 2.42 - 2.32 (m, 2H), 2.21 - 2.06 (m, 2H), 1.98 - 1.95 (m, 2H), 1.89 - 1.53 (m, 6H).

[0204] LC-MS (ESI): m / z = 461.2 [M + H] + .

[0205] Example 14

Chemical formula

[0206] Step 1: p-Chloroiodobenzene (2.5 g, 10.42 mmol) and anhydrous tetrahydrofuran (20 mL) were added to a 100 mL three-necked flask, replaced with nitrogen gas, and n-butyllithium (12 mmol, 4.8 mL) was added dropwise at -78 °C, followed by reaction at -78 °C for 2 h. Further, a tetrahydrofuran solution (10 mL) of 18A (2 g, 9.5 mmol) was added dropwise, and the reaction was carried out while maintaining the temperature at -78 °C for 1 h. Water (100 mL) and ethyl acetate were added for extraction (50 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated and purified by silica gel column chromatography (eluent EA / PE = 0 - 35%) to obtain the target compound 18B (2.4 g, 78%).

[0207] LC-MS (ESI): m / z = 324.1 [M + H] + 。

[0208] Step 2: 18B (2 g, 6.18 mmol), dichloroethane (30 mL), triethylsilane (3.59 g, 30.9 mmol), and boron trifluoride ethyl etherate (4.4 g, 3.81 mmol) were sequentially added to a 100 ml single-necked flask. The reaction was carried out at 80 °C for 3 h. After the temperature was lowered to room temperature, the reaction solution was directly concentrated under reduced pressure and then purified by a C18 reverse-phase column. Regarding the composition of mobile phases A and B: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% TFA), and separation and purification were carried out at (A / B = 30% / 70%) to obtain the title compound 18C (450 mg, 22%).

[0209] LC-MS (ESI): m / z = 208.1 [M + H] + 。

[0210] Step 3: 1E (0.15 g, 0.52 mmol), 18C (0.14 g, 0.68 mmol), dioxane (5 mL) and DIPEA (0.27 g, 2.05 mmol) were sequentially added to a 50 mL single-necked flask and reacted at 100 °C for 5 h. After cooling the temperature to room temperature, the reaction solution was directly concentrated under reduced pressure and then separated and purified by silica gel column chromatography (eluent MeOH / DCM = 0 - 10%) to obtain 220 mg of a mixture.

[0211] The title compound 18 (80 mg, 33%, retention time: 1.253 min) and the title compound 19 (78 mg, 32%, retention time: 1.392 min) were obtained by chiral separation. Chiral separation method: Instrument: Waters 150MGM, chromatographic column: Chiralpak Column, mobile phase: A: carbon dioxide and B: methanol (0.1% aqueous ammonia), isocratic elution: 30% mobile phase B, flow rate: 100 mL / min, back pressure: 100 bar, column temperature: 25 °C, wavelength: 220 nm, elution time: 2.7 min.

[0212] Compound 18: 1 H NMR (400 MHz, DMSO-d6) δ 7.37 - 7.31 (m, 2H), 7.21 (d, 1H), 7.15 (d, 1H), 7.09 (d, 1H), 4.89 - 4.78 (m, 1H), 4.65 (d, 1H), 3.79 - 3.69 (m, 1H), 3.65 - 3.57 (m, 1H), 3.52 - 3.44 (m, 1H), 3.43 - 3.33 (m, 1H), 3.27 - 3.03 (m, 3H), 3.01 - 2.68 (m, 3H), 2.46 - 2.22 (m, 2H), 2.21 - 2.09 (m, 2H), 2.04 - 1.93 (m, 1H), 1.91 - 1.58 (m, 5H).

[0213] LC-MS (ESI): m / z = 459.2 [M + H] + 。

[0214] Compound 19: 11H NMR (400 MHz, DMSO-d6) δ 7.35 - 7.25 (m, 3H), 7.15 - 7.11 (m, 2H), 4.84 (d, 1H), 4.66 (d, 1H), 3.78 - 3.71 (m, 1H), 3.66 - 3.57 (m, 1H), 3.48 - 3.42 (m, 2H), 3.24 - 3.19 (m, 1H), 3.18 - 3.04 (m, 2H), 3.00 - 2.69 (m, 3H), 2.45 - 2.32 (m, 1H), 2.30 - 2.11 (m, 3H), 2.05 - 1.93 (m, 1H), 1.92 - 1.83 (m, 2H), 1.81 - 1.59 (m, 3H).

[0215] LC-MS (ESI): m / z = 459.2 [M+H] + .

[0216] Example 15 [Chemical formula]

[0217] Step 1: At room temperature, under the protection of nitrogen gas, ethyl diazoacetate (2.50 g, 21.40 mmol) was slowly added dropwise to a dichloromethane (200 mL) solution containing 20A (2.00 g, 10.70 mmol, synthesized with reference to the literature: Chemistry - A European Journal, 2019, 25(14), 3521 - 3524) and rhodium acetate (190 mg, 0.4 mmol). After the addition was complete, the mixture was stirred at room temperature overnight. The reaction solution was filtered through diatomaceous earth to obtain a filtrate, which was concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography (eluent: PE:EA = 100:1 to 20:1) to obtain the target compound 20B (1.10 g, yield: 37.67%).

[0218] 1 1H NMR (400 MHz, CDCl 3) δ 7.19 (d, 2H), 6.97 (d, 2H), 4.20 - 4.13 (m, 2H), 3.96 - 3.91 (m, 1H), 3.81 - 3.76 (m, 1H), 2.60 - 2.57 (m, 1H), 2.14 - 2.10 (m, 1H), 2.02 - 1.96 (m, 1H), 1.27 - 1.22 (m, 3H).

[0219] Step 2: Compound 20B (1.00 g, 3.66 mmol) was dissolved in 7N ammonia methanol solution (40 mL), and heated to 80 °C and stirred for 16 h. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography (eluent: PE:EA = 100:1 to 1:1) to obtain the target compound 20C (400 mg, yield: 52.62%).

[0220] LC-MS (ESI): m / z = 208.0 [M+H] + .

[0221] 1 H NMR (400 MHz, CDCl 3 ) δ 7.27 - 7.23 (m, 2H), 6.99 - 6.96 (m, 2H), 5.58 (br s, 1H), 3.67 - 3.63 (m, 1H), 3.55 - 3.49 (m, 1H), 2.23 - 2.20 (m, 1H), 2.13 - 2.09 (m, 2H).

[0222] Step 3: Compound 20C (400 mg, 1.93 mmol) was dissolved in 20 mL of tetrahydrofuran, and lithium aluminum hydride (220 mg, 5.79 mmol) was added little by little at 0 °C, and then the temperature was raised to room temperature and stirred for 16 h. 0.3 mL of water, 0.3 mL of 15% aqueous sodium hydroxide solution and 0.9 mL of water were added, and after stirring for 1 h, suction filtration was carried out to remove the solid. The obtained filtrate was spin-dried to obtain compound 20D (310 mg, 83.10%), which was directly used in the reaction of the next step.

[0223] 1 H NMR (400 MHz, CDCl 3) δ 7.22 - 7.19 (m, 2H), 6.99 - 6.95 (m, 2H), 3.12 (d, 2H), 2.99 (d, 2H), 1.69 - 1.64 (m, 3H).

[0224] Step 4: Dissolve compound 1E (200 mg, 0.70 mmol) and compound 20D (150 mg, 0.78 mmol) in 1,4 - dioxane (8 mL), add DIPEA (270 mg, 2.09 mmol), after the addition is complete, heat the mixture to 100 °C under the protection of nitrogen gas and stir for 16 h. After the reaction is complete, concentrate the reaction solution under reduced pressure to obtain a crude product, and purify the crude product by column chromatography (eluent: DCM:MeOH = 100:1 to 9:1), and then further purify it by prep.HPLC (fractionation method: instrument: waters 2767 preparative liquid phase, chromatographic column: SunFire@Prep C18 (19 mm × 250 mm), dissolve the sample in DMF, filter it through a 0.45 μm filter, prepare the sample solution, and the conditions for preparative chromatography are as follows: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 5 mM aqueous ammonia), b. Gradient elution, the content of mobile phase A is 20% - 85%, c. Flow rate is 15 mL / min. d. Elution time is 15 min, retention time: 6.0 min) to obtain the target compound 20 (120 mg, 38.80%).

[0225] LCMS m / z = 445.1 [M + 1] + .

[0226] 1 H NMR (400 MHz, CDCl 3 ) δ 7.22 (d, 2H), 6.95 (d, 2H), 5.86 (s, 1H), 4.88 (s, 1H), 4.11 - 4.04 (m, 1H), 3.97 - 3.91 (m, 1H), 3.86 (s, 2H), 3.68 - 3.59 (m, 3H), 3.45 - 3.38 (m, 1H), 3.07 - 2.98 (m, 2H), 2.37 - 2.25 (m, 4H), 1.99 - 1.85 (m, 4H), 1.69 - 1.62 (m, 1H).

[0227] Example 16

Chemical formula

[0228] Step 1: Under the protection of nitrogen gas, (1R,5S)-3-benzyl-3-azabicyclo[3.1.1]heptan-6-one (3.00 g, 14.9 mmol) was dissolved in dry tetrahydrofuran (80 mL). After the temperature was lowered to 0 °C, a tetrahydrofuran solution of 4-chlorophenylmagnesium bromide (22.4 mL, 22.4 mmol) was added dropwise. After the addition was complete, the temperature was maintained at 0 °C and the reaction was carried out for about 1 hour. After monitoring the completion of the reaction by TLC, saturated aqueous ammonium chloride solution (80 mL) was added, and after warming to room temperature, the aqueous phase and the organic phase were separated. The aqueous phase was extracted with ethyl acetate (50 mL × 6). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue obtained was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain Compound 21B (3.69 g, 78.8%).

[0229] LC-MS (ESI): m / z = 314.2 [M + H] + 。

[0230] Step 2: Compound 21B (3.00 g, 9.58 mmol) was dissolved in 1,2-dichloroethane (80 mL). Boron trifluoride ethyl ether complex (4.08 g, 28.8 mmol) and triethylsilane (5.57 g, 47.9 mmol) were added at room temperature. After the addition was complete, the temperature was raised to 80 °C and the reaction was continued overnight. After monitoring the completion of the reaction by TLC, the temperature was lowered to room temperature, saturated aqueous sodium hydrogen carbonate solution (80 mL) and water (80 mL) were added, the aqueous phase and the organic phase were separated, the aqueous phase was extracted with ethyl acetate (50 mL × 4), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue obtained was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to obtain Compound 21C (1.38 g, 48.5%).

[0231] LC-MS (ESI): m / z = 298.1 [M+H] + 。

[0232] Step 3: Compound 21C (700 mg, 2.35 mmol) was added to a microwave reaction tube, and dry 1,2-dichloroethane (12 mL) was added and dissolved. Further, chloroformic acid 1-chloroethyl ester (1.68 g, 11.7 mmol) was added. After the addition was completed, it was placed in a microwave reactor and heated to 140 °C and reacted for 100 minutes. After the reaction was completed, the reaction solution was transferred to a round-bottom flask and dried, methanol (30 mL) was added and redissolved, and the reaction was carried out at 70 °C for about 3 hours. The reaction solution was concentrated again and separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1 to 5:1) to obtain Compound 21D (280 mg, 57.4%).

[0233] LC-MS (ESI): m / z = 208.0 [M+H] + 。

[0234] Step 4: 1E (300 mg, 1.04 mmol), Compound 21D (238 mg, 1.15 mmol) and N,N-diisopropylethylamine (673 mg, 5.21 mmol) were dissolved in 1,4-dioxane (15 mL), heated to 100 °C and reacted for about 3 hours. After monitoring the completion of the reaction by TLC, the temperature was lowered to room temperature, concentrated directly, and separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain Compound 21.

[0235] LC-MS (ESI): m / z = 459.2 [M+H] + 。

[0236] Furthermore, compound 21-1 (80.5 mg, 16.8%) and compound 21-2 (87.4 mg, 18.3%) were obtained by chiral separation. Chiral separation method: Instrument: Waters 150MGM, Chromatographic column: Chiralpak Column, Mobile phase: A: carbon dioxide and B: methanol (0.1% aqueous ammonia), Isocratic elution: 35% mobile phase B, Flow rate: 100 mL / min, Back pressure: 100 bar, Column temperature: 25 °C, Wavelength: 220 nm, Elution time: 2.9 min.

[0237] Compound 21-1, retention time 1.78 min, 1 H NMR (400 MHz, Methanol-d4) δ 7.26 (d, 2H), 7.06 (d, 2H), 3.93 (d, 2H), 3.81 (q, 1H), 3.70 - 3.49 (m, 3H), 3.42 - 3.29 (m, 2H), 3.22 - 3.10 (m, 2H), 3.09 - 2.96 (m, 2H), 2.58 (q, 1H), 2.44 - 2.16 (m, 3H), 2.13 - 1.99 (m, 2H), 1.94 - 1.67 (m, 3H); Compound 21-2, retention time 1.94 min, 1 H NMR (400 MHz, Methanol-d4) δ 7.26 (d, 2H), 7.06 (d, 2H), 4.02 - 3.87 (m, 2H), 3.81 (q, 1H), 3.75 - 3.47 (m, 3H), 3.42 - 3.29 (m, 2H), 3.21 - 2.94 (m, 4H), 2.58 (q, 1H), 2.44 - 2.16 (m, 3H), 2.13 - 1.98 (m, 2H), 1.95 - 1.68 (m, 3H).

[0238] Example 17

Chemical formula

[0239] Step 1: Under the protection of nitrogen gas, 22A (2.0 g, 9.29 mmol) was dissolved in dry tetrahydrofuran (80 mL). After the temperature was lowered to 0 °C, a tetrahydrofuran solution of 4-chlorophenylmagnesium bromide (18.6 mL, 18.6 mmol) was added dropwise. After the addition was completed, the temperature was maintained at 0 °C and the reaction was carried out for about 1 hour. After monitoring the completion of the reaction by TLC, saturated aqueous ammonium chloride solution (80 mL) was added, and the temperature was raised to room temperature. Then, the aqueous phase and the organic phase were separated. The aqueous phase was extracted with ethyl acetate (50 mL × 6). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 5:1) to obtain compound 22B (2.89 g, 94.8%).

[0240] LC-MS (ESI): m / z=328.1[M+H] + 。

[0241] Step 2: Compound 22B (710 mg, 2.16 mmol) was dissolved in 1,2-dichloroethane (30 mL). At room temperature, boron trifluoride ethyl ether complex (920 mg, 6.48 mmol) and triethylsilane (1.26 g, 10.8 mmol) were added. After the addition was completed, the temperature was raised to 80 °C and the reaction was continued for 3 hours. After monitoring the completion of the reaction by TLC, the temperature was lowered to room temperature, and saturated aqueous sodium bicarbonate solution (30 mL) and water (30 mL) were added. The aqueous phase and the organic phase were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 10:1) to obtain compound 22C (560 mg, 75.6%).

[0242] LC-MS (ESI): m / z=312.1[M+H] + 。

[0243] Step 3: Compound 22C (560 mg, 1.80 mmol) was added to a microwave reaction tube, and dry 1,2-dichloroethane (12 mL) was added and dissolved. Then chloroethyl chloroformate (1.28 g, 8.98 mmol) was added. After the addition was completed, it was placed in a microwave reactor and heated to 140 °C and reacted for 100 minutes. After the reaction was completed, the reaction solution was transferred to a round-bottom flask and dried, methanol (30 mL) was added and redissolved, and the reaction was carried out at 70 °C for about 3 hours. The reaction solution was concentrated again, separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1 to 5:1) to obtain 22D (340 mg, 85.4%).

[0244] LC-MS (ESI): m / z=222.1[M+H] + 。

[0245] Step 4: 1E (300 mg, 1.04 mmol), compound 22D (255 mg, 1.15 mmol) and N,N-diisopropylethylamine (673 mg, 5.21 mmol) were dissolved in 1,4-dioxane (15 mL), heated to 100 °C and reacted for about 3 hours. After monitoring the end of the reaction by TLC, the temperature was lowered to room temperature, the reaction solution was directly concentrated, and initially separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain 22. Then, it was further purified by preparative HPLC to obtain compound 22 (450 mg, 91.1%).

[0246] Preparative HPLC method: Instrument: Waters 150MGM, chromatographic column: Chiralpak Column, mobile phase: A: carbon dioxide and B: methanol (0.1% aqueous ammonia), isocratic elution: 30% mobile phase B, flow rate: 100 mL / min, back pressure: 100 bar, column temperature: 25 °C, wavelength: 220 nm, elution time: 2.9 min, retention time: 1.81 min.

[0247] 11H NMR (400 MHz, Methanol-d4) δ 7.44 - 7.20 (m, 4H), 4.26 (d, 2H), 3.91 (dd, 2H), 3.52 (dt, 1H), 3.38 - 3.27 (m, 1H, overlapped), 3.20 - 3.07 (m, 3H), 3.07 - 2.97 (m, 2H), 2.85 - 2.76 (m, 2H), 2.38 - 2.21 (m, 4H), 2.03 - 1.83 (m, 4H), 1.74 - 1.61 (m, 2H).

[0248] LC-MS (ESI): m / z = 473.5 [M + H] + 。

[0249] Example 18

Chemical Structure

[0250] Step 1: Under the protection of nitrogen gas, p-chloroiodobenzene (6.19 g, 26.0 mmol) was dissolved in dry tetrahydrofuran (150 mL). After the temperature was lowered to -78 °C, an n-hexane solution of n-butyllithium (10.4 mL, 26.0 mmol) was added dropwise. After the addition was completed, the reaction was continued for about 1 hour. Dry tetrahydrofuran (80 mL) of 23A (4.5 g, 20.0 mmol) was added dropwise again. After the addition was completed, the temperature was raised to -10 °C and stirred for 2 hours. After monitoring the completion of the reaction by TLC, saturated aqueous ammonium chloride solution (200 mL) was added. After the temperature was raised to room temperature, the aqueous phase and the organic phase were separated. The aqueous phase was extracted with ethyl acetate (50 mL × 6). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue obtained was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain compound 23B (5.70 g, 84.4%).

[0251] LC-MS (ESI): m / z = 338.2 [M + H] + 。

[0252] Step 2: Compound 23B (3.00 g, 15.1 mmol) was dissolved in dichloromethane (50 mL), trifluoroacetic acid (10 mL) was added at room temperature, and the reaction was continued for 1 hour after the addition was complete. After monitoring the completion of the reaction by TLC, it was directly concentrated to obtain the trifluoroacetate of 23C, and the crude product was directly introduced into the reaction of the next step without further purification.

[0253] LC-MS (ESI): m / z = 220.1 [M+H] + 。

[0254] Step 3: The crude trifluoroacetate of compound 23C (4.10 g) was added to a round-bottom flask, methanol (80 mL) was added to dissolve it, and further palladium-carbon catalyst (615 mg, 0.580 mmol) was added. After inserting a hydrogen balloon, the reaction was carried out at room temperature for 20 minutes while maintaining the temperature. After monitoring the disappearance of the raw material by TLC, the reaction solution was directly filtered, washed with methanol, and the obtained filtrate was dried under reduced pressure and then directly sent to preparative liquid phase for purification to obtain the trifluoroacetate of compound 23D (312 mg, two-step yield 10.5%).

[0255] Separation and purification method by preparative HPLC: 1. Instrument: waters 2767 preparative liquid phase, chromatographic column: SunFire@Prep C18 (19 mm×250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare the sample solution. 3. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.5% trifluoroacetic acid), b. Gradient elution, the content of mobile phase A is 5% - 50%, c. Flow rate is 12 mL / min, d. Elution time is 10 min.

[0256] LC-MS (ESI): m / z = 222.1 [M+H] + 。

[0257] Step 4: 1E (266 mg, 0.923 mmol), the trifluoroacetate of compound 23D (310 mg, 0.923 mmol) and N,N-diisopropylethylamine (595 mg, 4.62 mmol) were dissolved in 1,4-dioxane (15 mL), heated to 100 °C, and reacted for about 3 hours. After monitoring the completion of the reaction by TLC, it was cooled to room temperature, the reaction solution was directly concentrated, and preliminarily separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1), and after concentration, it was further purified by preparative HPLC to obtain compound 23 (252 mg, 57.7%).

[0258] Preparative HPLC method: Instrument: Waters 150MGM, chromatographic column: Chiralpak Column, mobile phase: A: carbon dioxide and B: methanol (0.1% aqueous ammonia), isocratic elution: 30% mobile phase B, flow rate: 100 mL / min, back pressure: 100 bar, column temperature: 25 °C, wavelength: 220 nm, elution time: 2.9 min, retention time: 1.62 min.

[0259] 1 1H NMR (400 MHz, Methanol-d4) δ 7.23 (q, 4H), 4.81 - 4.76 (m, 1H), 4.75 - 4.68 (m, 1H), 4.01 - 3.87 (m, 2H), 3.66 - 3.53 (m, 1H), 3.44 - 3.33 (m, 1H), 3.16 - 3.02 (m, 2H), 2.57 - 2.43 (m, 3H), 2.43 - 2.23 (m, 4H), 2.13 - 2.00 (m, 2H), 2.01 - 1.84 (m, 2H), 1.79 (d, 2H), 1.75 - 1.61 (m, 2H).

[0260] LC-MS (ESI): m / z = 473.3 [M + H] + 。

[0261] Example 19

Chemical Structure

[0262] Step 1: 1-Bromo-4-chlorobenzene (15.0 g, 78.3 mmol), 1,4-dioxaspiro[4.5]decane (11.8 g, 82.2 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (2.9 g, 4.7 mmol), and tris[di(benzylideneacetone)]dipalladium (2.2 g, 2.4 mmol) were dissolved in 150 mL of dioxane and stirred at room temperature for 15 min. Sodium tert-butoxide (0.75 g, 7.8 mmol) was added. The system was heated to 80 °C and reacted for 2 h. The reaction system was poured into ice water and extracted twice with ethyl acetate. The organic phases were combined, dried, and rotary evaporated to remove the solvent. Purification by silica gel column chromatography using a mobile phase of PE:EA = 20:1 gave the target compound 24B (3.5 g, yield 19%).

[0263] LCMS(ESI): m / z = 254.2 [M+H] + 。

[0264] Step 2: The starting material 24B (3.5 g, 13.8 mmol) was dissolved in 30 mL of tetrahydrofuran, 120 mL of 10% sulfuric acid was added, and the mixture was heated to 90 °C and refluxed for 12 h. After confirming a complete reaction by TLC spot plate, it was cooled to room temperature and the pH was adjusted to neutral with saturated sodium bicarbonate. It was washed three times with 100 mL of ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then rotary evaporated to remove the solvent to obtain 24C (2.2 g, yield 76%), which was directly used in the next step reaction.

[0265] LCMS(ESI): m / z = 210.1 [M+H] + 。

[0266] Step 3: Raw material 24C (2.2 g, 10.5 mmol) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (3.82 g, 12.6 mmol) were dissolved in 25 mL of tetrahydrofuran, DBU (1.92 g, 12.6 mmol) was added, and after stirring at room temperature for 4 h, after monitoring the complete reaction by TLC, it was concentrated and then purified by silica gel column chromatography using a mobile phase system of PE:EA = 50:1 to obtain 24D (3.9 g, yield 75%).

[0267] LCMS(ESI): m / z = 492.1[M+H] + 。

[0268] Step 4: Raw material 24D (3.9 g, 8.0 mmol), bis(pinacolato)diboron (2.42 g, 9.6 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (173 mg, 0.24 mmol), 1,1'-bis(diphenylphosphino)ferrocene (132 mg, 0.24 mmol) were suspended in dioxane (100 mL), reacted and stirred at room temperature for 15 min, potassium acetate (2.4 g, 24.5 mmol) was added, and reacted at 90 °C for 16 h. After monitoring the end of the reaction by TLC and LCMS(ESI), the sample was directly stirred and silica gel column chromatography was carried out using PE:EA = 20:1 as the mobile phase to obtain the title compound 24E (0.9 g, yield 38%).

[0269] LCMS(ESI): m / z = 320.1[M+H] + 。

[0270] Step 5: Compound 24E (900 mg, 2.8 mmol), XphosPd G2 (443 mg, 0.56 mmol), Xphos (538 mg, 1.12 mmol), and potassium phosphate (1.50 g, 7.0 mmol) were suspended in 10 mL of a mixed solvent of dioxane:water = 4:1 and reacted at 90 °C for 4 h. After the reaction was completed, the reaction solution was added dropwise to ice water and filtered. The filtrate was extracted three times with dichloromethane, and the organic phase and the filtration residue were combined and concentrated. Silica gel column chromatography was performed using DCM:MeOH = 15:1 as the mobile phase to obtain the target compound 24 (280 mg, 22%).

[0271] 1 H NMR (400 MHz, DMSO-d6) δ 7.84 - 7.82 (s, 1H), 7.28 - 7.19 (m, 3H), 7.03 - 6.94 (m, 2H), 4.87 - 4.83 (m, 1H), 3.94 - 3.90 (m, 2H), 3.77 - 3.73 (m, 2H), 3.56 (m, 1H), 3.46 - 3.40 (m, 2H), 3.35 - 3.30 (m, 1H), 3.20 - 3.07 (m, 1H), 3.03 - 2.96 (m 1H), 2.68 - 2.64 (s, 2H), 2.44 - 2.18 (m, 4H), 1.88 - 1.72 (m, 2H).

[0272] LCMS(ESI): = 445.1[M + H] + 。

[0273] Example 20

Chem.

[0274] Step 1: Weigh (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (2.12 g, 10 mmol), 2,5-dichloropyrimidine (1.64 g, 11 mmol), tris[di(benzylideneacetone)]dipalladium (915 mg, 1 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (952 mg, 2 mmol) and sodium tert-butoxide (1.15 g, 12 mmol) into a 250 mL three-necked flask, add toluene (50 mL) and tert-butyl alcohol (10 mL), replace with nitrogen gas, react at 100 °C for 2 h, monitor the complete reaction by LCMS, then cool the system to room temperature, filter, wash the filter cake with ethyl acetate (50 mL), concentrate the filtrate and separate by silica gel column chromatography (PE:EA = 10:1~5:1) to obtain the target compound 25A (2.86 g, 88.2%).

[0275] LC-MS (ESI): m / z = 325.1 [M+H] + 。

[0276] Step 2: Dissolve 25A (2.86 g, 0.85 mmol) in methanol (30 mL), add dioxane hydrochloride (5 mL, 4M) solution, react at room temperature for four hours, and spin dry to obtain the title compound 25B (2.01 g, crude product).

[0277] LC-MS (ESI): m / z = 225.1 [M+H] + 。

[0278] Step 3: Dissolve 1E (287 mg, 1 mmol) and 25B (300 mg) in 1,4-dioxane (20 mL), add DIPEA (1 mL), stay overnight at 90 °C, detect the complete reaction of the raw materials by LCMS, concentrate the system, add water (20 mL), extract with a mixed solution of DCM:MeOH = 20:1 (20 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate and pass through a column (DCM:MeOH = 1:0~0:1) to obtain compound 25 (262 mg, 55.1%).

[0279] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.39 (s, 2H), 7.22 (s, 1H), 4.84 - 4.71 (m, 1H), 3.82 - 3.69 (m, 6H), 3.47 - 3.34 (m, 5H), 3.25 - 3.15 (m, 1H), 3.12 - 3.03 (m, 2H), 2.96 - 2.79 (m, 2H), 2.42 - 2.27 (m, 2H), 2.19 - 2.10 (m, 2H), 1.85 - 1.67 (m, 2H).

[0280] LC-MS (ESI): m / z = 476.5 [M + H] + .

[0281] Example 21

Chemical Structure

[0282] Step 1: Compound 8B (0.50 g, 1.75 mmol) was weighed into a 100 mL single-necked flask, then methanol (10 mL) was added and dissolved. A dioxane hydrochloride solution (4N, 10 mL) was added, and after the addition was complete, the mixture was stirred for 2 h. The organic phase was concentrated under reduced pressure until the liquid stopped dropping to obtain the target compound 26A (0.40 g, yield: 100%).

[0283] LCMS m / z = 186.1 [M + 1] + .

[0284] Step 2: Compound 1E (0.20 g, 0.69 mmol), compound 26A (0.15 g, 0.83 mmol) and N,N-dimethylethylamine (0.27 g, 2.07 mmol) were added to a 100 mL single-necked flask. After the addition was complete, the system was protected with nitrogen gas and stirred at 90 °C for 16 h. After the reaction solution was concentrated under reduced pressure, a crude product of the target compound was obtained, and the title compound 26 (170 mg, 56%) was obtained by preparative HPLC.

[0285] Fractionation method: Instrument: Waters 2767 fractionation liquid phase, chromatographic column: SunFire@Prep C18 (19 mm × 250 mm). Dissolve the sample in DMF, filter it through a 0.45 μm filter to prepare the sample solution. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 5 mM aqueous ammonia); b. Gradient elution, the content of mobile phase A is 40% - 80%; c. Flow rate is 15 mL / min; d. Elution time is 20 min, retention time: 11.25 min.

[0286] LCMS m / z = 437.2 [M + 1] + 。

[0287] 1 H NMR (400 MHz, DMSO - d6) δ 7.31 (s, 1H), 7.25 (d, 1H), 7.16 (s, 1H), 7.04 (s, 1H), 6.13 (s, 1H), 4.82 (t, 1H), 4.33 (s, 2H), 3.96 (t, 2H), 3.74 (d, 2H), 3.46 - 3.38 (m, 1H), 3.30 (s, 2H), 3.18 - 3.25 (m, 1H), 3.12 (s, 4H), 2.83 - 2.98 (m, 2H), 2.30 - 2.42 (m, 2H), 2.15 - 2.23 (m, 2H), 1.75 - 1.85 (m, 2H).

[0288] Example 22

Chemical formula

[0289] Step 1: Compound 27A (2.00 g, 10.91 mmol) and compound 27B (3.52 g, 10.91 mmol, for the synthesis method, refer to patent WO2021158829) were weighed into a 100 mL single-neck flask. Then, 1,4-dioxane (15 mL) was added and dissolved. A sodium carbonate solution (2N, 15 mL) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.71 g, 1.09 mmol) were added to the reaction solution. After the addition was completed, the mixture was stirred at 100 °C for 4 h. When the TLC spotting plate (petroleum ether:ethyl acetate = 5:1) showed complete reaction, water (20 mL) was added to the reaction solution, and the mixture was stirred for 5 min. Then, ethyl acetate (20 mL) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure. It was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain the target compound 27C (0.50 g, yield: 15%).

[0290] LCMS m / z = 300.1[M+1] + 。

[0291] Step 2: Compound 27C (0.50 g, 1.67 mmol) was weighed into a 100 mL single-neck flask. Then, methanol (10 mL) was added and dissolved. A dioxane hydrochloride solution (4N, 10 mL) was added. After the addition was completed, the mixture was stirred for 2 h. The organic phase was concentrated under reduced pressure until no liquid dropped to obtain the target compound 27D (0.40 g, yield: 100%).

[0292] LCMS m / z = 200.2[M+1] + 。

[0293] Step 3: Compound 1E (0.20 g, 0.69 mmol), compound 27D (0.17 g, 0.83 mmol), and N,N-dimethylethylamine (0.27 g, 2.07 mmol) were added to a 100 mL single-neck flask. After the addition was completed, the system was protected with nitrogen gas and stirred at 100 °C for 4 h. After the reaction solution was concentrated under reduced pressure, a crude product of the target compound was obtained, and the title compound 27 (12 mg, 3.9%) was obtained by preparative HPLC.

[0294] Fractionation method: Instrument: Waters 2767 Fractionation Liquid Phase, Chromatographic Column: SunFire@Prep C18 (19 mm × 250 mm). Dissolve the sample in DMF, filter it through a 0.45 μm filter to prepare the sample solution. Conditions for fractionation chromatography: a. Composition of mobile phases A and B: Mobile phase A: Acetonitrile, Mobile phase B: Water (containing 5 mM aqueous ammonia); b. Gradient elution, the content of mobile phase A is 40% - 80%; c. Flow rate is 15 mL / min; d. Elution time is 15 min, retention time: 9.0 min.

[0295] LCMS m / z = 451.6 [M + 1] + 。

[0296] 1 1H NMR (400 MHz, DMSO - d6) δ 7.24 (s, 1H), 7.11 (d, 1H), 6.97 - 7.00 (m, 2H), 5.84 (t, 1H), 5.82 (t, 1H), 3.77 - 4.03 (m, 4H), 3.71 (d, 2H), 3.37 - 3.45 (m, 1H), 3.17 - 3.25 (m, 1H), 3.09 (s, 4H), 2.83 - 2.96 (m, 2H), 3.72 (m, 2H), 2.29 - 2.47 (m, 4H), 2.12 - 2.18 (m, 2H), 1.69 - 1.81 (m, 2H).

[0297] Example 23

Chemical Structure

[0298] Step 1: To a 250 mL single-necked flask, add substrate 28A (5.0 g, 20.77 mmol), dioxane (100 mL) and water (20 mL), and dissolve them. Then add sodium carbonate (6.6 g, 62.31 mmol), 1B (7.1 g, 22.85 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (1.5 g, 2.08 mmol), and stir at 100 °C overnight under the protection of nitrogen gas. Dilute the reaction solution with water (50 mL), perform suction filtration with diatomaceous earth, extract the filtrate with ethyl acetate (2 × 100 mL), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and obtain the title compound 28B (5.0 g, 81%) by column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1).

[0299] LC-MS(ESI): m / z = 240.1[M - 56 + H] + 。

[0300] Step 2: To a 50 mL single-necked flask, add substrate 28B (1.0 g, 3.38 mmol), methanol (5 mL) and dioxane hydrochloride (4M, 5 mL), and dissolve them. Stir at room temperature for 3 h, concentrate the reaction solution to obtain the title compound 28C (0.79 g, 100%).

[0301] LC-MS(ESI): m / z = 196.2[M + H] + 。

[0302] Step 3: To a 50 mL single-necked flask, add substrate 1E (0.20 g, 0.69 mmol) and dioxane (10 mL), and dissolve them. Then add 28C (0.21 g, 0.92 mmol) and diisopropylethylamine (0.26 g, 2.05 mmol), react at 90 °C overnight, concentrate the reaction solution, purify by HPLC, and lyophilize to obtain the title compound 28 (130 mg, 42%).

[0303] Fractionation method: Instrument: Waters 2767 Fractionation Liquid Phase, Chromatographic Column: SunFire@Prep C18 (19mm×250mm), Dissolve the sample in DMF, filter with a 0.45μm filter to prepare the sample solution. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: Acetonitrile, Mobile phase B: Water (containing 5mM aqueous ammonia), b. Gradient elution, the content of mobile phase A is 30% - 70%, c. Flow rate is 15mL / min. d. Elution time is 15min, retention time: 8.0min.

[0304] 1 H NMR (400MHz, DMSO-d6) δ 8.89 (s, 2H), 7.34 (s, 1H), 7.31 - 7.26 (m, 1H), 4.83 (t, 1H), 4.46 (s, 2H), 3.97 (t, 2H), 3.75 (d, 2H), 3.45 - 3.41 (m, 1H), 3.24 - 3.21 (m, 1H), 2.98 - 2.83 (m, 2H), 2.65 (s, 2H), 2.43 - 2.28 (m, 2H), 2.25 - 2.14 (m, 2H), 1.90 - 1.73 (m, 2H).

[0305] LC-MS (ESI): m / z = 447.1 [M + H] + 。

[0306] Example 24

Chemical formula

[0307] Step 1: Dissolve compound 29A (7.3g, 40.0mmol) in tetrahydrofuran (100mL), slowly add methylmagnesium chloride solution (20.0mL, 3.0 M in THF, 60.0mmol) under an ice bath. After the addition is complete, slowly warm to room temperature and react for 2h. Add saturated ammonium chloride solution to quench, extract with ethyl acetate (50.0mL×3), dry, filter, and concentrate to obtain compound 29B (8.0g, 100%), and directly carry out the reaction of the next step.

[0308] LC-MS (ESI): m / z = 181.0 [M - OH] + 。

[0309] Step 2: Compound 29B (8.0 g, 40.0 mmol) was dissolved in methanol (100 mL), and p-toluenesulfonic acid (350.0 mg, 2.0 mmol) was further added. After heating to 70 °C and reacting for 2 h, it was cooled to room temperature, concentrated to remove the solvent, and compound 29C (2.6 g, 36%) was obtained by column chromatography (petroleum ether / ethyl acetate = 20 / 1).

[0310] LC-MS (ESI): m / z = 181.0 [M + H] + 。

[0311] Step 3: Compound 29C (1.8 g, 10.0 mmol) was dissolved in glacial acetic acid (3.5 mL), and further aqueous formaldehyde solution (37% in H 2 O, 43.0 mmol) and ammonium chloride (1.1 g, 20.0 mmol) were added. After heating to 100 °C and reacting for 18 h, sodium hydroxide solution was added to adjust to alkaline, extracted with dichloromethane (50 mL × 3), dried, concentrated, and compound 29D (1.9 g, 80%) was obtained and used directly in the next step.

[0312] Step 4: Compound 29D (1.9 g, 8.0 mmol) was dissolved in concentrated hydrochloric acid (30.0 mL), heated to reflux for 3 h to react, then cooled to room temperature, sodium hydroxide solution was added to adjust to alkaline, extracted with ethyl acetate (50 mL × 3), dried, concentrated, and compound 29E (0.6 g, 27%) was obtained by column chromatography (dichloromethane / methanol = 15 / 1).

[0313] LC-MS (ESI): m / z = 222.0 [M + H] + 。

[0314] Step 5: Compound 29E (110.0 mg, 0.5 mmol) was dissolved in 1,4-dioxane (10.0 mL), and compound 1E (140.0 mg, 0.5 mmol) was further added. After heating to 90 °C and reacting for 12 h, it was cooled to room temperature, concentrated, and compound 29 (0.05 g, 21%) was obtained by column chromatography (dichloromethane / methanol = 15 / 1).

[0315] LC-MS (ESI): m / z = 473.1 [M+H] + 。

[0316] 1 1H NMR (400 MHz, DMSO-d6) δ 7.39 (s, 1H), 7.14 (d, 1H), 6.98 - 6.95 (m, 1H), 6.88 (d, 1H), 4.85 - 4.82 (m, 1H), 4.74 (s, 2H), 4.20 (s, 2H), 4.01 - 3.98 (m, 2H), 3.74 (d, 2H), 3.50 - 3.35 (m, 1H), 3.26 - 3.18 (m, 1H), 2.97 - 2.84 (m, 2H), 2.46 - 2.26 (m, 4H), 2.19 (s, 2H), 1.91 - 1.70 (m, 2H).

[0317] Example 25

Chemical formula

[0318] Step 1: Compound 30A (7.2 g, 40.0 mmol) was dissolved in tetrahydrofuran (100 mL), and methylmagnesium chloride solution (20.0 mL, 3.0 M in THF, 60.0 mmol) was slowly added under an ice bath. After the addition was complete, the temperature was slowly raised to room temperature and reacted for 2 h. Saturated ammonium chloride solution was added to quench the reaction, and it was extracted with ethyl acetate (50.0 mL × 3), dried, filtered, and concentrated to obtain compound 30B (8.0 g, 99%), and the reaction of the next step was carried out directly.

[0319] LC-MS (ESI): m / z = 179.0 [M - OH]+ .

[0320] Step 2: Compound 30B (8.0 g, 40.0 mmol) was dissolved in methanol (100 mL), and p-toluenesulfonic acid (350.0 mg, 2.0 mmol) was further added. After heating to 70 °C and reacting for 2 h, it was cooled to room temperature, concentrated to remove the solvent, and compound 30C (5.6 g, 80%) was obtained by column chromatography (petroleum ether / ethyl acetate = 20 / 1).

[0321] LC-MS (ESI): m / z = 179.0 [M+H] + .

[0322] Step 3: Compound 30C (3.6 g, 20.0 mmol) was dissolved in glacial acetic acid (7.0 mL), and aqueous formaldehyde solution (37% in H 2 O, 86.0 mmol) and ammonium chloride (2.2 g, 40.0 mmol) were further added. After heating to 100 °C and reacting for 18 h, sodium hydroxide solution was added to adjust to alkaline, extracted with dichloromethane (50 mL×3), dried, concentrated, and compound 30D (5.0 g, 89%) was obtained and used directly in the next step.

[0323] Step 4: Compound 30D (5.0 g, 21.0 mmol) was dissolved in concentrated hydrochloric acid (50.0 mL), heated to reflux for 3 h to react, then cooled to room temperature, sodium hydroxide solution was added to adjust to alkaline, extracted with ethyl acetate (50 mL×3), dried, concentrated, and compound 30E (1.0 g, 22%) was obtained by column chromatography (dichloromethane / methanol = 15 / 1).

[0324] LC-MS (ESI): m / z = 220.0 [M+H] + .

[0325] Step 5: Compound 30E (110.0 mg, 0.5 mmol) was dissolved in 1,4-dioxane (10.0 mL), and compound 1E (140.0 mg, 0.5 mmol) was further added. After heating to 90 °C and reacting for 12 h, it was cooled to room temperature, concentrated, and compound 30 (0.04 g, 19%) was obtained by column chromatography (dichloromethane / methanol = 15 / 1).

[0326] LC-MS (ESI): m / z = 471.1 [M+H] + 。

[0327] 1 H NMR (400 MHz, DMSO-d6) δ 7.33 (s, 1H), 7.22 (s, 2H), 7.20 - 7.13 (m, 1H), 4.85 - 4.83 (m, 1H), 4.27 (s, 2H), 3.99 (s, 2H), 3.75 (s, 2H), 3.45 - 3.38 (m, 1H), 3.27 - 3.16 (m, 1H), 2.97 - 2.83 (m, 2H), 2.79 - 2.75 (t, 2H), 2.45 - 2.34 (m, 4H), 2.20 (d, 4H), 1.79 (d, 2H).

[0328] Example 26

Chemical Structure

[0329] Step 1: After weighing compound 33A (3.00 g, 19.40 mmol) and compound 1B (7.20 g, 23.28 mmol) into a 100 mL single-neck flask, 1,4-dioxane (15 mL) was added and dissolved. Then, a sodium carbonate solution (2N, 15 mL) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (1.42 g, 1.94 mmol) were added to the reaction solution. After the addition was complete, the mixture was stirred at 100 °C for 4 h. When the TLC spotting plate (petroleum ether:ethyl acetate = 5:1) showed complete reaction, water (20 mL) was added to the reaction solution, and the mixture was stirred for 5 min. Then, ethyl acetate (20 mL) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure and purified by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain the target compound 33B (4.0 g, yield: 68%).

[0330] LCMS m / z = 302.1[M+1] + 。

[0331] 1 H NMR (400 MHz, CDCl 3 ) δ 8.46 (s, 1H), 7.10 (s, 1H), 4.16 (s, 2H), 3.62 (t, 2H), 2.92 - 3.00 (m, 4H), 2.73 (s, 2H), 2.11 - 2.19 (m, 2H), 1.49 (s, 9H).

[0332] Step 2: After weighing compound 33B (1.00 g, 3.32 mmol) into a 100 mL single-neck flask, ethyl acetate (20 mL) was added and dissolved. Then, palladium on carbon (0.18 g, 1.66 mmol) was added to the reaction solution. After the addition was complete, hydrogen gas was stirred under normal pressure conditions for 2 h. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the target compound 33C (0.90 g, yield: 89%).

[0333] LCMS m / z = 304.2[M+1] + 。

[0334] Step 3: Compound 33C (0.90 g, 2.97 mmol) was weighed into a 100 mL single-neck flask, then methanol (10 mL) was added and dissolved, dioxane hydrochloride solution (4N, 10 mL) was added, and after the addition was complete, the mixture was stirred for 2 h. The organic phase was concentrated under reduced pressure to obtain the target compound 33D (0.70 g, crude product).

[0335] LCMS m / z = 204.1 [M+1] + 。

[0336] Step 4: Compound 1E (0.20 g, 0.69 mmol), compound 33D (0.17 g, 0.83 mmol) and N,N-diisopropylethylamine (0.26 g, 2.05 mmol) were added to a 100 mL single-neck flask. After the addition was complete, the system was protected with nitrogen gas and stirred at 90 °C for 16 h. After the reaction solution was concentrated under reduced pressure, a crude product of the target compound was obtained, and the title compound 33 (120 mg, 38%) was obtained by preparative HPLC.

[0337] Preparative method: Instrument: waters 2767 preparative liquid phase, chromatographic column: SunFire@Prep C18 (19 mm × 250 mm, the sample was dissolved in DMF, filtered through a 0.45 μm filter to prepare the sample solution, and the conditions for preparative chromatography were as follows: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 5 mM aqueous ammonia), b. Gradient elution, the content of mobile phase A was 40% - 80%, c. Flow rate was 15 mL / min. d. Elution time was 20 min, retention time: 10.38 min.

[0338] LCMS m / z = 455.2 [M+1] + 。

[0339] 11H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.29 (s, 1H), 4.84 (s, 1H), 4.71 (d, 2H), 3.72 (t, 2H), 3.37 - 3.45 (m, 1H), 3.18 - 3.25 (m, 1H), 2.94 - 3.15 (m, 4H), 2.82 - 2.89 (m, 5H), 2.27 - 2.38 (m, 2H), 2.12 - 2.19 (m, 2H), 2.00~2.11 (m, 2H), 1.86 - 1.93 (m, 2H), 1.61 - 1.80 (m, 4H).

[0340] Example 27 [Chemical Structure]

[0341] Step 1: Substrate 28A (1.1 g, 4.55 mmol), dioxane (20 mL) and water (5 mL) were added to a 100 mL single-necked flask and dissolved. Sodium carbonate (1.5 g, 13.70 mmol), 34B (2.1 g, 4.55 mmol, containing 50% positional isomers, for the synthesis method, refer to Patent WO2021158829), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.33 g, 0.45 mmol) were added. The mixture was stirred at 100 °C overnight under nitrogen gas protection. The reaction solution was diluted with water (50 mL), filtered by suction through diatomaceous earth, and the filtrate was extracted with ethyl acetate (2 × 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the title compound 34C (1.0 g, 71%, containing 50% positional isomers) was obtained by column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1).

[0342] LC-MS (ESI): m / z = 254.3 [M - 56 + H] + .

[0343] Step 2: Substrate 34C (1.0 g, 3.23 mmol), methanol (10 mL), and dioxane hydrochloride (4 M, 10 mL) were added to a 50 mL single-neck flask and dissolved. The mixture was stirred at room temperature for 3 h, and the reaction solution was concentrated to obtain the title compound 34D (0.80 g, 100%, containing 50% positional isomers).

[0344] LC-MS (ESI): m / z = 210.2 [M+H] + 。

[0345] Step 3: Substrate 1E (0.10 g, 0.35 mmol) and dioxane (10 mL) were added to a 50 mL single-neck flask and dissolved. 34D (0.11 g, 0.52 mmol) and diisopropylethylamine (0.14 g, 1.05 mmol) were added, and the reaction was carried out at 90 °C overnight. The reaction solution was concentrated, purified by HPLC, and lyophilized to obtain the title compound 34 (16 mg, 10%).

[0346] Fractionation method: Instrument: Waters 2767 preparative liquid phase, chromatographic column: SunFire@Prep C18 (19 mm × 250 mm). The sample was dissolved in DMF, filtered through a 0.45 μm filter to prepare the sample solution. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 5 mM aqueous ammonia). b. Gradient elution, the content of mobile phase A was 30% - 80%. c. Flow rate was 15 mL / min. d. Elution time was 15 min, retention time: 7.5 min.

[0347] 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 2H), 7.39 (s, 1H), 7.24 (s, 1H), 4.83 (t, 1H), 3.93 - 3.88 (m, 4H), 3.73 - 3.72 (m, 2H), 3.23 - 3.20 (m, 1H), 3.06 - 2.79 (m, 5H), 2.60 (s, 2H), 2.42 - 2.25 (m, 2H), 2.17 (s, 2H), 1.79 (s, 2H).

[0348] LC-MS (ESI): m / z = 461.2 [M+H] + 。

[0349] Example 28

Chemical Structure

[0350] Step 1: Weighed 35A (2.00 g, 8.79 mmol) and 1B (3.26 g, 10.55 mmol) into a 100 mL single-necked flask, added 1,4-dioxane (20 mL) to dissolve, then added sodium carbonate solution (2N, 20 mL) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (0.64 g, 0.88 mmol) to the reaction solution. After the addition was complete, stirred at 100 °C for 4 h. When the TLC spotting plate (petroleum ether:ethyl acetate = 5:1) showed complete reaction, added water (20 mL) to the reaction solution, stirred for 5 min, added ethyl acetate (20 mL) for extraction, separated the organic phase, dried the organic phase over anhydrous sodium sulfate, concentrated the crude product under reduced pressure, and purified it by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain the target compound 35B (2.0 g, yield: 69%).

[0351] LCMS m / z = 330.1 [M+1] + 。

[0352] 1 H NMR (400 MHz, CDCl 3 ) δ 6.93 (s, 1H), 6.91 (s, 1H), 5.81 (s, 1H), 4.06 (d, 2H), 3.62 (t, 2H), 2.38 (s, 2H), 1.49 (s, 9H).

[0353] Step 2: Weighed 35B (0.30 g, 1.02 mmol) into a 100 mL single-necked flask, added methanol (10 mL) to dissolve, then added dioxane hydrochloride solution (4N, 10 mL). After the addition was complete, stirred for 2 h. Concentrated the organic phase under reduced pressure to obtain the target compound 35C (0.20 g, crude product).

[0354] LCMS m / z = 230.1 [M+1] + 。

[0355] Step 3: To a 100 mL single-necked flask were added Compound 1E (0.20 g, 0.69 mmol), Compound 35C (0.19 g, 0.83 mmol), and N,N-diisopropylethylamine (0.26 g, 2.05 mmol). After the addition was completed, the system was protected with nitrogen gas and stirred at 90 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product of the target compound, and the title compound 35 (220 mg, 66%) was obtained by preparative HPLC.

[0356] Preparative method: Instrument: Waters 2767 preparative liquid phase, chromatographic column: SunFire@Prep C18 (19 mm × 250 mm). The sample was dissolved in DMF, filtered through a 0.45 μm filter to prepare a sample solution. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 5 mM aqueous ammonia); b. Gradient elution, the content of mobile phase A was 40% - 80%; c. Flow rate was 15 mL / min; d. Elution time was 20 min, retention time: 11.20 min.

[0357] LCMS m / z = 481.1 [M+1] + 。

[0358] 1 1H NMR (400 MHz, DMSO-d6) δ 7.35 - 7.40 (m, 3H), 6.00 (s, 1H), 4.83 (t, 1H), 4.34 (s, 2H), 3.96 (t, 2H), 3.73 (d, 2H), 3.39 - 3.47 (m, 1H), 3.19 - 3.26 (m, 1H), 2.84 - 2.98 (m, 2H), 2.27 - 2.40 (m, 4H), 2.15 - 2.21 (m, 2H), 1.69 - 1.82 (m, 2H).

[0359] Example 29

Chemical formula

[0360] Step 1: After weighing 36A (2.00 g, 9.39 mmol) into a 100 mL single-neck flask, add tetrahydrofuran (40 mL) to dissolve it. Then add 4-chlorophenylmagnesium chloride (11.27 mL, 11.27 mmol) to the reaction solution. After the addition is complete, stir at room temperature for 4 h. When the TLC spotting plate (petroleum ether:ethyl acetate = 3:1) indicates complete reaction, add water (40 mL) to the reaction solution, stir for 5 min, add ethyl acetate (20 mL) for extraction, separate the organic phase, dry the organic phase over anhydrous sodium sulfate, concentrate the crude product under reduced pressure, and purify it by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain the target compound 36B (2.0 g, yield: 65%).

[0361] LCMS m / z = 326.1[M + 1] + 。

[0362] Step 2: After weighing 36B (0.30 g, 0.97 mmol) into a 100 mL single-neck flask, add methanol (10 mL) to dissolve it. Then add a dioxane hydrochloride solution (4N, 10 mL). After the addition is complete, stir for 2 h. Concentrate the organic phase under reduced pressure until no more liquid drips to obtain the target compound 36C (0.20 g, crude product).

[0363] LCMS m / z = 208.1[M + 1] + 。

[0364] Step 3: Add compound 1E (0.20 g, 0.69 mmol), compound 36C (0.17 g, 0.83 mmol), and N,N - diisopropylethylamine (0.26 g, 2.05 mmol) to a 100 mL single-neck flask. After the addition is complete, protect the system with nitrogen gas and stir at 90 °C for 16 h. Concentrate the reaction solution under reduced pressure and purify it by preparative HPLC to obtain the title compound 36 (88 mg, 27%).

[0365] Fractionation method: Instrument: Waters 2767 preparative liquid phase, chromatographic column: SunFire@Prep C18 (19mm×250mm). Dissolve the sample in DMF, filter it through a 0.45μm filter to prepare the sample solution. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 5mM ammonium acetate). b. Gradient elution, the content of mobile phase A is 30% - 90%. c. Flow rate is 15mL / min. d. Elution time is 20min, retention time: 12.82min.

[0366] LCMS m / z = 459.2 [M+1] + 。

[0367] 1 H NMR (400MHz, DMSO-d6) δ7.40 (d, 2H), 7.32 (s, 1H), 7.24 (d, 2H), 4.84 (t, 1H), 4.20 (s, 2H), 3.94 (t, 2H), 3.73 (d, 2H), 3.39 - 3.47 (m, 1H), 3.19 - 3.27 (m, 1H), 2.84 - 2.99 (m, 2H), 2.29 - 2.42 (m, 4H), 2.14 - 2.19 (m, 2H), 1.73 - 1.84 (m, 2H), 1.63 (s, 3H).

[0368] Example 30

Chemical formula

[0369] Step 1: Dissolve compound 37A (1.4 g, 5.0 mmol) in 1,4-dioxane (30 mL), and further add 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (360.0 mg, 0.5 mmol), potassium carbonate (1.4 g, 10.0 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (1.8 g, 6.0 mmol) and water (6.0 mL). Aspirate and ventilate with nitrogen gas three times, heat to 45 °C and react for 14 h. Then, pass through a silica gel plug, wash with ethyl acetate, concentrate, and obtain compound 37B (1.7 g, 99%) by column chromatography (dichloromethane / methanol = 20 / 1).

[0370] LC-MS (ESI): m / z=284.1[M-56] + 。

[0371] Step 2: Dissolve compound 37B (340.0 mg, 1.0 mmol) in tetrahydrofuran (10 mL), and further add bis(triphenylphosphine)palladium dichloride (70.0 mg, 0.1 mmol), triethylamine (202.0 mg, 2.0 mmol), trimethylsilylacetylene (130.0 mg, 1.3 mmol) and cuprous iodide (8.0 mg, 0.05 mmol). Aspirate and ventilate with nitrogen gas three times, heat to 50 °C and react for 14 h. Then, pass through a silica gel plug, wash with ethyl acetate, concentrate, and obtain compound 37C (240.0 mg, 72%) by column chromatography (dichloromethane / methanol = 20 / 1).

[0372] LC-MS (ESI): m / z=302.1[M-56] + 。

[0373] Step 3: Dissolve compound 37C (240.0 mg, 0.67 mmol) in dichloromethane (10 mL), and further add trifluoroacetic acid (1.0 mL). React at room temperature for half an hour, then concentrate to obtain compound 37D (150.0 mg, 87%), which was directly used in the next step.

[0374] LC-MS (ESI): m / z = 258.1 [M+H] + 。

[0375] Step 4: Compound 37D (150.0 mg, 0.58 mmol) was dissolved in methanol (10.0 mL), and potassium carbonate (150.0 mg, 1.1 mmol) was further added. After reacting at room temperature for 2 h, it was concentrated, and compound 37E (70.0 mg, 65%) was obtained by column chromatography (dichloromethane / methanol = 15 / 1).

[0376] LC-MS (ESI): m / z = 186.1 [M+H] + 。

[0377] Step 5: Compound 37E (70.0 mg, 0.38 mmol) was dissolved in 1,4-dioxane (10.0 mL), and compound 1E (115.0 mg, 0.4 mmol) was further added. After heating to 90 °C and reacting for 12 h, it was cooled to room temperature, concentrated, and compound 37 (20.0 mg, 12%) was obtained by column chromatography (dichloromethane / methanol = 10 / 1).

[0378] LC-MS (ESI): m / z = 437.1 [M+H] + 。

[0379] 1 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 7.36 (s, 1H), 7.34 (s, 1H), 4.84 (t, 1H), 4.68 (s, 1H), 4.48 (s, 2H), 3.97 (t, 2H), 3.75 (d, 2H), 3.51 - 3.36 (m, 1H), 3.28 - 3.18 (m, 1H), 2.98 - 2.84 (m, 2H), 2.66 (s, 2H), 2.43 - 2.30 (m, 2H), 2.24 - 2.17 (m, 2H), 1.86 - 1.71 (m, 2H).

[0380] Example 31

Chemical Structure

[0381] Step 1: Under the protection of nitrogen gas, 38A (2.50 g, 21.5 mmol) was dissolved in dry tetrahydrofuran (80 mL). After the temperature was lowered to 0 °C, a tetrahydrofuran solution of 4-chlorophenylmagnesium bromide (32.3 mL, 32.3 mmol) was added dropwise. After the addition was complete, the temperature was maintained at 0 °C and the reaction was carried out for about 1 hour. After monitoring the completion of the reaction by TLC, saturated aqueous ammonium chloride solution (100 mL) was added, and after warming to room temperature, the aqueous phase and the organic phase were separated. The aqueous phase was extracted with ethyl acetate (50 mL × 5), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue obtained was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain compound 38B (4.51 g, 91.7%).

[0382] LC-MS (ESI): m / z = 229.1 [M+H] + 。

[0383] Step 2: Compound 38B (4.00 g, 17.5 mmol) was dissolved in 1,2-dichloroethane (200 mL). Triethylsilane (10.2 g, 87.4 mmol) and trifluoroacetic acid (5.98 g, 52.5 mmol) were sequentially added at room temperature. After the addition was complete, the reaction was continued at room temperature overnight. After monitoring the completion of the reaction by TLC, saturated aqueous sodium hydrogen carbonate solution (80 mL) and water (80 mL) were added, and the aqueous phase and the organic phase were separated. The aqueous phase was extracted with ethyl acetate (50 mL × 4), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue obtained was preliminarily separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to obtain the crude product of compound 38C. Further purification by preparative HPLC gave compound 38C (950 mg, 25.5%).

[0384] Separation and purification method by preparative HPLC: 1. Instrument: Waters 2767 preparative liquid phase, chromatographic column: SunFire@Prep C18 (19mm×250mm). 2. The sample was filtered through a 0.45μm filter to prepare the sample solution. 3. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% ammonium acetate), b. Gradient elution, the content of mobile phase A is 5% - 50%, c. Flow rate is 12mL / min, d. Elution time is 30min. Compound 38C, retention time 17.2min.

[0385] 1 H NMR (400MHz, Chloroform-d) δ 7.27 (d, 2H), 7.12 (d, 2H), 2.83 (ddd, 2H), 2.75 - 2.65 (m, 2H), 2.50 (tt, 1H), 2.11 (dq, 2H), 1.82 (qd, 2H).

[0386] Step 3: Compound 38C (600mg, 2.82mmol) and ammonium carbamate (418mg, 5.36mmol) were added to methanol (15mL), and after stirring uniformly, iodosobenzene diacetate (2.27g, 7.05mmol) was added. After the addition was completed, the reaction was carried out at room temperature overnight in an air environment. After the reaction was completed, saturated aqueous ammonium chloride solution (50mL) was added, the aqueous phase was extracted with ethyl acetate (30mL×6), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v)=1:2) to obtain compound 38D (250mg, 36.4%) and 38E (240mg, 34.9%).

[0387] LC-MS (ESI): m / z = 244.1[M + H] + 。

[0388] Step 4: Under the protection of nitrogen gas, compound 38D (150 mg, 0.615 mmol), (R)-2-chloro-4-(1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-5-oxide (230 mg, 0.800 mmol), palladium acetate (27.6 mg, 0.123 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (153 mg, 0.246 mmol) and potassium phosphate (327 mg, 1.54 mmol) were dissolved in toluene (10 mL), heated to 110 °C and reacted for about 5 hours. After monitoring the completion of the reaction by TLC, the temperature was lowered to room temperature and directly concentrated, and preliminarily separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v)=10:1), and further purified by preparative HPLC to obtain compound 38-1 (95 mg, 31.2%).

[0389] Separation and purification method by preparative HPLC: 1. Instrument: waters 2767 preparative liquid phase, chromatographic column: SunFire@Prep C18 (19 mm×250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare the sample solution. 3. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: methanol, Mobile phase B: water (containing 0.1% ammonium acetate), b. Gradient elution, the content of mobile phase A is 5% - 50%, c. Flow rate is 12 mL / min, d. Elution time is 30 min.

[0390] Compound 38-1, retention time 20.2 min, 1 1H NMR (400 MHz, DMSO-d6) δ 7.42 - 7.32 (m, 3H), 7.29 - 7.21 (m, 2H), 4.88 (t, 1H), 4.00~3.87 (m, 2H), 3.77 - 3.63 (m, 2H), 3.58 - 3.39 (m, 3H), 3.30 - 3.22 (m, 1H), 3.12 - 2.83 (m, 3H), 2.40 - 2.17 (m, 4H), 2.16 - 2.00 (m, 4H), 1.87 - 1.67 (m, 2H).

[0391] LC-MS (ESI): m / z = 495.1 [M+H] + 、 Referring to the above synthesis method, using compound 38E (150 mg, 0.615 mmol) as the raw material, compound 38-2 (107 mg, 35.1%) was synthesized.

[0392] Compound 38-2, retention time 16.3 min, 1 H NMR (400 MHz, DMSO-d6) δ 7.45 - 7.36 (m, 2H), 7.36 - 7.26 (m, 3H), 4.90 (t, 1H), 3.89 - 3.75 (m, 2H), 3.75 - 3.63 (m, 2H), 3.58 - 3.37 (m, 3H), 3.29 - 3.22 (m, 1H), 3.10 - 2.83 (m, 3H), 2.39 - 2.24 (m, 2H), 2.24 - 2.09 (m, 6H), 1.86 - 1.65 (m, 2H).

[0393] LC-MS (ESI): m / z = 495.1 [M+H] + 。

[0394] Example 32

Chemical Structure

[0395] Step 1: Add 18B (500 mg, 1.55 mmol) and dichloromethane (20 mL) to a 100 mL three-necked flask, replace with nitrogen gas, dropwise add bis(2-methoxyethyl)aminosulfur trifluoride (685 mg, 3.1 mmol) at -78 °C, allow to warm naturally to room temperature, and react for 1 h. Add saturated aqueous sodium bicarbonate solution (50 mL) and dichloromethane (50 mL × 2), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and then separate and purify by silica gel column chromatography (eluent EA / PE = 0 - 20%) to obtain the target compound (0.5 g, 99%).

[0396] LC-MS (ESI): m / z = 270.1 [M - 56 + H]+ .

[0397] Step 2: 39A (0.5 g, 1.54 mmol) and hydrogen chloride-dioxane (4 M, 20 mL) were sequentially added to a 50 mL single-neck flask. The reaction was carried out at room temperature for 1 h. The reaction solution was directly concentrated under reduced pressure to obtain the title compound (400 mg, 100%).

[0398] LC-MS (ESI): m / z = 226.1 [M+H] + .

[0399] Step 3: 1E (287 mg, 1 mmol), 39B (261 mg, 1 mmol), dioxane (5 mL) and DIPEA (645 mg, 5 mmol) were sequentially added to a 50 mL single-neck flask, and the reaction was carried out at 100 °C for 8 h. After cooling to room temperature and directly concentrating the reaction solution under reduced pressure, it was separated and purified by silica gel column chromatography (eluent MeOH / DCM = 0~10%) to obtain 400 mg of a mixture.

[0400] The title compound 39-1 (160 mg, 33%, retention time: 1.311 min) and the title compound 39-2 (101 mg, 21%, retention time: 1.501 min) were obtained by chiral preparative separation. Chiral preparative separation method: Instrument: Waters 150MGM, chromatographic column: Chiralpak Column, mobile phase: A: carbon dioxide and B: methanol (0.1% aqueous ammonia), isocratic elution: 30% mobile phase B, flow rate: 100 mL / min, back pressure: 100 bar, column temperature: 25 °C, wavelength: 220 nm, elution time: 2.0 min.

[0401] Compound 39-1: 11H NMR (400 MHz, DMSO-d6) δ 7.49 - 7.41 (m, 2H), 7.38 - 7.25 (m, 2H), 4.91 - 4.79 (m, 2H), 3.80 - 3.69 (m, 1H), 3.66 - 3.53 (m, 1H), 3.47 - 3.31 (m, 2H), 3.30 - 3.05 (m, 3H), 3.02 - 2.93 (m, 1H), 2.88 - 2.77 (m, 2H), 2.49 - 2.14 (m, 6H), 2.08 - 1.89 (m, 2H), 1.86 - 1.52 (m, 2H).

[0402] LC-MS (ESI): m / z = 477.1 [M + H] + .

[0403] Compound 39-2: 1 1H NMR (400 MHz, DMSO-d6) δ 7.48 - 7.46 (m, 1H), 7.38 - 7.32 (m, 2H), 7.20 - 7.17 (m, 1H), 7.07 - 7.04 (m, 1H), 4.84 - 4.71 (m, 1H), 3.81 - 3.71 (m, 1H), 3.61 - 3.09 (m, 5H), 3.08 - 2.65 (m, 4H), 2.49 - 2.11 (m, 6H), 2.05 - 1.90 (m, 2H), 1.88 - 1.70 (m, 1H), 1.71 - 1.45 (m, 1H).

[0404] LC-MS (ESI): m / z = 477.1 [M + H] + .

[0405] Example 33

Chemical Structure

[0406] Step 1: 40A (0.15 g, 0.52 mmol), 13C (0.21 g, 0.62 mmol), dioxane (5 mL) and DIPEA (0.34 g, 2.59 mmol) were sequentially added to a 50 mL single-necked flask and reacted at 100 °C for 5 h. After cooling the temperature to room temperature, the reaction solution was directly concentrated under reduced pressure and then separated and purified by silica gel column chromatography (eluent MeOH / DCM = 0 - 10%) to obtain 220 mg of a mixture.

[0407] The title compound 40-1 (42 mg, 17%, retention time: 0.786 min) and the title compound 40-2 (82 mg, 33%, retention time: 0.993 min) were obtained by chiral separation. Chiral separation method: Instrument: Waters 150MGM, chromatographic column: Chiralpak Column, mobile phase: A: carbon dioxide and B: methanol (0.1% aqueous ammonia), isocratic elution: 30% mobile phase B, flow rate: 120 mL / min, back pressure: 100 bar, column temperature: 25 °C, wavelength: 220 nm, elution time: 5.5 min.

[0408] Compound 40-1: 1 H NMR (400 MHz, DMSO-d6) δ 7.50 - 7.48 (m, 2H), 7.39 - 7.37 (m, 2H), 7.18 (s, 1H), 6.26 (s, 1H), 4.82 (s, 1H), 3.87 (s, 1H), 3.79 - 3.54 (m, 5H), 3.44 - 3.34 (m, 1H), 3.22 - 3.12 (m, 2H), 3.12 - 3.05 (m, 1H), 2.98 - 2.77 (m, 3H), 2.62 (d, 1H), 2.40 - 2.29 (s, 2H), 2.15 (s, 2H), 1.85 - 1.70 (m, 2H).

[0409] LC-MS (ESI): m / z = 471.2 [M+H] + 。

[0410] Compound 40-2: 11H NMR (400 MHz, DMSO-d6) δ 7.50 - 7.48 (m, 2H), 7.39 - 7.37 (m, 2H), 7.18 (s, 1H), 6.26 (s, 1H), 4.82 (s, 1H), 3.90 - 3.83 (m, 1H), 3.79 - 3.54 (m, 5H), 3.46 - 3.32 (m, 1H), 3.24 - 3.13 (m, 2H), 3.12 - 3.05 (m, 1H), 2.97 - 2.78 (m, 3H), 2.65 - 2.58 (m, 1H), 2.43 - 2.28 (m, 2H), 2.14 (s, 2H), 1.85 - 1.68 (m, 2H).

[0411] LC-MS (ESI): m / z = 471.2 [M + H] + 。

[0412] Example 34

Chemical Structure

[0413] Step 1: 18B (0.5 g, 1.55 mmol) and hydrogen chloride - dioxane (4 M, 20 mL) were sequentially added to a 50 mL single-necked flask. The reaction was carried out at room temperature for 1 h. After directly concentrating the reaction solution under reduced pressure, the title compound (400 mg, 100%) was obtained.

[0414] LC-MS (ESI): m / z = 224.1 [M + H] + 。

[0415] Step 2: 1E (287 mg, 1.0 mmol), 41A (233 mg, 1.0 mmol), dioxane (5 mL) and DIPEA (645 mg, 5.0 mmol) were sequentially added to a 50 mL single-necked flask, and the reaction was carried out at 100 °C for 8 h. After cooling the temperature to room temperature and directly concentrating the reaction solution under reduced pressure, it was separated and purified by silica gel column chromatography (eluent MeOH / DCM = 0 - 10%) to obtain 410 mg of a mixture.

[0416] Chiral separation yielded the title compound 41-1 (150 mg, 32%, retention time: 1.302 min) and the title compound 41-2 (100 mg, 21%, retention time: 1.488 min). Chiral separation method: Instrument: Waters 150MGM, chromatographic column: Chiralpak Column, mobile phase: A: carbon dioxide and B: methanol (0.1% aqueous ammonia), isocratic elution: 30% mobile phase B, flow rate: 100 mL / min, back pressure: 100 bar, column temperature: 25 °C, wavelength: 220 nm, elution time: 2.0 min.

[0417] Compound 41-1: 1 H NMR (400 MHz, DMSO-d6) δ 7.53 (d, 2H), 7.42 - 7.33 (m, 2H), 7.20 (s, 1H), 5.43 (d, 1H), 4.87 (s, 1H), 4.55 (d, 1H), 4.12 - 3.97 (m, 1H), 3.90 - 3.62 (m, 2H), 3.46 - 3.38 (m, 1H), 3.30 - 3.16 (m, 2H), 3.01 - 2.81 (m, 2H), 2.79 - 2.67 (m, 1H), 2.46 - 2.07 (m, 5H), 1.87 - 1.54 (m, 5H).

[0418] LC-MS (ESI): m / z = 475.2 [M+H] + 。

[0419] Compound 41-2: 1 H NMR (400 MHz, DMSO-d6) δ 7.55 (d, 2H), 7.43 - 7.38 (m, 2H), 5.60 (d, 2H), 4.71 - 4.48 (m, 1H), 4.05 (d, 1H), 3.99 - 2.93 (m, 8H), 2.84 (d, 1H), 2.44 - 2.13 (m, 5H), 1.91 - 1.67 (m, 5H).

[0420] LC-MS (ESI): m / z = 475.2 [M+H] + 。

[0421] Example 35 [Chemical]

[0422] Step 1: Dissolve compound 42A (1 g, 4.44 mmol) in anhydrous tetrahydrofuran (10 ml), aspirate and ventilate with nitrogen gas three times, cool the reaction system to -78°C, dropwise add lithium bis(trimethylsilyl)amide (8.88 mmol), maintain at -78°C for 30 min, then dropwise add N-phenyltrifluoromethanesulfonimide (2.59 g, 6.66 mmol) dissolved in anhydrous tetrahydrofuran (5 ml), continue to maintain at -78°C for 30 min, then transfer to room temperature and react for 2 h. After the reaction is completed, add saturated ammonium chloride solution (30 ml) to quench, extract the organic phase with ethyl acetate (3×40 ml), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, and perform high-speed separation and purification by column chromatography (ratio of eluent: EA / PE = 0% - 10%) to obtain compound 42B (1.3 g, 82%).

[0423] LCMS (ESI): m / z = 302.2 [M + H - 56].

[0424] Step 2: Add bis(triphenylphosphine)palladium dichloride (260 mg, 0.37 mmol), bis(pinacolato)diboron (1.11 g, 4.37 mmol) and potassium acetate (1.07 g, 10.92 mmol) to compound 42B (1.3 g, 3.64 mmol) dissolved in 1,4-dioxane (20 ml) under nitrogen gas, and react in an oil bath at 90°C for 18 h. After the reaction is completed, cool to room temperature, filter through diatomaceous earth, wash with ethyl acetate, concentrate the filtrate, and perform direct high-speed separation and purification by column chromatography (ratio of eluent: EA / PE = 0% - 10%) to obtain the target compound 42C (0.89 g, 73%).

[0425] LCMS (ESI): m / z = 280.2 [M + H - 56].

[0426] Step 3: To Compound 42C (0.89 g, 2.65 mmol) dissolved in 1,4-dioxane / water (10 mL / 2 mL) under nitrogen gas, 5-chloro-2-iodopyrimidine (578 mg, 2.41 mmol), 1,1-bis(diphenylphosphino)ferrocenedichloropalladium (176 mg, 0.24 mmol) and sodium carbonate (766 mg, 7.32 mmol) were added, and the mixture was reacted in an oil bath at 90 °C for 18 h. After the reaction was completed, it was cooled to room temperature, filtered through diatomaceous earth, washed with ethyl acetate, the filtrate was concentrated, and directly purified by high-speed separation by column chromatography (ratio of eluent: EA / PE = 0% - 10%) to obtain the target compound 42D (0.44 g, 52%).

[0427] LCMS (ESI): m / z = 266.1[M+H-56].

[0428] Step 4: Compound 42D (220 mg, 0.69 mmol) was dissolved in 1,4-dioxane (2 mL) of hydrochloric acid, stirred at room temperature for 1 h, and directly spin-dried to obtain the hydrochloride compound of 42E (170 mg).

[0429] LCMS (ESI): m / z = 222.1[M+H] + .

[0430] Step 5: Intermediate 1E (198 mg, 0.69 mmol) was dissolved in 1,4-dioxane (5 ml), 42E (170 mg, 0.69 mmol) and diisopropylethylamine (267 mg, 2.07 mmol) were added, and the reaction system was placed in an oil bath at 100 °C and reacted for 15 h. After the reaction was completed, it was cooled to room temperature, the reaction was monitored by LCMS, spin-dried, and then sent for preparative separation. The preparative HPLC separation method is as follows. 1. Instrument: Waters 2767 preparative liquid phase, chromatography column: SunFire@Prep C18 (19 mm × 250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare a sample solution. 3. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% ammonium acetate). b. Gradient elution, the content of mobile phase A is 10% - 55%. c. Flow rate is 12 mL / min. Compound 42 (240 mg, 74%) was obtained with a retention time of 7.0 min.

[0431] LCMS (ESI): m / z = 473.2[M + H] + 。

[0432] The resolution of Compound 42 is as follows.

[0433] Compound 42 (240 mg) was taken for resolution. After separation, Compound 42-1 (retention time: 1.257 min, 74 mg, ee% = 100%) and Compound 42-2 (retention time: 1.553 min, 77 mg, ee% = 100%) were obtained.

[0434] The resolution conditions are as follows. Instrument: Waters 150MGM, column: DAICEL CHIRALPAK AD, mobile phase: A for CO2 and B for EtOH (0.1% NH3·H2O)), gradient: B 40%, flow rate: 120 mL / min, back pressure: 100 bar, column temperature: 35 °C, wavelength: 220 nm, cycle: 13 min, Compound 42-1: 1 H NMR (400 MHz, CDCl3 ) δ = 8.61 (s, 2H), 6.85 (s, 1H), 5.91 (s, 1H), 5.11 (s, 1H), 3.99 (d, 1H), 3.84 (s, 2H), 3.78 (s, 1H), 3.70 (d, 1H), 3.64 - 3.51 (m, 1H), 3.39 (d, 1H), 3.30 (d, 1H), 3.24 - 3.12 (m, 1H), 3.11 - 2.91 (m, 3H), 2.85 (d, 1H), 2.45 - 2.12 (m, 4H), 1.91 (d, 2H), 1.67 (s, 1H).

[0435] Compound 42 - 2: 1 H NMR (400 MHz, CDCl 3 ) δ = 8.62 (s, 2H), 6.85 (s, 1H), 5.88 (s, 1H), 5.10 (d, 1H), 4.10 - 3.92 (m, 1H), 3.81 (d, 3H), 3.68 (s, 1H), 3.58 (d, 1H), 3.43 - 3.28 (m, 2H), 3.17 (s, 1H), 3.12 - 2.92 (m, 3H), 2.85 (d, 1H), 2.29 (t, 4H), 1.91 (d, 2H), 1.69 (d, 1H).

[0436] Example 36 [Chemical formula]

[0437] Step 1: After weighing Compound 27A (1.00 g, 5.45 mmol) and Compound 31A (1.16 g, 5.45 mmol) into a 100 mL single-neck flask, 1,4-dioxane (30 mL) was added and dissolved. Sodium tert-butoxide (1.57 g, 16.34 mmol), tris(dibenzylideneacetone)dipalladium (0.15 g, 0.27 mmol), and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.34 g, 0.55 mmol) were added to the reaction solution. After the addition was complete, the mixture was stirred at 90 °C for 16 h. When the TLC spotting plate (petroleum ether:ethyl acetate = 5:1) showed complete reaction, water (20 mL) was added to the reaction solution, and the mixture was stirred for 5 min. Then ethyl acetate (20 mL) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain the target compound 31B (1.0 g, yield: 58%).

[0438] LCMS m / z = 315.1[M+1] + 。

[0439] Step 2: After weighing Compound 31B (0.30 g, 0.95 mmol) into a 100 mL single-neck flask, methanol (10 mL) was added and dissolved. A dioxane hydrochloride solution (4N, 10 mL) was added, and after the addition was complete, the mixture was stirred for 2 h. The organic phase was concentrated under reduced pressure until no liquid dropped to obtain the target compound 31C (0.20 g, crude product).

[0440] LCMS m / z = 215.1[M+1] + 。

[0441] Step 3: Compound 1E (0.20 g, 0.69 mmol), Compound 31C (0.15 g, 0.69 mmol), and N,N-diisopropylethylamine (0.26 g, 2.05 mmol) were added to a 100 mL single-neck flask. After the addition was complete, the system was protected with nitrogen gas and stirred at 90 °C for 16 h. After the reaction solution was concentrated under reduced pressure, a crude product of the target compound was obtained, and the title compound 31 (120 mg, 37%) was obtained by preparative HPLC.

[0442] Fractionation method: Instrument: Waters 2767 fractionation liquid phase, chromatographic column: SunFire@Prep C18 (19 mm × 250 mm). Dissolve the sample in DMF, filter it through a 0.45 μm filter to prepare the sample solution. Conditions for fractionation chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 5 mM aqueous ammonia); b. Gradient elution, the content of mobile phase A is 40% - 80%; c. Flow rate is 15 mL / min; d. Elution time is 20 min, retention time: 10.20 min.

[0443] LCMS m / z = 466.2 [M + 1] + 。

[0444] 1 H NMR (400 MHz, DMSO - d6) δ 7.21 (s, 1H), 6.85 (d, 1H), 6.34 - 6.37 (m, 2H), 4.81 (t, 1H), 3.75 - 3.80 (m, 2H), 3.72 (d, 2H), 3.35 - 3.45 (m, 5H), 2.97 - 3.24 (m, 9H), 2.81 - 2.94 (m, 2H), 2.29 - 2.42 (m, 2H), 2.11 - 2.17 (m, 2H), 1.69 - 1.81 (m, 2H).

[0445] Example 37

Chemical formula

[0446] Step 1: 2,5-Dichloropyrimidine (5.0 g, 33.6 mmol), 1,4-dioxaspiro[4.5]decane (5.3 g, 36.9 mmol), and DIPEA (13.0 g, 100.8 mmol) were dissolved in 100 mL of dioxane. The system was heated to 80 °C and reacted for 2 h. The reaction system was poured into ice water and extracted twice with ethyl acetate. The organic phases were combined, dried, and the solvent was removed by rotary evaporation. Purification by silica gel column chromatography with a mobile phase of PE:EA = 20:1 gave the target compound 32B. (8.5 g, yield 99%).

[0447] LCMS(ESI): m / z = 256.2 [M+H] + 。

[0448] Step 2: The raw material 32B (8.5 g, 33.2 mmol) was dissolved in 30 mL of tetrahydrofuran, 120 mL of 10% sulfuric acid was added, and the mixture was heated to 90 °C and refluxed for 12 h. After confirming a complete reaction by TLC spot plate, it was cooled to room temperature and then the pH was adjusted to neutral with saturated sodium bicarbonate. It was washed with 100 mL × 3 of ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by rotary evaporation. The obtained solid 32C (6.2 g, yield 88%) was directly used in the reaction of the next step.

[0449] LCMS(ESI): m / z = 212.3 [M+H] + 。

[0450] Step 3: The raw material 32C (6.2 g, 29.2 mmol) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (10.6 g, 35.0 mmol) were dissolved in 62 mL of tetrahydrofuran, DBU (5.3 g, 35.0 mmol) was added, and the mixture was stirred at room temperature for 4 h. After monitoring a complete reaction by TLC, it was concentrated and then purified by silica gel column chromatography using a mobile phase system of PE:EA = 50:1 to obtain an oily substance 32D (10.6 g, yield 73%).

[0451] LCMS (ESI): m / z = 494.0 [M+H] + 。

[0452] Step 4: Raw material 32D (6.50 g, 13.2 mmol), bis(pinacolato)diboron (4.02 g, 15.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (190 mg, 0.26 mmol), 1,1'-bis(diphenylphosphino)ferrocene (144 mg, 0.26 mmol) were suspended in dioxane (65 mL), reacted at room temperature for 15 min with stirring, potassium acetate (2.58 g, 26.4 mmol) was added, and the reaction was carried out at 90 °C for 16 h. After monitoring the completion of the reaction by TLC and LCMS, silica gel column chromatography was performed using PE:EA = 20:1 as the mobile phase to obtain the white title compound 32E (3.37 g, yield 79%).

[0453] LCMS (ESI): m / z = 322.4 [M+H] + 。

[0454] Step 5: Compound 32E (500 mg, 1.55 mmol), 1E (405 mg, 1.40 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (22 mg, 0.03 mmol), 1,1'-bis(diphenylphosphino)ferrocene (17 mg, 0.03 mmol), sodium carbonate (493 mg, 4.65 mmol) were suspended in a 10 mL mixed solvent of dioxane:water = 4:1 and reacted at 90 °C for 4 h. After the reaction was completed, the reaction solution was dropped into ice water and extracted three times with 20 mL of dichloromethane. The organic phases were combined, concentrated, and silica gel column chromatography was performed using DCM:MeOH = 15:1 as the mobile phase to obtain the target compound 32. 142 mg, 23%).

[0455] 11H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 2H), 7.84 (s, 1H), 7.32 - 7.16 (m, 1H), 4.87 (t, 1H), 4.39 (q, 2H), 3.94 (t, 2H), 3.80 - 3.70 (m, 2H), 3.61 - 3.55 (m, 1H), 3.35 - 3.29 (m, 1H), 3.18 - 3.09 (m, 1H), 3.03 - 2.95 (m, 1H), 2.65 - 2.57 (m, 2H), 2.49 - 2.12 (m, 4H), 1.86 - 1.72 (m, 2H).

[0456] LCMS(ESI): m / z = 447.6 [M + H]-.

[0457] Example 38

Chemical Structure

[0458] Step 1: The raw material ±2B (1.5 g, 4.81 mmol) and Dess-Martin periodinane (5.1 g, 12.0 mmol) were dissolved in 15 mL of dichloromethane and reacted for 4 h. After confirming a complete reaction by TLC monitoring, the reaction system was filtered, the filter cake was immersed in 15 mL of dichloromethane and sonicated, then filtered, the filtrates were combined, the solvent was removed by a rotary evaporator, and purification by silica gel column chromatography (PE:EA = 5:1) gave the target compound 43B (970 mg, yield 66%).

[0459] LCMS(ESI): m / z = 254.2 [M + H - tBu] + .

[0460] Step 2: The raw material 43B (970 mg, 3.13 mmol) was dissolved in 10 mL of tetrahydrofuran, and diethylaminosulfur trifluoride (2.53 g, 15.69 mmol) was slowly added dropwise at -20 °C and reacted for 4 h. After confirming a complete reaction by TLC monitoring, it was quenched by adding it to 20 ml of saturated sodium bicarbonate under an ice bath. It was extracted with 20 mL×2 of dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by a rotary evaporator, and the target compound 43C (126 mg, yield 13%) was obtained by silica gel column chromatography (PE:EA = 40:1).

[0461] LCMS (ESI): m / z = 256.3 [M + H - tBu] + 。

[0462] Step 3: The raw material 43C (126 mg, 0.41 mmol) was dissolved in a mixed solution of 0.5 mL of 4N dioxane hydrochloride and 0.5 mL of methanol, stirred at room temperature for 4 h, and after monitoring a complete reaction by LCMS, it was concentrated to obtain the target compound 43D (84 mg, yield 98%).

[0463] LCMS (ESI): m / z = 212.1 [M + H] + 。

[0464] Step 4: Compound 43D (84 mg, 0.40 mmol), 1E (104 mg, 0.37 mmol), and DIPEA (258 mg, 2.00 mmol) were dissolved in 2 mL of dioxane and reacted at 80 °C for 4 h. After the reaction was completed, the reaction solution was added dropwise to 10 mL of ice water, extracted three times with 10 mL×3 of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the target compound 43 (39 mg, 23%) was obtained by HPLC preparative separation.

[0465] 11H NMR (400 MHz, DMSO-d6) δ 7.50 (s, 1H), 7.49 - 7.40 (m, 4H), 4.86 (s, 1H), 4.42 (s, 2H), 3.99 - 3.93 (m, 2H), 3.76 - 3.70 (m, 2H), 3.51 - 3.40 (m, 1H), 3.27 - 3.19 (m, 1H), 3.02 - 2.85 (m, 2H), 2.61 - 2.51 (m, 2H), 2.43 - 2.27 (m, 2H), 2.24 - 2.15 (m, 2H), 1.78 - 1.73 (m, 2H).

[0466] LCMS (ESI): = 463.1 [M + H] + 。

[0467] 19 19F NMR (376 MHz, DMSO) δ -116.81.

[0468] Example 39

Chemical Structure

[0469] Step 1: Weigh compound 44A (4.00 g, 20.67 mmol) into a 100 mL single-neck flask, then add anhydrous toluene (50 mL) to dissolve it. Add n-butyllithium (1.32 g, 20.67 mmol) to the reaction solution at -78 °C. After the addition is complete, stir for 0.5 h, then add compound 10A (5.24 g, 24.80 mmol). After the addition is complete, warm the temperature up to 0 °C and continue stirring for 2 h. When the TLC spotting plate (petroleum ether:ethyl acetate = 3:1) indicates complete reaction, add saturated ammonium chloride solution (50 mL) to the reaction solution, stir for 5 min, add ethyl acetate (30 mL) for extraction, separate the organic phase, dry the organic phase with anhydrous sodium sulfate, concentrate the crude product under reduced pressure, and purify it by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain the target compound 44B (1.0 g, 15%).

[0470] LCMS m / z = 326.1 [M + 1] + 。

[0471] Step 2: After weighing compound 44B (1.00 g, 3.01 mmol) into a 100 mL single-neck flask, pyridine (15 mL) was added and dissolved. Thionyl chloride (0.22 mL) was added to the reaction solution. After the addition was complete, the mixture was stirred at room temperature for 16 h. After the reaction was completed, the filtrate was concentrated under reduced pressure until the liquid stopped dripping, and the crude product was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to obtain the target compound 44C (0.26 g, 27%).

[0472] LCMS m / z = 308.1 [M+1] + 。

[0473] Step 3: After weighing compound 44C (0.10 g, 0.32 mmol) into a 100 mL single-neck flask, ethyl acetate (5 mL) was added and dissolved. Palladium on carbon (0.10 g, 0.97 mmol) was added. After the addition was complete, the mixture was stirred for 2 h. After the reaction was completed, the reaction solution was filtered, and the organic phase was concentrated under reduced pressure until the liquid stopped dripping to obtain the target compound 44D (0.09 g, crude product).

[0474] LCMS m / z = 310.1 [M+1] + 。

[0475] Step 4: After weighing compound 44D (0.09 g, 0.29 mmol) into a 50 mL single-neck flask, methanol (5 mL) was added and dissolved. A dioxane hydrochloride solution (4 N, 5 mL) was added. After the addition was complete, the mixture was stirred for 2 h. The organic phase was concentrated under reduced pressure until the liquid stopped dripping to obtain the target compound 44E (0.07 g, crude product).

[0476] LCMS m / z = 210.2 [M+1] + 。

[0477] Step 5: Compound 1E (0.10 g, 0.35 mmol) and compound 44E (0.07 g, 0.35 mmol) were added to a 100 mL single-necked flask, 1,4-dioxane (10 mL) was added and dissolved, and finally N,N-diisopropylethylamine (0.13 g, 1.03 mmol) was added. After the addition was completed, the system was protected with nitrogen gas, stirred at 100 °C for 16 h, the reaction solution was concentrated under reduced pressure to obtain a crude product of the target compound, and the title compound 44 (3.3 mg, 2%) was obtained by preparative HPLC.

[0478] Preparative method: Instrument: Waters 2767 preparative liquid phase, chromatographic column: SunFire@Prep C18 (19 mm × 250 mm). The sample was dissolved in DMF, filtered through a 0.45 μm filter to prepare the sample solution. The conditions for preparative chromatography were as follows: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 5 mM aqueous ammonia); b. Gradient elution, the content of mobile phase A was 30% - 80%; c. Flow rate was 15 mL / min; d. Elution time was 20 min, retention time: 10.20 min.

[0479] LCMS m / z = 461.2 [M + 1] + 。

[0480] 1 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 2H), 7.29 (s, 1H), 4.87 (t, 1H), 4.13 (s, 2H), 3.95 (s, 2H), 3.62 - 3.72 (m, 3H), 3.36 - 3.43 (m, 2H), 3.14 - 3.25 (m, 1H), 2.82 - 2.95 (m, 2H), 2.59 - 2.65 (m, 2H), 2.51 - 2.54 (m, 1H), 2.23 - 2.41 (m, 2H), 2.13 (t, 2H), 1.69 - 1.85 (m, 2H).

[0481] Example 40

Chemical formula

[0482] Step 1: Dissolve compound 42D (1 g, 3.11 mmol) in 150 ml of ethyl acetate, add palladium carbon (100 mg), aspirate and ventilate with hydrogen gas three times, and stir at room temperature overnight in a hydrogen gas atmosphere. After the reaction is completed, filter, spin-dry and send to preparative separation. The separation method by preparative HPLC is as follows. 1. Instrument: Waters 2767 preparative liquid phase, chromatography column: SunFire@Prep C18 (19 mm×250 mm). 2. Filter the sample with a 0.45 μm filter to prepare the sample solution. 3. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% ammonium acetate). b. Gradient elution, the content of mobile phase A is 10% - 55%. c. Flow rate is 12 mL / min. Compound 45A (300 mg, 30%) was obtained with a retention time of 10.0 min.

[0483] LCMS (ESI): m / z = 268.3[M + H - 56] + 。

[0484] Step 2: Dissolve compound 45A (300 mg, 0.93 mmol) in 1,4-dioxane (2 ml) of hydrochloric acid, stir at room temperature for 1 h, and directly spin-dry to obtain the hydrochloride compound of 45B (242 mg).

[0485] LCMS (ESI): m / z = 224.1[M + H] + 。

[0486] Step 3: Intermediate 1E (267 mg, 0.93 mmol) was dissolved in 1,4-dioxane (5 ml), the hydrochloride compound of 45B (242 mg, 0.93 mmol) and diisopropylethylamine (360 mg, 2.79 mmol) were added, and the reaction system was placed in an oil bath at 100 °C and reacted for 15 h. After the reaction was completed, it was cooled to room temperature, the reaction was monitored by LCMS, spin-dried and then sent for preparative separation. The separation method by preparative HPLC is as follows. 1. Instrument: Waters 2767 preparative liquid phase, chromatography column: SunFire@Prep C18 (19 mm × 250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare a sample solution. 3. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% ammonium acetate). b. Gradient elution, the content of mobile phase A is 10% - 55%. c. Flow rate is 12 mL / min. Compound 45 (300 mg, 68%) was obtained with a retention time of 7.0 min.

[0487] LCMS (ESI): m / z = 475.2 [M + H] + 。

[0488] The resolution of Compound 45 is as follows.

[0489] Compound 45 (130 mg) was taken for resolution. After separation, Compound 45-1 (retention time: 1.344 min, 254 mg, ee% = 100%) and Compound 45-2 (retention time: 1.621 min, 20 mg, ee% = 100%) were obtained.

[0490] The resolution conditions are as follows.

[0491] Instrument: Waters 150 MGM, column: DAICEL CHIRALPAK AD, Mobile phase: A for CO 2 and B for EtOH(0.1% NH 3 ·H 2 O)), gradient: B 40%, flow rate: 120 mL / min, back pressure: 100 bar, Column temperature: 35 °C, wavelength: 220 nm, period: 13 min, Compound 45-1: 1 H NMR (400 MHz, CDCl 3 ) δ = 8.58 (s, 2H), 5.94 (s, 1H), 5.17 (s, 1H), 3.85 (s, 2H), 3.75 - 3.70 (m, 2H), 3.68 - 3.48 (m, 4H), 3.43 - 3.36 (m, 1H), 3.09 - 2.94 (m, 2H), 2.88 (s, 2H), 2.44 - 2.37 (m, 2H), 2.36 - 2.17 (m, 4H), 2.02 - 1.81 (m, 4H).

[0492] Compound 45-2: 1 H NMR (400 MHz, CDCl 3 ) δ = 8.60 (s, 2H), 5.93 (s, 1H), 3.92 - 3.85 (m, 4H), 3.64 - 3.58 (m, 2H), 3.53 - 3.39 (m, 3H), 3.15 - 2.96 (m, 4H), 2.33 (s, 2H), 2.33 - 2.23 (m, 5H), 2.09 - 2.01 (m, 2H), 2.00~1.94 (m, 1H), 1.94 - 1.87 (m, 1H).

[0493] Example 41

Chemical formula

[0494] Step 1: To Compound 42C (1 g, 2.99 mmol) dissolved in 1,4-dioxane / water (10 ml / 2 ml) under nitrogen gas, 4-bromobenzocyclobutane (497 mg, 2.71 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (220 mg, 0.3 mmol) and sodium carbonate (951 mg, 8.97 mmol) were added, and the reaction was carried out in an oil bath at 90 °C for 18 h. After the reaction was completed, it was cooled to room temperature, filtered through diatomaceous earth, washed with ethyl acetate, the filtrate was concentrated, and directly purified by high-speed separation by column chromatography (ratio of eluent: EA / PE = 0% - 10%) to obtain the target compound 46A (0.44 g, 52%).

[0495] LCMS (ESI): m / z=256.2[M+H-56] + 。

[0496] Step 2: Compound 46A (220 mg, 0.69 mmol) was dissolved in 1,4-dioxane (2 ml) of hydrochloric acid, stirred at room temperature for 1 h, and directly spin-dried to obtain the hydrochloride compound of 46B (170 mg).

[0497] LCMS (ESI): m / z=212.1[M+H] + 。

[0498] Step 3: Intermediate 1E (200 mg, 0.69 mmol) was dissolved in 1,4-dioxane (5 ml), the hydrochloride compound of 46B (170 mg) and diisopropylethylamine (267 mg, 2.07 mmol) were added, and the reaction system was placed in an oil bath at 100 °C and reacted for 15 h. After the reaction was completed, it was cooled to room temperature, the reaction was monitored by LCMS, spin-dried and then sent for preparative separation. The separation method by preparative HPLC is as follows. 1. Instrument: Waters 2767 preparative liquid phase, chromatography column: SunFire@Prep C18 (19 mm×250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare a sample solution. 3. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% ammonium acetate). b. Gradient elution, the content of mobile phase A is 10% - 55%. c. Flow rate is 12 mL / min. Compound 46 (200 mg, 63%) was obtained with a retention time of 7.0 min.

[0499] LCMS (ESI): m / z = 463.3 [M + H] + 。

[0500] The resolution of Compound 46 is as follows.

[0501] Compound 46 (200 mg) was taken and used for resolution. After separation, Compound 46-1 (retention time: 1.214 min, 73 mg, ee% = 100%) and Compound 46-2 (retention time: 1.541 min, 68 mg, ee% = 100%) were obtained.

[0502] The resolution conditions are as follows.

[0503] Instrument: Waters 150MGM, column: DAICEL CHIRALPAK AD, Mobile phase: A for CO2 and B for EtOH (0.1% NH3·H2O)), gradient: B 40%, flow rate: 120 mL / min, back pressure: 100 bar, column temperature: 35 °C, wavelength: 220 nm, cycle: 13 min, Compound 46-1: 1 H NMR (400 MHz, CDCl 3 ) δ = 7.24 (s, 1H), 7.11 (s, 1H), 6.99 (d, 1H), 5.95 (s, 1H), 5.89 (s, 1H), 4.08 - 3.87 (m, 1H), 3.88 - 3.78 (m, 3H), 3.80 - 3.65 (m, 2H), 3.64 - 3.52 (m, 2H), 3.44 - 3.33 (m, 1H), 3.32 - 3.19 (m, 1H), 3.15 (s, 4H), 3.13 - 3.05 (m, 1H), 3.06 - 2.92 (m, 3H), 2.72 - 2.58 (m, 1H), 2.36 - 2.21 (m, 4H), 1.98 - 1.85 (m, 2H).

[0504] Compound 46 - 2: 1 H NMR (400 MHz, CDCl 3 ) δ = 7.24 (s, 1H), 7.12 (s, 1H), 6.99 (d, 1H), 5.95 (s, 1H), 5.88 (s, 1H), 4.04 - 3.91 (m, 1H), 3.84 (d, J = 14.1, 2H), 3.80 - 3.66 (m, 2H), 3.60 (s, 2H), 3.44 - 3.20 (m, 2H), 3.15 (s, 4H), 3.13 - 3.06 (m, 1H), 3.00 (t, 3H), 2.64 (d, 1H), 2.43 - 2.14 (m, 4H), 1.98 - 1.80 (m, 2H).

[0505] Example 42 [Chemical Structure]

[0506] Step 1: To a 250 mL single-necked flask, 47A (10.0 g, 46.3 mmol), 1,2-difluoro-4-nitrobenzene (7.3 g, 46.3 mmol), potassium hydroxide (7.8 g, 138.9 mmol) and N,N-dimethylformamide (100 mL) were added sequentially. After reacting at room temperature for 6 hours, the temperature was further raised to 60 °C and reacted for 24 hours. After filtration, the filtrate was added to ethyl acetate (500 mL), washed with water (100 mL × 3), the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and then separated and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 20 / 100) to obtain 47B (10.0 g, yield 64.5%).

[0507] LC-MS (ESI): m / z=336.2[M+H] + 。

[0508] Step 2: To a 250 mL single-necked flask, 47B (10.0 g, 29.9 mmol), ethyl acetate (100 mL) and palladium on carbon (2 g) were added sequentially. The hydrogenation reaction was carried out at room temperature for 12 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain 47C (7.0 g, yield 76.9%).

[0509] LC-MS (ESI): m / z=306.2[M+H] + 。

[0510] Step 3: To a 100 mL single-necked flask, acetonitrile (30 mL), tert-butyl nitrite (1.5 g, 14.7 mmol), cuprous chloride (1.2 g, 11.8 mmol) were added sequentially, heated to 65 °C, and a solution of 47C (3.0 g, 9.8 mmol) in acetonitrile (10 mL) was added dropwise. After the addition was complete, the reaction was carried out at 65 °C for 4 hours. After stopping the heating, the reaction was continued for 12 hours. After concentration under reduced pressure, it was separated and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 20 / 100) to obtain 47D (0.4 g, yield 12.6%).

[0511] LC-MS (ESI): m / z=269.2[M-56+H]+ .

[0512] Step 4: 47D (0.4 g, 1.2 mmol) and hydrogen chloride - dioxane solution (4 N, 10 mL) were sequentially added to a 50 mL single - neck flask, reacted at room temperature for 1 hour, concentrated under reduced pressure, and then 47E (0.4 g, yield 100.0%) was obtained.

[0513] LC - MS (ESI): m / z = 225.1[M + H] + .

[0514] Step 5: 1E (344 mg, 1.2 mmol), 47E (400 mg, 1.2 mmol), dioxane (5 mL) and DIPEA (774 mg, 6.0 mmol) were sequentially added to a 50 mL single - neck flask and reacted at 100 °C for 12 hours. After cooling the temperature to room temperature and directly concentrating the reaction solution under reduced pressure, it was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v)=100 / 8) to obtain 400 mg of a mixture.

[0515] The title compound 47 - 1 (90 mg, 31.6%, retention time: 1.897 min) and the title compound 47 - 2 (80 mg, 28.0%, retention time: 2.355 min) were obtained by chiral preparative separation. Chiral preparative separation method: Instrument: Waters 150MGM, chromatographic column: Chiralpak Column, mobile phase: A: carbon dioxide and B: isopropyl alcohol (0.1% aqueous ammonia), isocratic elution: 30% mobile phase B, flow rate: 100 mL / min, back pressure: 100 bar, column temperature: 25 °C, wavelength: 220 nm, elution time: 20 min.

[0516] (Compound 47 - 1) 1 H NMR (400MHz,DMSO - d 6) δ 7.45 (s,1H),6.92 (d,1H),6.86 - 6.81 (m,1H),6.77 (d,1H),4.93 - 4.80 (m,1H),4.77 - 4.58 (m,2H),4.45 - 4.30 (m,1H),4.05 - 3.92 (m,1H),3.88 - 3.78 (m,1H),3.77 - 3.65 (m,2H),3.52 - 3.39 (m,1H),3.26 - 3.17 (m,1H),3.14 - 2.84 (m,4H),2.77 - 2.57 (m,2H),2.40 - 2.25 (m,2H),2.23 - 2.14 (m,2H),1.89 - 1.66 (m,2H).

[0517] LC - MS (ESI): m / z = 476.2[M + H] + .

[0518] (Compound 47 - 2) 1 H NMR (400MHz, DMSO - d 6 ) δ 7.45 (s,1H),6.92 (d,1H),6.86 - 6.80 (m,1H),6.77 (d,1H),4.90 - 4.78 (m,1H),4.80 - 4.58 (m,2H),4.43 - 4.31 (m,1H),4.07 - 3.93 (m,1H),3.89 - 3.80 (m,1H),3.76 - 3.68 (m,2H),3.52 - 3.38 (m,1H),3.27 - 3.17 (m,1H),3.13 - 2.83 (m,4H),2.76 - 2.57 (m,2H),2.44 - 2.25 (m,2H),2.24 - 2.12 (m,2H),1.86 - 1.66 (m,2H).

[0519] LC - MS (ESI): m / z = 476.2[M + H] + .

[0520] Example 43 [Chemical formula]

[0521] Step 1: tert-Butyl nitrite (3.55 g, 34.38 mmol) and cuprous iodide (5.24 g, 27.50 mmol) were added to acetonitrile (70 mL), and the temperature was raised to 65 °C. Then, a solution of 48A (7 g, 22.92 mmol) in acetonitrile (20 mL) was added dropwise. The reaction was carried out at 65 °C for 4 h. After the temperature was lowered to room temperature, the reaction solution was concentrated under reduced pressure. Then, water (50 mL) was added, and the mixture was washed with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated and purified by silica gel column chromatography (eluent EA / PE = 0 - 25%) to obtain crude product 48B (5 g). It was directly used in the reaction of the next step.

[0522] LC-MS (ESI): m / z = 361.3 [M + H - 56] + 。

[0523] Step 2: 48B (5 g), trimethylsilylacetylene (1.42 g, 14.41 mmol), bis(triphenylphosphine)palladium dichloride (0.84 g, 1.20 mmol), cuprous iodide (0.46 g, 2.40 mmol), and triethylamine (3.65 g, 36.03 mmol) were added to tetrahydrofuran (40 mL). After replacing with nitrogen gas, the reaction was carried out at room temperature overnight. The reaction solution was directly concentrated under reduced pressure and then separated and purified by silica gel column chromatography (eluent EA / PE = 0 - 25%) to obtain 3.5 g of crude product. Further purification was carried out using a C18 reverse-phase column. Regarding the composition of the mobile phase, mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% TFA), and separation and purification were carried out at (A / B = 25% / 75%) to obtain 48C (2 g, 43%).

[0524] LC-MS (ESI): m / z = 387.2 [M + H] + 。

[0525] Step 3: 48C (1.5 g, 3.88 mmol) and potassium carbonate (1.07 g, 7.76 mmol) were added to methanol (15 mL), and the mixture was reacted at room temperature for 3 h. The completion of the reaction was monitored by LC-MS. Most of the methanol was concentrated under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 48D (1.1 g, 90.18%).

[0526] LC-MS (ESI): m / z = 315.5 [M+H] + 。

[0527] Step 4: 48D (0.35 g, 1.11 mmol) and triethylamine (1.12 g, 11.11 mmol) were added to dichloromethane (15 mL), and iodotrimethylsilane (1.34 g, 6.69 mmol) was added dropwise. The mixture was reacted at room temperature for 2 h. After complete reaction, the reaction solution was directly concentrated under reduced pressure to dryness to obtain the crude product 48E (1.7 g). It was directly charged into the reaction of the next step.

[0528] LC-MS (ESI): m / z = 215.5 [M+H] + 。

[0529] Step 5: Crude product 48E (1.7 g), 1E (0.32 g, 1.1 mmol), and N,N - diisopropylethylamine (0.57 g, 4.41 mmol) were added to 1,4 - dioxane (15 mL). The temperature was raised to 100 °C and reacted for 5 h. After cooling the temperature to room temperature, the reaction solution was directly concentrated under reduced pressure and then separated and purified by silica gel column chromatography (eluent MeOH / DCM = 0 - 10%) to obtain 0.4 g of a mixture. By chiral separation, 48 - 1 (120 mg, 23.4%, retention time: 1.249 min) and 48 - 2 (130 mg, 25.4%, retention time: 1.586 min) were obtained. Chiral separation method: Instrument: Waters 150 preparative SFC (SFC - 26), chromatographic column: ChiralPak AD, 250×30 mm I.D., 10 μm, mobile phase: A: carbon dioxide and B: isopropyl alcohol (0.1% aqueous ammonia), isocratic elution: 40% mobile phase B, flow rate: 100 mL / min, back pressure: 100 bar, column temperature: 38 °C, wavelength: 220 nm, elution time: 3.4 min.

[0530] (Compound 48 - 1) 1 H NMR (400 MHz, CDCl 3 ) δ 7.02 - 7.00 (m, 1H), 6.92 (d, 1H), 6.72 (d, 1H), 6.13 (s, 1H), 4.86 - 4.65 (m, 2H), 4.31 - 4.25 (m, 1H), 4.14 - 3.93 (m, 2H), 3.90 - 3.80 (m, 2H), 3.79 - 3.72 (m, 1H), 3.65 - 3.53 (m, 1H), 3.45 - 3.36 (m, 1H), 3.24 - 3.12 (m, 2H), 3.10 - 2.97 (m, 2H), 2.96 (s, 1H), 2.85 - 2.72 (m, 2H), 2.39 - 2.29 (m, 2H), 2.28 - 2.19 (m, 2H), 2.01 - 1.83 (m, 2H).

[0531] LC - MS (ESI): m / z = 466.6 [M + H] + .

[0532] (Compound 48 - 2) 1 1H NMR (400 MHz, CDCl 3 ) δ 7.04 - 6.99 (m, 1H), 6.92 (d, 1H), 6.72 (d, 1H), 6.12 (s, 1H), 4.88 - 4.62 (m, 2H), 4.33 - 4.25 (m, 1H), 4.15 - 3.95 (m, 2H), 3.90 - 3.79 (m, 2H), 3.78 - 3.72 (m, 1H), 3.65 - 3.54 (m, 1H), 3.45 - 3.35 (m, 1H), 3.23 - 3.13 (m, 2H), 3.10 - 2.96 (m, 2H), 2.96 (s, 1H), 2.85 - 2.73 (m, 2H), 2.39 - 3.00 (m, 2H), 2.29 - 2.18 (m, 2H), 2.01 - 1.84 (m, 2H).

[0533] LC - MS (ESI): m / z = 466.6 [M + H] + .

[0534] Example 44 [Chemical formula]

[0535] Step 1: Dissolve compound 49A (15 g, 96.03 mmol) in carbon tetrachloride (600 mL), add N - bromosuccinimide (17.09 g, 96.03 mmol) and azobisisobutyronitrile (1.58 g, 9.60 mmol) thereto, heat to 70 °C with stirring under the protection of nitrogen gas, react overnight, cool to room temperature, wash with water and saturated brine, dry over anhydrous sodium sulfate, and then spin - dry the filtrate to obtain compound 49B (24 g, crude product), which was used directly in the reaction of the next step without separation and purification.

[0536] LCMS (ESI): = 235.1, 237.1 [M + H] + .

[0537] Step 2: The crude product 49B (17 g, 63.8 mmol) was dissolved in an ammonia-methanol solution (7.0 M, 20 mL) and methanol (20 mL), stirred at room temperature for 2 hours, the solvent was evaporated under reduced pressure, and then separated by a silica gel chromatography column (DCM:MeOH, v / v = 10:1) to obtain compound 49C (8 g, 2-step yield 48.7%).

[0538] LCMS(ESI): = 172.1 [M+H] + 。

[0539] Step 3: Compound 49C (8 g, 46.73 mmol) was dissolved in a mixed solvent of methanol / ethanol (120 mL, v / v = 1:1), potassium carbonate (12.92 g, 93.45 mmol) was added thereto, stirred, heated to 90 °C and reacted for 3 hours, cooled to room temperature, the solvent was evaporated under reduced pressure, 150 ml of ethyl acetate was added, after dissolution, the solid was filtered off, and the solvent was spin-dried to obtain compound 49D (3.25 g, 36%).

[0540] LCMS(ESI): = 140.0 [M+H] + 。

[0541] Step 4: 49D (3.25 g, 23.35 mmol) was dissolved in dichloromethane (50 mL), triethylamine (7.09 g, 70.06 mmol) and a catalytic amount of 4-dimethylaminopyridine (285 mg, 2.34 mmol) were added thereto, cooled in an ice bath, di-tert-butyl dicarbonate (10.2 g, 46.71 mmol) was added dropwise, stirred at room temperature for 3 hours, directly spin-dried, and separated by a silica gel chromatography column (EA:PE = 1:3) to obtain compound 49E (4.45 g, 79.6%).

[0542] LCMS(ESI): = 184.1 [M+H] + 。

[0543] Step 5: 49E (4.45 g, 18.60 mmol) was dissolved in tetrahydrofuran (50 mL). Under the protection of nitrogen gas, it was cooled with ice water, and borane tetrahydrofuran complex (55.8 mL, 1.0 mol / L) was added dropwise thereto. After the addition was completed, the reaction was carried out at room temperature for 3 hours. It was cooled with ice water, the reaction was quenched with a small amount of methanol, the solvent was evaporated under reduced pressure to obtain a crude product, which was separated by a silica gel chromatography column (EA:PE = 1:3) to obtain 49F (2.26 g, 53.9%).

[0544] LCMS(ESI): = 170.1[M+H] + 。

[0545] Step 6: 49F (2.26 g, 10.03 mmol) was dissolved in chloroform (25 mL), a catalytic amount of glacial acetic acid was added, and liquid bromine (1.6 g, 10.03 mmol) was added dropwise while cooling with ice water. It was stirred at room temperature overnight, triethylamine (3.04 g, 30.09 mmol) and a catalytic amount of 4-dimethylaminopyridine (123 mg, 1.00 mmol) were added thereto, it was cooled in an ice bath, di-tert-butyl dicarbonate (4.38 g, 20.06 mmol) was added dropwise, and it was stirred at room temperature for 3 hours and directly spin-dried, which was separated by a silica gel chromatography column (EA:PE = 1:3) to obtain 49G (2.26 g, 74.1%).

[0546] LCMS(ESI): = 248.1, 250.1[M+H] + 。

[0547] Step 7: 49G (1 g, 3.29 mmol), 4-chlorophenylboronic acid (616.8 mg, 3.94 mmol), sodium carbonate (697 mg, 6.57 mmol) and tetrakis(triphenylphosphine)palladium (380 mg, 0.33 mmol) were added to a mixed solution of 1,4-dioxane and water (27.5 mL, v / v = 10:1). After replacing with nitrogen gas, the mixture was reacted at 80 °C for 3 hours, quenched by adding water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and separated by a silica gel chromatography column to obtain 49H (640 mg, 58.0%).

[0548] LCMS(ESI): = 280.1, 282.1 [M+H] + 。

[0549] Step 8: 49H (300 mg) was added to dioxane hydrochloride (5 mL, 4N), reacted at room temperature for 2 hours, and the system was spin-dried to obtain compound 49I (300 mg, crude product), which was directly used in the reaction of the next step.

[0550] LCMS(ESI): = 236.1, 238.1 [M+H] + 。

[0551] Step 9: Compound 49I (0.28 g, 1.18 mmol) and 1E (0.34 g, 1.18 mmol) were dissolved in 1,4-dioxane (10 ml), N,N-diisopropylethylamine (0.46 g, 3.54 mmol) was added. After the addition was completed, the temperature was raised to 100 °C and reacted for 5 hours. After the reaction was completed, it was cooled to room temperature and then filtered. The filter cake was heated to 70 °C with acetonitrile / water (v / v = 9 / 1, 5 mL), hot-pulverized for 1 hour, and then hot-filtered. The filter cake was washed with a small amount of acetonitrile and then dried to obtain the title compound 49 (350.0 mg, 60.9%).

[0552] 1 H NMR (400MHz, DMSO-d 6) δ 7.69 - 7.64 (m, 2H), 7.51 - 7.47 (m, 3H), 4.92 - 4.70 (m, 4H), 3.81 (s, 2H), 3.67 - 3.62 (m, 1H), 3.39 - 3.32 (m, 2H), 3.07 - 3.03 (m, 1H), 2.39 - 2.30 (m, 4H), 1.87 - 1.84 (m, 2H).

[0553] MS M / Z(ESI): m / z = 487.1[M + 1] + .

[0554] Example 45

Chemical Structure

[0555] Step 1: Dissolve compound 37B (2.0 g, 5.9 mmol) in N,N-dimethylformamide (50 ml), add zinc cyanide (0.7 g, 5.9 mmol) and tetrakis(triphenylphosphine)palladium (0.7 g, 5.9 mmol), aspirate and ventilate with nitrogen gas three times, heat to 90 °C and react for 3 h, then pass through a silica gel plug, wash with ethyl acetate, concentrate, and obtain compound 50A (1.5 g, 89%) by column chromatography (ethyl acetate / petroleum ether = 1 / 9).

[0556] LC-MS (ESI): m / z = 287.4[M + H] + .

[0557] Step 2: Dissolve compound 50A (1.5 g, 5.2 mmol) in dichloromethane (50 mL), add trifluoroacetic acid (6.0 mL), react at room temperature for half an hour, then concentrate to obtain compound 50B (0.9 g, 92%), which was directly used in the next step.

[0558] LC-MS (ESI): m / z = 187.2[M + H] + .

[0559] Step 3: Compound 50B (0.9 mg, 4.8 mmol) was dissolved in 1,4-dioxane (50.0 mL), and further compound 1E (1.4 g, 4.8 mmol) and N,N-diisopropylethylamine (0.7 g, 5.3 mmol) were added. After heating to 90 °C and reacting for 12 h, it was cooled to room temperature, concentrated, and compound 50 (0.3 g, 14%) was obtained by column chromatography (dichloromethane / methanol = 10 / 1).

[0560] LC-MS (ESI): m / z = 438.5[M+H] + 。

[0561] 1 H NMR (400 MHz, CDCl 3 ) δ 8.92 (s, 1H), 7.52 (s, 1H), 6.21 (s, 1H), 4.55 (s, 1H), 4.05 (t, 2H), 3.93 - 3.82 (m, 2H), 3.65 - 3.57 (m, 1H), 3.43 - 3.35 (m, 1H), 3.08 - 2.99 (m, 2H), 2.78 (s, 2H), 2.39 - 2.31 (m, 2H), 2.31 - 2.25 (m, 2H), 1.97 - 1.84 (m, 2H).

[0562] Example 46

Chemical Structure

[0563] Step 1: Compound 51A (0.9 g, 3.2 mmol) was dissolved in 1,4-dioxane (40 mL), and further 1,1-bis(diphenylphosphino)ferrocenedichloropalladium (0.2 mg, 0.3 mmol), cesium carbonate (2.1 g, 6.3 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (1.1 g, 3.5 mmol) and water (10 mL) were added. After purging with nitrogen gas three times, it was heated to 90 °C and reacted for 4 h, then passed through a silica gel plug, washed with ethyl acetate, concentrated, and compound 51B (0.7 g, 57%) was obtained by column chromatography (petroleum ether / ethyl acetate = 9 / 1).

[0564] LC-MS (ESI): m / z = 386.4 [M+H] + 。

[0565] Step 2: Compound 51B (0.7 g, 1.8 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (2.8 mL) was further added. After reacting at room temperature for half an hour, it was concentrated to obtain compound 51C (0.5 g, 96%), which was directly used in the next step.

[0566] Step 3: Compound 50C (0.5 mg, 1.8 mmol) was dissolved in 1,4-dioxane (30.0 mL), and compound 1E (0.5 g, 1.8 mmol) and N,N-diisopropylethylamine (1.8 g, 14.5 mmol) were further added. After heating to 90 °C and reacting for 12 h, it was cooled to room temperature, concentrated, and compound 51 (0.5 g, 53%) was obtained by column chromatography (dichloromethane / methanol = 10 / 1).

[0567] LC-MS (ESI): m / z = 537.1 [M+H] + 。

[0568] 1 H NMR (400 MHz, CDCl 3 ) δ 7.74 (s, 1H), 7.64 (d, 1H), 7.51 (d, 1H), 7.43 (t, 1H), 6.34 (s, 1H), 6.18 (s, 1H), 4.43 (s, 2H), 4.07 (s, 2H), 3.90 - 3.81 (m, 2H), 3.67 - 3.59 (m, 1H), 3.42 - 3.34 (m, 1H), 3.08 - 3.04 (m, 2H), 2.61 (s, 2H), 2.40 - 2.33 (m, 2H), 2.27 - 2.22 (m, 2H), 1.96 - 1.83 (m, 2H).

[0569] 19 F NMR (377 MHz, CDCl 3 ) δ 64.91 (s), 64.62 (s).

[0570] Example 47 [Chemical formula]

[0571] Step 1: Dissolve compound 52A (1.0 g, 3.8 mmol) in 1,4-dioxane (40 mL). Further add 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (0.3 mg, 0.4 mmol), cesium carbonate (2.5 g, 7.7 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (1.3 g, 4.3 mmol) and water (10 mL). Aspirate and ventilate with nitrogen gas three times. Heat to 90 °C and react for 3 h. Then pass through a silica gel plug, wash with ethyl acetate, concentrate, and obtain compound 52B (1.3 g, 94%) by column chromatography (petroleum ether / ethyl acetate = 9 / 1).

[0572] LC-MS (ESI): m / z = 360.4 [M+H] + .

[0573] Step 2: Dissolve compound 52B (1.3 g, 3.6 mmol) in dichloromethane (20 mL). Further add trifluoroacetic acid (2.8 mL). React at room temperature for half an hour, then concentrate to obtain compound 52C (0.8 g, 85%), which was directly used in the next step.

[0574] Step 3: Dissolve compound 52C (0.7 mg, 2.7 mmol) in 1,4-dioxane (30.0 mL). Further add compound 1E (0.78 g, 2.7 mmol) and N,N-diisopropylethylamine (1.1 g, 8.1 mmol). Heat to 90 °C and react for 12 h. Then cool to room temperature, concentrate, and obtain compound 52 (0.55 g, 40%) by column chromatography (dichloromethane / methanol = 10 / 1).

[0575] LC-MS (ESI): m / z = 511.1 [M+H] + .

[0576] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.66 (s, 1H), 7.55 (d, 1H), 7.50 (d, 1H), 7.39 (t, 1H), 6.18 (s, 1H), 6.13 (s, 1H), 4.41 (s, 2H), 4.35 (s, 1H), 4.05 (s, 2H), 3.87 (s, 2H), 3.65 - 3.57 (m, 1H), 3.43 - 3.35 (m, 1H), 3.08 - 2.96 (m, 2H), 2.60 (s, 2H), 3.35 - 3.25 (m, 4H), 2.00~1.85 (m, 2H).

[0577] 19 19F NMR (377 MHz, CDCl 3 ) δ -40.50 (s).

[0578] Example 48 [Chemical Structure]

[0579] Step 1: To a mixture of compound 37B (1.0 g, 3.0 mmol), cyclopropylboronic acid (356.0 mg, 4.0 mmol), palladium acetate (25.0 mg, 0.15 mmol), tricyclohexylphosphine (84.2 mg, 0.3 mmol), and potassium phosphate (2.3 g, 10.5 mmol) was added, and finally toluene (14 mL) and water (0.7 mL) were added. The mixture was evacuated and backfilled with nitrogen gas three times, heated to 100 °C and reacted for 3 h. Then, it was passed through a silica gel plug, washed with ethyl acetate, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 53A (820.0 mg, 91%).

[0580] LC-MS (ESI): m / z = 302.1 [M + H] + .

[0581] Step 2: Compound 53A (820.0 mg, 2.7 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (5.0 mL) was further added. After reacting at room temperature for half an hour, it was concentrated to obtain compound 53B (1.0 g, 99%), which was directly used in the next step.

[0582] LC-MS (ESI): m / z=202.1[M+H] + 。

[0583] Step 3: Compound 53B (400.0 mg, 2.0 mmol) was dissolved in 1,4-dioxane (10.0 mL), and compound 1E (540.0 mg, 2.0 mmol) and diisopropylethylamine (1.0 g, 8.0 mmol) were further added. After heating to 90 °C and reacting for 12 h, it was cooled to room temperature, concentrated, and compound 53 (180.0 mg, 20%) was obtained by column chromatography (dichloromethane / methanol = 10 / 1).

[0584] LC-MS (ESI): m / z=453.1[M+H] + 。

[0585] 1 H NMR (400MHz,DMSO-d 6 ) δ 8.54 (s,2H),7.35 (s,1H),7.18 (s,1H),4.86-4.83 (m,1H),4.43 (s,2H),3.97-3.94 (m,2H),3.75 (d,2H),3.45-3.38 (m,1H),3.23-3.18 (m,1H),3.00~2.78 (m,2H),2.64 (s,2H),2.43-2.29 (m,2H),2.22-2.18 (m,2H),2.02-1.89 (m,1H),1.89-1.69 (m,2H),1.13-0.96 (m,2H),0.89-0.77 (m,2H).

[0586] Example 49

Chemical Structure

[0587] Step 1: Dissolve compound 37B (1.0 g, 2.9 mmol) in toluene (50 mL), and further add tris(dibenzylideneacetone)dipalladium (266.1 mg, 0.29 mmol), 2-(di-tert-butylphosphine)biphenyl (179.0 mg, 0.6 mmol), and sodium tert-butoxide (576.0 mg, 6.0 mmol). Aspirate and ventilate with nitrogen gas three times, heat to 100 °C and react for 3 h, then pass through a silica gel plug, wash with ethyl acetate, concentrate, and obtain compound 54A (258.0 mg, 23%) by column chromatography (ethyl acetate / petroleum ether = 1 / 9).

[0588] LC-MS (ESI): m / z = 389.2 [M+H] + 。

[0589] Step 2: Dissolve compound 54A (258.0 mg, 0.66 mmol) in dichloromethane (50 mL), and further add trifluoroacetic acid (3.0 mL). React at room temperature for half an hour, then concentrate to obtain compound 54B (218.0 mg, 99%), which was directly used in the next step.

[0590] LC-MS (ESI): m / z = 289.2 [M+H] + 。

[0591] Step 3: Dissolve compound 54B (218.0 mg, 0.66 mmol) in 1,4-dioxane (30.0 mL), and further add compound 1E (190.0 mg, 0.66 mmol) and N,N-diisopropylethylamine (0.35 g, 2.6 mmol). Heat to 90 °C and react for 3 h, then cool to room temperature, concentrate, and obtain compound 54 (0.06 g, 17%) by column chromatography (dichloromethane / methanol = 10 / 1).

[0592] LC-MS (ESI): m / z = 540.2 [M+H] + 。

[0593] 11H NMR (400 MHz, DMSO-d 6 ) δ 8.30 (s, 2H), 7.30 (s, 1H), 6.86 (s, 1H), 4.80 - 4.78 (m, 1H), 4.31 (s, 2H), 3.87 (s, 2H), 3.76 - 3.47 (m, 6H), 3.37 - 3.31 (m, 1H), 3.17 - 3.09 (m, 1H), 2.90 - 2.76 (m, 2H), 2.55 (s, 2H), 2.34 - 2.21 (m, 2H), 2.15 - 2.10 (m, 2H), 1.83 - 1.60 (m, 2H), 0.76 - 0.53 (m, 4H), 0.00 (s, 6H).

[0594] Example 50

Chemical Structure

[0595] Step 1: Dissolve compound 55A (750 mg, 4.6 mmol) in 1,4 - dioxane (12 mL). Further add 1,1 - bis(diphenylphosphino)ferrocene dichloropalladium (340 mg, 0.46 mmol), cesium carbonate (4.5 g, 13.8 mmol), N - Boc - 1,2,5,6 - tetrahydropyridine - 4 - boronic acid pinacol ester (2.1 g, 6.89 mmol) and water (3 mL). Aspirate and ventilate with nitrogen gas three times, heat to 90 °C and react for 16 h. Then pass through a silica gel plug, wash with ethyl acetate, concentrate, and obtain compound 55B (0.8 g, 66%) by column chromatography (petroleum ether / ethyl acetate = 1 / 1).

[0596] LC - MS (ESI): m / z = 266.1 [M + H] + .

[0597] Step 2: Compound 55B (400 mg, 1.51 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5.0 mL) was further added. After reacting at room temperature for half an hour, it was concentrated. The residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried and concentrated to obtain compound 55C (240 mg, 96%), which was directly used in the next step.

[0598] LC-MS (ESI): m / z = 166.1 [M+H] + 。

[0599] Step 3: Compound 55C (390 mg, 1.36 mmol) was dissolved in 1,4-dioxane (10.0 mL), and compound 1E (220 mg, 1.33 mmol) and N,N-diisopropylethylamine (530 mg, 4.08 mmol) were further added. After heating to 90 °C and reacting for 12 h, it was cooled to room temperature and concentrated. Compound 55 (440 mg, 78%) was obtained by column chromatography (dichloromethane / methanol = 10 / 1).

[0600] LC-MS (ESI): m / z = 417.2 [M+H] + 。

[0601] 1 H NMR (400 MHz, CDCl 3 ) δ 6.75 - 6.70 (m, 1H), 6.24 (s, 1H), 4.46 (s, 2H), 4.03 (s, 2H), 3.95 - 3.79 (m, 2H), 3.67 - 3.53 (m, 1H), 3.44 - 3.34 (m, 1H), 3.10 - 2.96 (m, 2H), 2.76 - 2.68 (m, 2H), 2.54 (s, 3H), 2.42 - 2.20 (m, 4H), 2.00~1.78 (m, 2H).

[0602] Example 51

Chemical Structure

[0603] Step 1: Compound 56A (2.00 g, 7.67 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (2.84 mg, 9.19 mmol), tetrakis(triphenylphosphine)palladium (886 mg, 0.767 mmol), and sodium carbonate (2.43 mg, 23.0 mmol) were suspended in 50 mL of a mixed solvent of dioxane:water = 4:1 and reacted at 80 °C for 16 h. After the reaction was completed, the reaction solution was added dropwise to 100 mL of ice water and filtered. The filtrate was extracted with dichloromethane (100 mL × 3), the organic phases were combined, concentrated, and purified by silica gel column chromatography (PE:EA = 40:1) to obtain the target compound 56B (420 mg, 17%).

[0604] LCMS (ESI): m / z = 317.1 [M+H] + 。

[0605] Step 2: Compound 56B (420 mg, 1.33 mmol) was dissolved in 2 mL of methanol, 2 mL of hydrochloric acid / dioxane was added, and the mixture was stirred at room temperature for 1.5 h and filtered. The filter cake was the target compound 56C (260 mg, 77%), which was used directly in the next-step reaction without purification.

[0606] LCMS (ESI): m / z = 217.1 [M+H] + 。

[0607] Step 3: Compound 56C (200 mg, 1.02 mmol), intermediate 1E (355 mg, 1.23 mmol), and DIPEA (33 mg, 0.03 mmol) were suspended in 2 mL of dioxane and reacted at 80 °C for 16 h. After the reaction was completed, the mixture was filtered. The filter cake was triturated with 5 mL of methanol, stirred at room temperature for 0.5 h, and filtered. The filter cake was the target compound 56 (190 mg, 51%).

[0608] LCMS (ESI): m / z = 468.1 [M+H] + 。

[0609] 11H NMR (400 MHz, DMSO-d 6 ) δ 8.07 (d, 1H), 7.97 (d, 1H), 7.53 - 7.47 (m, 1H), 7.46 - 7.37 (m, 2H), 6.92 - 6.89 (m, 1H), 4.84 (t, 1H), 4.47 (s, 2H), 4.01 (t, 2H), 3.76 (d, 2H), 3.50 - 3.39 (m, 1H), 3.29 - 3.17 (m, 1H), 3.02 - 2.83 (m, 2H), 2.76 (s, 2H), 2.44 - 2.29 (m, 2H), 2.29 - 2.17 (m, 2H), 1.91 - 1.61 (m, 2H).

[0610] Example 52

Chemical Structure

[0611] Step 1: Weigh compound 57A (3.00 g, 16.92 mmol) and compound tert-butyl piperazine-1-carboxylate (3.78 g, 20.30 mmol) into a 100 mL single-neck flask, dissolve them in 1,4-dioxane (30 mL), add N,N-diisopropylethylamine (6.56 g, 50.76 mmol). After the addition is complete, stir at 80 °C for 16 h. Detect the complete reaction by TLC spotting plate (petroleum ether:ethyl acetate = 5:1). Add water (20 mL), stir for 5 min, add ethyl acetate (20 mL) for extraction. Separate the organic phase, dry it over anhydrous sodium sulfate, concentrate it under reduced pressure, and purify it by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain the target compound 57B (2.8 g, yield: 48%).

[0612] LCMS m / z = 343.1 [M + 1] + .

[0613] Step 2: Compound 57B (1.0 g, 2.92 mmol) and trimethylsilylacetylene (1.43 g, 14.61 mmol) were weighed into a 100 mL Schlenk flask, dissolved in tetrahydrofuran (20 mL), and triethylamine (1.21 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.24 g, 0.29 mmol), and cuprous iodide (56 mg, 0.29 mmol) were added. After the addition was complete, the mixture was stirred at 80 °C for 12 h. The complete reaction was monitored by TLC spotting plate (petroleum ether:ethyl acetate = 5:1). Water (20 mL) was added, and the mixture was stirred for 5 min. Ethyl acetate (20 mL) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain the target compound 57C (0.50 g, 47%).

[0614] LCMS m / z = 361.1 [M+1] + 。

[0615] Step 3: Compound 57C (0.5 g, 1.39 mmol) was weighed into a 100 mL single-neck flask, dissolved in methanol (10 mL), and potassium carbonate (0.58 g, 4.2 mmol) was added. After the addition was complete, the mixture was stirred at room temperature for 2 h. The complete reaction was monitored by TLC spotting plate (petroleum ether:ethyl acetate = 3:1). The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to obtain the target compound 57D (0.40 g, 100%).

[0616] LCMS m / z = 289.2 [M+1] + 。

[0617] Step 4: Compound 57D (0.2 g, 0.69 mmol) was weighed into a 100 mL single-neck flask, dissolved in methanol (5 mL), and dioxane hydrochloride solution (4 N, 5 mL) was added. After the addition was complete, the mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to obtain the target compound 57E (0.15 g, crude product).

[0618] LCMS m / z = 189.1 [M+1] + 。

[0619] Step 5: Compound 1E (200 mg, 0.66 mmol) was added to a 100 mL single-necked flask, dissolved in 1,4-dioxane (8 mL), and compound 57E (131 mg, 0.66 mmol) and N,N-diisopropylethylamine (0.26 g, 1.98 mmol) were added. After the addition was completed, the system was protected with nitrogen gas, stirred at 90 °C for 16 h, the reaction solution was concentrated under reduced pressure to obtain a crude product of the target compound, and the title compound 57 (100 mg, 33%) was obtained by preparative HPLC separation.

[0620] Preparative method: Instrument: Waters 2767 preparative liquid phase, chromatographic column: SunFire@Prep C18 (19 mm × 250 mm, the sample was dissolved in DMF, filtered through a 0.45 μm filter to prepare the sample solution, and the conditions for preparative chromatography were as follows: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 5 mM aqueous ammonia), b. Gradient elution, the content of mobile phase A was 40% - 80%, c. Flow rate was 15 mL / min. d. Elution time was 20 min, retention time: 10.50 min.

[0621] LCMS m / z = 440.2 [M+1] + 。

[0622] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.51 (s, 2H), 7.46 (s, 1H), 4.85 (t, 1H), 4.31 (s, 1H), 3.83 (s, 8H), 3.72 (d, 2H), 3.33 - 3.45 (m, 1H), 3.15 - 3.25 (m, 1H), 2.84 - 2.98 (m, 2H), 2.26 - 2.40 (m, 2H), 2.13 - 2.17 (m, 2H), 1.71 - 1.82 (m, 2H).

[0623] Example 53

Chemical Structure

[0624] Step 1: Dissolve 58A (1.00 g, 8.39 mmol) in tetrahydrofuran (30 mL) under the protection of nitrogen gas. After lowering the temperature of the solution to -78 °C, slowly add n-butyllithium (810 mg, 12.59 mmol). After the addition is complete, warm the reaction solution to -40 °C, stir for 1 h, and then lower the temperature to -78 °C. Add a solution of iodine (2.56 g, 10.07 mmol) in tetrahydrofuran (10 mL). Allow the system to naturally recover to room temperature and stir for 1 h. Quench the reaction with water (100 mL) and extract three times with ethyl acetate (100 mL). Combine the organic phases, dry over anhydrous sodium sulfate, and then concentrate in vacuo to obtain a crude product. Purify the crude product by column chromatography (eluent: PE:EA = 100:1 to 20:1) to obtain the target compound 58B (700 mg, yield: 34.03%).

[0625] 1 H NMR (400 MHz, DMSO-d6) δ 7.76 - 7.73 (m, 2H), 7.38 - 7.36 (m, 2H).

[0626] Step 2: Add compound 58B (700 mg, 2.86 mmol), [1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]boronic acid (910 mg, 4.00 mmol), potassium carbonate (990 mg, 7.14 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (110 mg, 0.14 mmol) to a reaction flask. Add 20 mL of tetrahydrofuran and water (5 mL), displace with nitrogen gas, then warm to 85 °C and react for 16 h. Detect the disappearance of the raw materials by spot plate, dilute with water (100 mL), and extract three times with ethyl acetate (100 mL). Combine the organic phases, dry over anhydrous sodium sulfate, and then concentrate in vacuo to obtain a crude product. Purify the crude product by column chromatography (eluent: PE:EA = 100:1 to 20:1) to obtain the target compound 58C (850 mg, yield: 99.06%).

[0627] LC-MS (ESI): m / z = 301.2 [M+H] + 。

[0628] 1 H NMR (400 MHz, CDCl 3 ) δ 7.72 - 7.70 (m, 1H), 7.51 - 7.48 (m, 1H), 7.33 - 7.31 (m, 2H), 6.97 (s, 1H), 4.21 - 4.20 (m, 2H), 3.68 - 3.65 (m, 2H), 2.76 (s, 2H), 1.50 (s, 9H).

[0629] Step 3: Compound 58C (850 mg, 2.83 mmol) was dissolved in 20 mL of dichloromethane, dioxane hydrochloride (4 mL) was added, and the mixture was stirred at 0 °C for 30 min. After detecting the disappearance of the starting material by spot plate, the reaction solution was concentrated at room temperature to obtain crude product 58D (850 mg), which was used directly in the next step reaction.

[0630] Step 4: Compound 1E (300 mg, 1.04 mmol) and compound 58D (320 mg, 1.36 mmol) were dissolved in 1,4-dioxane (8 mL), and DIPEA (405 mg, 3.13 mmol) was added. After the addition was completed, the temperature was raised to 85 °C under the protection of nitrogen gas and stirred for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography (eluent: DCM:MeOH = 100:1 to 9:1), and then further purified by preparative HPLC (preparative method: instrument: waters 2767 preparative liquid phase, chromatographic column: SunFire@PrepC18 (19 mm × 250 mm), the sample was dissolved in DMF, filtered through a 0.45 μm filter, the sample solution was prepared, and the conditions for preparative chromatography were: a. The composition of mobile phases A and B: mobile phase A: acetonitrile, mobile phase B: water (containing 5 mM aqueous ammonia), b. Gradient elution, the content of mobile phase A was 25% - 90%, c. The flow rate was 15 mL / min. d. The elution time was 15 min, retention time: 6.0 min) to obtain the target compound 58 (105 mg, 22.30%).

[0631] LCMS m / z = 452.2 [M + H] + 。

[0632] 1 H NMR (400 MHz, CDCl 3 ) δ 7.73 - 7.70 (m, 1H), 7.52 - 7.50 (m, 1H), 7.34 - 7.31 (m, 2H), 7.05 (s, 1H), 6.24 (s, 1H), 4.52 (s, 2H), 4.08 (s, 2H), 3.92 - 3.84 (m, 2H), 3.67 - 3.58 (m, 1H), 3.43 - 3.35 (m, 1H), 3.09 - 2.99 (m, 2H), 2.83 (s, 2H), 2.42 - 2.23 (m, 5H), 1.99 - 1.84 (m, 2H).

[0633] Example 54

Chemical Structure

[0634] Step 1: Add 37B (1.1 g, 3.23 mmol) and dioxane (20 mL) to a 100 mL single-neck flask and dissolve. Sequentially add dimethylphosphine oxide (0.38 g, 4.88 mmol), potassium phosphate anhydrous (0.75 g, 3.53 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.37 g, 0.65 mmol), and tris(dibenzylideneacetone)dipalladium (0.30 g, 0.32 mmol). Under the protection of nitrogen gas, react at 100 °C for 7 h, concentrate, and purify by column chromatography (DCM:MeOH = 10:1) to obtain the title compound 59A (0.8 g, 73%).

[0635] LC-MS (ESI): m / z = 282.4[M - 56 + H] + 。

[0636] Step 2: Add 59A (0.5 g, 1.48 mmol), methanol (10 mL), and dioxane hydrochloride (4M, 10 mL) to a 50 mL single-neck flask and dissolve. Stir at room temperature for 3 h, concentrate the reaction solution to obtain the title compound 59B (0.40 g, 100%).

[0637] LC-MS (ESI): m / z = 238.1[M + H] + 。

[0638] Step 3: Add 1E (0.15 g, 0.52 mmol) and dioxane (10 mL) to a 50 mL single-neck flask and dissolve. Add 59B (0.25 g, 1.06 mmol) and diisopropylethylamine (0.27 g, 2.05 mmol), react at 90 °C overnight, concentrate the reaction solution, purify by HPLC, and lyophilize to obtain the title compound 59 (23 mg, 7%).

[0639] Fractionation method: Instrument: Waters 2767 preparative liquid phase, chromatographic column: SunFire@Prep C18 (19 mm×250 mm). Dissolve the sample in DMF, filter it through a 0.45 μm filter to prepare the sample solution. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% TFA); b. Gradient elution, the content of mobile phase A is 5% - 60%; c. Flow rate is 15 mL / min; d. Elution time is 15 min, retention time: 8.0 min.

[0640] 1 H NMR (400 MHz, DMSO-d6) δ 9.08 (d, 2H), 8.29 - 8.14 (m, 1H), 7.46 - 7.38 (m, 1H), 4.50 (s, 2H), 3.99 (t, 2H), 3.80 - 3.74 (m, 2H), 3.61 - 3.49 (m, 1H), 3.34 - 3.24 (m, 1H), 3.15 - 3.09 (m, 1H), 3.04 - 2.92 (m, 1H), 2.74 (s, 2H), 2.42 - 2.19 (m, 4H), 1.85 - 1.76 (m, 8H).

[0641] LC-MS (ESI): m / z = 489.5 [M + H] + 。

[0642] Example 55

Chemical Structure

[0643] Step 1: Dissolve compound 60A (800 mg, 4.94 mmol) in 1,4-dioxane (20 mL). Further add 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (360 mg, 0.49 mmol), cesium carbonate (4.83 g, 14.82 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (2.29 g, 7.41 mmol) and water (4 mL). Aspirate and ventilate with nitrogen gas three times. Heat to 90 °C and react for 16 h. Then pass through a silica gel plug, wash with ethyl acetate, concentrate, and obtain compound 60B (0.9 g, 69%) by column chromatography (petroleum ether / ethyl acetate = 1 / 1).

[0644] LC-MS (ESI): m / z=265.1[M+H] + 。

[0645] Step 2: Dissolve compound 60B (5800 mg, 1.89 mmol) in dichloromethane (10 mL). Further add trifluoroacetic acid (5.0 mL). React at room temperature for half an hour. Then concentrate. Dissolve the residue in dichloromethane, wash with saturated aqueous sodium bicarbonate solution, dry the organic phase, concentrate, and obtain compound 60C (300 mg, 97%), which was directly used in the next step.

[0646] LC-MS (ESI): m / z=165.1[M+H] + 。

[0647] Step 3: Dissolve compound 60C (300 mg, 1.04 mmol) in 1,4-dioxane (10.0 mL). Further add compound 1E (170 mg, 1.04 mmol) and N,N-diisopropylethylamine (400 mg, 3.12 mmol). Heat to 90 °C and react for 12 h. Then cool to room temperature, concentrate, and obtain compound 60 (340 mg, 79%) by column chromatography (dichloromethane / methanol = 10 / 1).

[0648] LC-MS (ESI): m / z=416.2[M+H] + 。

[0649] 1 H NMR (400 MHz, CDCl 3 ) δ 7.30 (d, 1H), 6.71 - 6.67 (m, 1H), 6.30 (s, 1H), 4.42 (s, 2H), 4.01 (s, 2H), 3.93 - 3.77 (m, 2H), 3.67 - 3.54 (m, 1H), 3.42 - 3.32 (m, 1H), 3.09 - 2.96 m, 2H), 2.72 - 2.64 (m, 2H), 2.45 - 2.20 (m, 4H), 2.18 (d, 3H), 1.97 - 1.79 (m, 2H).

[0650] Example 56

Chemical Structure

[0651] Step 1: Methanol (10 mL), 48B (0.5 g, 1.20 mmol), and palladium carbon (100 mg) were sequentially added to a 50 mL single-neck flask. After subjecting the mixture to a hydrogenation reaction at room temperature for 16 hours, the filtrate was filtered and concentrated under reduced pressure to obtain 61A (0.3 g, yield 86.1%).

[0652] LC-MS (ESI): m / z = 235.2 [M - 56 + H] + .

[0653] Step 2: 61A (0.3 g, 1.03 mmol) and hydrogen chloride - dioxane solution (4N, 15 mL) were sequentially added to a 50 mL single-neck flask. After reacting the mixture at room temperature for 1 hour and concentrating under reduced pressure, 61B (0.27 g, yield 99.6%) was obtained.

[0654] LC-MS (ESI): m / z = 191.2 [M + H] + .

[0655] Step 3: 1E (287 mg, 1.0 mmol), 61B (270 mg, 1.03 mmol), dioxane (10 mL) and DIPEA (774 mg, 6.0 mmol) were sequentially added to a 50 mL single-necked flask and reacted at 100 °C for 12 h. After cooling the temperature to room temperature, the reaction solution was directly concentrated under reduced pressure and then separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 100 / 8) to obtain 400 mg of a mixture.

[0656] The title compound 61-1 (62 mg, 14.1%, retention time: 1.733 min) and the title compound 61-2 (51 mg, 11.5%, retention time: 1.884 min) were obtained by chiral preparative separation. Chiral preparative separation method: Instrument: Waters 150MGM, chromatographic column: Chiralpak Column, mobile phase: A: carbon dioxide and B: methanol (0.1% aqueous ammonia), isocratic elution: 30% mobile phase B, flow rate: 100 mL / min, back pressure: 100 bar, column temperature: 25 °C, wavelength: 220 nm, elution time: 3.0 min.

[0657] (Compound 61-1) 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.43 (s,1H),6.98 - 6.86 (m,1H),6.86 - 6.75 (m,1H),6.76 - 6.59 (m,2H),4.90 - 4.79 (m,1H),4.78 - 4.59 (m,2H),4.37 - 4.28 (m,1H),4.00~3.92 (m,1H),3.90 - 3.78 (m,1H),3.78 - 3.68 (m,2H),3.49 - 3.36 (m,1H),3.27 - 2.81 (m,5H),2.76 - 2.55 (m,2H),2.41 - 2.12 (m,4H),1.87 - 1.70 (m,2H).

[0658] LC-MS (ESI): m / z = 442.2[M + H] + .

[0659] (Compound 61-2) 11H NMR (400 MHz, DMSO-d 6 ) δ 7.44 (s, 1H), 6.95 - 6.89 (m, 1H), 6.84 - 6.77 (m, 1H), 6.75 - 6.62 (m, 2H), 4.89 - 4.78 (m, 1H), 4.79 - 4.59 (m, 2H), 4.39 - 4.28 (m, 1H), 4.02 - 3.81 (m, 2H), 3.79 - 3.68 (m, 2H), 3.51 - 3.39 (m, 1H), 3.26 - 3.16 (m, 1H), 3.14 - 2.83 (m, 4H), 2.76 - 2.55 (m, 2H), 2.43 - 2.25 (m, 2H), 2.26 - 2.13 (m, 2H), 1.89 - 1.69 (m, 2H).

[0660] LC-MS (ESI): m / z = 442.2 [M + H] + .

[0661] Example 57 [Chemical formula]

[0662] Step 1: Dissolve compound 62A (1.0 g, 4.5 mmol) in DMF (30 mL), add cesium carbonate (2.2 g, 6.7 mmol) and 4-chlorobenzyl bromide (1.4 g, 6.7 mmol) further, aspirate and ventilate with nitrogen gas three times, heat to 50 °C and react for 5 h. After passing through a silica gel plug, wash with ethyl acetate, concentrate, and obtain a mixture of 62B-1 and 62B-2 (0.5 g, 32%) by column chromatography (dichloromethane / methanol = 9 / 1).

[0663] LC-MS (ESI): m / z = 348.8 [M + H] + .

[0664] Step 2: A mixture of compounds 62B-1 and 62B-2 (0.5 g, 1.4 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (2.5 mL) was further added. After reacting at room temperature for half an hour, it was concentrated to obtain a mixture of compounds 62C-1 and 62C-2 (0.3 g, 85%), which was directly used in the next step.

[0665] Step 3: A mixture of compounds 62C-1 and 62C-2 (0.3 g, 1.2 mmol) was dissolved in 1,4-dioxane (30.0 mL), and compound 1E (0.35 g, 1.2 mmol) and N,N-diisopropylethylamine (0.47 g, 3.7 mmol) were further added. After heating to 90 °C and reacting for 12 h, it was cooled to room temperature, concentrated, and a crude mixture of compounds 62-1 and 62-2 was obtained by column chromatography (dichloromethane / methanol = 10 / 1).

[0666] The crude mixture of compounds 62-1 and 62-2 (380 mg) was subjected to chiral resolution to obtain compound 62-1 (175 mg) and compound 62-2 (45 mg).

[0667] Fractionation method: Instrument: Waters 150SFC, Column: Chiralpak AS, Mobile phase: (A for CO 2 and B for MeOH(0.1%NH 3 ·H 2 O), Gradient: 35% phase B elution, Flow rate: 100 mL / min, Back pressure: 100 bar, Column temperature: 25 °C, Wavelength: 220 nm, Cycle time: 2.2 min, Sample preparation: Sample concentration 10 mg / mL, Acetonitrile solution, Sample injection: 3.5 mL each time. After separation, it was dried at a bath temperature of 35 °C using a rotary evaporator and fractionated to obtain P1 (Retention time: 1.905 minutes, designated as compound 62-1) and P2 (Retention time: 2.072 minutes, designated as compound 62-2).

[0668] LC-MS (ESI): m / z = 499.6[M+H] + 。

[0669] 11H NMR (400 MHz, DMSO-d 6 ) δ 7.64 (s, 1H), 7.4 - 7.38 (m, 2H), 7.34 (s, 1H), 7.25 - 7.23 (m, 2H), 5.22 (s, 1H), 4.82 (t, 2H), 4.76 (s, 2H), 4.03 - 3.98 (m, 2H), 3.73 (d, 2H), 3.45 - 3.36 (m, 1H), 3.22 - 2.18 (m, 1H), 2.95 - 2.82 (m, 2H), 2.67 (t, 2H), 2.37 - 2.27 (m, 2H), 2.22 - 2.14 (m, 2H), 1.82 - 1.73 (m, 2H).

[0670] LC-MS (ESI): m / z = 499.7 [M + H] + .

[0671] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.38 (s, 1H), 7.29 - 7.27 (m, 2H), 7.07 (s, 1H), 7.05 (s, 1H), 5.98 (s, 1H), 5.19 (s, 2H), 4.79 (s, 2H), 4.07 (s, 2H), 3.91 - 3.83 (m, 2H), 3.62 - 3.54 (m, 2H), 3.41 - 3.32 (m, 2H), 3.07 - 2.94 (m, 2H), 2.62 (t, 2H), 2.34 - 2.23 (m, 2H), 1.97 - 1.86 (m, 2H).

[0672] Example 58 [Chemical formula]

[0673] Step 1: Dissolve 63A (5.00 g, 17.67 mmol) in N,N-dimethylformamide (60 mL) under the protection of nitrogen gas. While stirring at room temperature, add dimethylphosphine oxide (1.70 g, 21.20 mmol), palladium acetate (0.43 g, 1.77 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.00 g, 3.53 mmol) and potassium phosphate (10.00 g, 47.11 mmol) sequentially. After the addition is completed, raise the temperature of the reaction solution to 100 °C, stir for 16 h, then lower the temperature to room temperature, concentrate under reduced pressure with an oil pump, dilute the reaction solution with water (100 mL), and extract three times with ethyl acetate (100 mL). Combine the organic phases, dry over anhydrous sodium sulfate, and then concentrate in vacuo to obtain a crude product. Purify the crude product by column chromatography (eluent: DCM:MeOH = 100:1 to 20:1) to obtain the target compound 63B (2.00 g, yield: 48.56%).

[0674] 1 H NMR (400MHz,CDCl 3 ) δ 7.89-7.85 (m,1H),7.69-7.64 (m,2H),7.40-7.29 (m,1H),1.76 (s,3H),1.73 (s,3H).

[0675] Step 2: Under the protection of nitrogen gas, compound 63B (2.00 g, 8.58 mmol) was added to a mixed solution of 1,4-dioxane (40 mL) and water (8 mL), and while stirring at room temperature, [1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]boronic acid (2.34 g, 10.30 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (630 mg, 0.86 mmol), and potassium carbonate (3.56 g, 25.75 mmol) were sequentially added. After the addition was completed, the reaction solution was heated to 85 °C and stirred for 16 h under the protection of nitrogen gas. The disappearance of the raw material was detected by spot plate, and then the temperature was lowered to room temperature. After concentration under reduced pressure, it was diluted with water (100 mL) and extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated in vacuo to obtain a crude product, which was purified by column chromatography (eluent: DCM:MeOH = 100:1 to 20:1) to obtain the target compound 63C (2.50 g, yield: 86.86%).

[0676] LC-MS (ESI): m / z = 280.60[M + H - 56] + 。

[0677] 1 H NMR (400 MHz, CDCl 3 ) δ 7.80 - 7.77 (m, 1H), 7.53 - 7.51 (m, 1H), 7.48 - 7.44 (m, 2H), 6.11 (s, 1H), 4.09 - 4.08 (m, 2H), 3.66 - 3.60 (m, 2H), 2.55 (s, 2H), 1.76 (s, 3H), 1.73 (s, 3H), 1.48 (s, 9H).

[0678] Step 3: Compound 63C (1.10 g, 3.28 mmol) was dissolved in 20 mL of dichloromethane, dioxane hydrochloride (4 mL) was added, and the mixture was stirred at 0 °C for 30 min. After detecting the disappearance of the raw material by TLC, the reaction solution was concentrated at room temperature to obtain a crude product 63D (800 mg), which was directly used in the next step reaction.

[0679] Step 4: Compound 1E (500 mg, 1.74 mmol) and Compound 63D (800 mg, 2.94 mmol) were dissolved in 1,4-dioxane (8 mL), and DIPEA (675 mg, 5.21 mmol) was added. After the addition was complete, the temperature was raised to 85 °C under the protection of nitrogen gas and stirred for 16 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography (eluent: DCM:MeOH = 100:1 to 9:1) and then further purified by a reverse-phase column (eluent: water:acetonitrile = 100:1 to 1:9) to obtain the target compound 63 (320 mg, 37.85%).

[0680] LCMS m / z = 487.3 [M+H] + 。

[0681] 1 H NMR (400 MHz, DMSO-d6) δ 7.82 - 7.79 (m, 1H), 7.68 - 7.61 (m, 2H), 7.51 - 7.47 (m, 1H), 7.39 (s, 1H), 6.35 (s, 1H), 4.87 - 4.85 (m, 1H), 4.38 (s, 2H), 4.00~3.98 (m, 2H), 3.76 - 3.75 (m, 2H), 3.48 - 2.39 (m, 1H), 3.26 - 3.18 (m, 1H), 2.98 - 2.84 (m, 2H), 2.57 (s, 2H), 2.43 - 2.30 (m, 2H), 2.23 - 2.17 (m, 2H), 1.86 - 1.73 (m, 2H), 1.67 (s, 3H), 1.64 (s, 3H).

[0682] Example 59

Chemical Structure

[0683] Step 1: Dissolve compound 37B (3.4 g, 10 mmol) in N,N-dimethylformamide (100 mL). Further add 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (725 mg, 1.0 mmol), potassium fluoride (1.7 g, 30 mmol), 4-isoxazoleboronic acid pinacol ester (2.4 g, 12 mmol) and water (30 mL). Aspirate and ventilate with nitrogen gas three times. Heat to 90 °C and react for 4 h. Then pass through a silica gel plug, wash with ethyl acetate, concentrate, and obtain compound 64A (1.3 g, 39%) by column chromatography (petroleum ether / ethyl acetate = 5 / 1).

[0684] LC-MS (ESI): m / z=329.1[M+H] + 。

[0685] Step 2: Dissolve compound 64A (1.3 g, 4.0 mmol) in methanol (40 mL). Further add potassium fluoride (0.7 g, 12 mmol) and water (12 mL). Heat to 90 °C and react for 4 h. Then pass through a silica gel plug, wash with ethyl acetate, concentrate, and obtain compound 64B (1.0 g, 84%) by column chromatography (petroleum ether / ethyl acetate = 4 / 1).

[0686] LC-MS (ESI): m / z=301.2[M+H] + 。

[0687] Step 3: Dissolve compound 64B (1.0 g, 3.3 mmol) in water (5 mL). Further add tetrabutylammonium bromide (96 mg, 0.3 mmol), 1,2-dibromoethane (751 mg, 4 mmol) and potassium hydroxide (560 mg, 10 mmol). Heat to 50 °C and react for 4 h. Then pass through a silica gel plug, wash with ethyl acetate, concentrate, and obtain compound 64C (0.7 g, 65%) by column chromatography (petroleum ether / ethyl acetate = 9 / 1).

[0688] LC-MS (ESI): m / z=327.2[M+H] + 。

[0689] Step 4: Compound 64C (0.7 g, 2.1 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (2.8 mL) was further added. After reacting at room temperature for half an hour, it was concentrated to obtain compound 64D (0.4 g, 90%), which was directly used in the next step.

[0690] Step 5: Compound 64D (0.4 mg, 1.7 mmol) was dissolved in 1,4 - dioxane (30.0 mL), and compound 1E (0.5 g, 1.8 mmol) and N,N - diisopropylethylamine (1.8 g, 14.5 mmol) were further added. After heating to 90 °C and reacting for 12 h, it was cooled to room temperature, concentrated, and compound 64 (0.4 g, 49%) was obtained by column chromatography (dichloromethane / methanol = 10 / 1).

[0691] LC - MS (ESI): m / z = 478.2[M + H] + 。

[0692] 1 H NMR (400 MHz, CDCl 3 ) δ 8.77 (s, 2H), 7.36 (s, 1H), 7.29 (s, 1H), 4.84 (t, 1H), 4.46 (s, 2H), 3.97 (t, 2H), 3.75 (d, 2H), 3.47 - 3.39 (m, 1H), 3.26 - 3.18 (m, 1H), 2.98 - 2.92 (m, 1H), 2.89 - 2.84 (m, 1H), 2.66 (s, 2H), 2.43 - 2.30 (m, 2H), 2.23 - 2.18 (m, 2H), 1.84 - 1.75 (m, 4H), 1.71 - 1.67 (m, 2H).

[0693] Example 60

Chemical Structure

[0694] Step 1: Methyl thiocyanate (131.45 g, 1.80 mol) and 1,2-dichloroethane (1.2 L) were added to a 3 L three-necked flask and dissolved. Trifluoromethanesulfonic anhydride (265.7 g, 0.94 mol) was added, and cyclobutanone (60.0 g, 0.86 mol) was slowly added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature overnight. The reaction solution was washed with saturated sodium bicarbonate solution, adjusted to pH = 8 - 9, allowed to stand for layering, and the organic phase was dried over anhydrous sodium sulfate, concentrated, purified by silica gel column chromatography (DCM:EA = 100:1 - 20:1), and recrystallized (EA:PE = 1:2) to obtain the target compound 65C (15.0 g, yield: 9%).

[0695] LCMS m / z = 199.1[M+1] + 。

[0696] Step 2: 65C (15.0 g, 75.6 mmol) and dichloromethane (300 mL) were added to a 500 mL single-necked flask and dissolved. Meta-chloroperbenzoic acid (78.3 g, 453.8 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was washed with 10% sodium hydroxide (100 mL), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 1:1 - EA) to obtain the target compound 65D (3.8 g, yield: 19%).

[0697] LCMS m / z = 263.1[M+1] + 。

[0698] Step 3: 65D (3.8 g, 14.5 mmol) and dichloromethane (40 mL) were added to a 100 mL single-necked flask and dissolved. Ammonia water (20 mL) was added, and the mixture was stirred at room temperature for 4 h. The reaction solution was directly phase-separated, the aqueous phase was extracted once with dichloromethane (20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:EA = 2:1 - EA) to obtain the target compound 65E (2.2 g, yield: 76%).

[0699] LCMS m / z = 200.1 [M+1] + 。

[0700] Step 4: Add 65E (2.2 g, 11.04 mmol) and acetonitrile (40 ml) to a 100 mL single-neck flask and dissolve. Add isoamyl nitrite (3.9 g, 33.12 mmol) and copper bromide (4.9 g, 22.07 mmol), and stir at 75 °C under nitrogen gas protection for 6 h. Concentrate the reaction solution, add water (100 mL) and dichloromethane (2 × 100 mL) for extraction. Combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (PE:EA = 3:1 - 1:1) to obtain the target compound 65G (2.0 g, yield: 69%).

[0701] LCMS m / z = 263.0 [M+1] + 。

[0702] Step 5: Add 65G (2.0 g, 7.6 mmol) and ethyl acetate (40 mL) to a 100 mL single-neck flask and dissolve. Add palladium on carbon (10%, 6.0 g), and stir at 60 °C for 72 h. Filter the reaction solution through diatomaceous earth, concentrate the filtrate, and purify by column chromatography (DCM:EA = 2:1 - EA) to obtain the target compound 65H (0.48 g, yield: 34%).

[0703] LCMS m / z = 185.1 [M+1] + 。

[0704] Step 6: Add 65H (0.18 g, 0.98 mmol) and dioxane (8 mL) to a 50 mL single-neck flask and dissolve. Add 31A (0.42 g, 1.96 mmol) and N,N-diisopropylethylamine (0.38 g, 2.94 mmol), and stir at 95 °C overnight. Concentrate the reaction solution and purify by column chromatography (DCM:EA = 5:1 - 1:1) to obtain the target compound 65I (60 mg, yield: 19%).

[0705] LCMS m / z = 317.2 [M+1] + 。

[0706] Step 7: 65I (60 mg, 0.19 mmol) and dioxane (3 mL) were added to a 50 mL single-neck flask and dissolved, then hydrogen chloride in dioxane (4 M, 3 mL) was added, and the mixture was stirred at room temperature for 4 h. The reaction solution was concentrated to obtain the target compound 65J (48 mg, yield: 100%), which was directly used in the next step reaction.

[0707] LCMS m / z = 217.2 [M+1] + 。

[0708] Step 8: 1E (42 mg, 0.15 mmol) and dioxane (6 mL) were added to a 50 mL single-neck flask and dissolved, then 65J (48 mg, 0.18 mmol) and N,N-diisopropylethylamine (59 mg, 0.45 mmol) were sequentially added, and the mixture was stirred at 95 °C overnight. The reaction solution was concentrated and purified by HPLC to obtain the target compound 65 (30 mg, yield: 43%).

[0709] Fractionation method: Instrument: Waters 2767 preparative liquid phase, chromatographic column: SunFire@Prep C18 (19 mm × 250 mm). The sample was dissolved in DMF, filtered through a 0.45 μm filter to prepare the sample solution. The conditions for preparative chromatography were as follows: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 5 mM ammonium acetate); b. Gradient elution, the content of mobile phase A was 20% - 70%; c. Flow rate was 15 mL / min; d. Elution time was 20 min, retention time: 9.5 min.

[0710] LCMS m / z = 468.1 [M+1] + 。

[0711] 11H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.23 (s, 1H), 4.81 (s, 1H), 3.83 - 3.66 (m, 6H), 3.43 - 3.35 (m, 6H), 3.23 - 3.18 (m, 2H), 3.07 - 3.00 (m, 4H), 2.94 - 2.76 (m, 2H), 2.42 - 2.26 (m, 2H), 2.17 - 2.12 (m, 2H), 1.84 - 1.68 (m, 2H).

[0712] Example 61

Chem.

[0713] Step 1: Under the protection of nitrogen gas, compound 66A (10.00 g, 31.96 mmol) was added to a mixed solution of 1,4-dioxane (100 mL) and water (10 mL). While stirring at room temperature, [1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]boronic acid (7.98 g, 35.15 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (2.30 g, 3.20 mmol), and potassium carbonate (11.04 g, 79.89 mmol) were sequentially added. After the addition was completed, the reaction solution was heated to 85 °C and stirred for 16 h. The disappearance of the raw material was detected by TLC, and then the temperature was lowered to room temperature. After concentrating under reduced pressure to a small volume, it was diluted with water (150 mL) and extracted three times with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography (eluent: DCM:MeOH = 100:1 to 20:1) to obtain the target compound 66B (8.00 g, yield: 67.98%).

[0714] LC-MS (ESI): m / z = 312.20 & 314.20 [M + H - 56] + .

[0715] 1 1H NMR (400 MHz, CDCl 3) δ 7.51 - 7.46 (m, 2H), 7.15 - 7.12 (m, 1H), 6.04 (s, 1H), 4.73 (s, 2H), 4.05 - 4.03 (m, 2H), 3.62 - 3.60 (m, 2H), 2.49 (s, 2H), 1.48 (s, 3H).

[0716] Step 2: Under the protection of nitrogen gas, compound 66B (2.00 g, 5.43 mmol) was dissolved in dichloromethane (40 mL), triethylamine (1.37 g, 13.58 mmol) was added while stirring in an ice bath, and acetyl chloride (0.49 g, 6.25 mmol) was slowly added dropwise. After the addition was completed, the reaction solution was stirred at 0 °C for 1 h. The disappearance of the raw material was detected by TLC, and saturated ammonium chloride aqueous solution (100 mL) was added to quench the reaction, and the mixture was extracted three times with dichloromethane (50 mL). The combined organic phases were dried over anhydrous sodium sulfate and then concentrated in vacuo to obtain a crude product, which was purified by column chromatography (eluent: PE:EA = 100:1 to 4:1) to obtain the target compound 66C (2.00 g, yield: 95.96%).

[0717] 1 H NMR (400 MHz, CDCl 3 ) δ 7.54 - 7.52 (m, 1H), 7.40 - 7.39 (m, 1H), 7.20 - 7.17 (m, 1H), 6.05 (s, 1H), 5.19 (s, 2H), 4.07 - 4.06 (m, 2H), 3.65 - 3.62 (m, 2H), 2.50 (s, 2H), 2.14 (s, 3H), 1.49 (s, 9H).

[0718] Step 3: Under the protection of nitrogen gas, compound 66C (2.00 g, 4.87 mmol) was dissolved in 1,4-dioxane (80 mL), and while stirring at room temperature, bis(pinacolato)diboron (1.49 g, 5.85 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (178 mg, 0.24 mmol) and potassium acetate (1.44 g, 14.62 mmol) were added sequentially. After the addition was completed, the reaction solution was heated to 80 °C and stirred for 5 h. The disappearance of the raw material was detected by TLC, and then the temperature was lowered to room temperature. After concentration under reduced pressure to a small volume, it was diluted with water (100 mL) and extracted three times with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated in vacuo to obtain crude product 66D (2.5 g), which was directly used in the reaction of the next step.

[0719] Step 4: The crude compound 66D (2.5 g, 5.47 mmol) was dissolved in methanol (60 mL), and an aqueous solution of 1 M sodium hydroxide (655 mg, 16.40 mmol) was added. After the addition was completed, it was stirred at room temperature for 16 h under the protection of nitrogen gas. After the reaction solution was concentrated under reduced pressure to a small volume, it was diluted with water (50 mL) and extracted twice with ethyl acetate (100 mL). The aqueous phase was further concentrated and then purified by a reverse-phase column (eluent: water:acetonitrile = 100:1 to 1:9) to obtain compound 66E (1.20 g, 69.66%).

[0720] LCMS m / z = 260.30 [M - 56 + H] + 。

[0721] 1 H NMR (400 MHz, D 2 O) δ 7.34 - 7.32 (m, 1H), 7.18 - 7.16 (m, 1H), 7.11 (s, 1H), 5.96 (s, 1H), 4.63 (s, 2H), 3.93 (s, 2H), 3.50 (s, 2H), 2.41 (s, 2H), 1.34 (s, 9H).

[0722] Step 5: Compound 66E (380 mg, 1.21 mmol) was dissolved in dichloromethane (6 mL), and a 4 M dioxane hydrochloride solution (176 mg, 4.82 mmol) was added under an ice bath. After the addition was complete, the mixture was stirred in an ice bath for 1.5 h under the protection of nitrogen gas. The reaction solution was concentrated under reduced pressure to obtain the crude compound 66F (310 mg), which was directly used in the reaction of the next step.

[0723] LCMS m / z = 216.30 [M+H] + 。

[0724] Step 6: Compound 1E (300 mg, 1.04 mmol) and compound 66F (310 mg, 1.23 mmol) were dissolved in 1,4-dioxane (8 mL), and DIPEA (405 mg, 3.13 mmol) was added. After the addition was complete, the temperature was raised to 85 °C under the protection of nitrogen gas, and the mixture was stirred for 16 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (eluent: DCM:MeOH = 100:1 to 9:1) and then further purified by a reverse-phase column (eluent: water:acetonitrile = 100:1 to 1:9) to obtain the target compound 66 (150 mg, 30.85%).

[0725] LCMS m / z = 467.20 [M+H] + 。

[0726] 1 H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.70 - 7.68 (m, 1H), 7.46 - 7.44 (m, 2H), 7.38 (s, 1H), 6.34 (s, 1H), 4.98 (s, 2H), 4.87 - 4.84 (m, 1H), 4.37 (s, 2H), 4.00~3.97 (m, 2H), 3.76 - 3.75 (m, 2H), 3.47 - 3.39 (m, 1H), 3.26 - 3.18 (m, 1H), 2.98 - 2.84 (m, 2H), 2.56 (s, 2H), 2.43 - 2.30 (m, 2H), 2.22 - 2.18 (m, 2H), 1.82 - 1.76 (m, 2H).

[0727] Example 62 [Chemical formula]

[0728] Step 1: To a 250 mL single-necked flask, 67A (5.0 g, 31.3 mmol), tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (6.8 g, 31.3 mmol), potassium hydroxide (5.3 g, 93.9 mmol), and N,N-dimethylformamide (100 mL) were sequentially added. After reacting at room temperature for 6 hours, the temperature was further raised to 80 °C and reacted for 24 hours. After filtration, ethyl acetate (500 mL) was added to the filtrate, washed with water (100 mL × 3), washed with saturated brine (100 mL × 1), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 67B (10.0 g, yield 95.2%).

[0729] LC-MS (ESI): m / z=281.1[M-56+H] + .

[0730] Step 2: To a 1000 mL single-necked flask, 67B (10.0 g, 29.8 mmol), ethyl acetate (300 mL), and palladium on carbon (2 g) were sequentially added, and the hydrogenation reaction was carried out at room temperature for 12 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain 67C (8.0 g, yield 87.9%).

[0731] LC-MS (ESI): m / z=307.1[M+H] + .

[0732] Step 3: Add acetonitrile (30 mL), tert-butyl nitrite (3.5 g, 33.83 mmol), and cuprous iodide (5.1 g, 27.06 mmol) sequentially to a 100 mL single-necked flask, heat to 65 °C, and add dropwise a solution of 67C (6.9 g, 22.55 mmol) in acetonitrile (40 mL). After the addition is complete, react at 65 °C for 4 hours. After closing the heating, continue the reaction for 12 hours. Concentrate under reduced pressure and then separate and purify by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 20 / 100) to obtain 67D (1.5 g, yield 15.6%).

[0733] LC-MS (ESI): m / z=418.4[M+H] + 。

[0734] Step 4: Add 67D (1.4 g, 3.36 mmol), tetrahydrofuran (30 mL), cuprous iodide (127 mg, 0.67 mmol), triethylamine (1.0 g, 10.08 mmol), bis(triphenylphosphine)palladium dichloride (238 mg, 0.34 mmol), and trimethylsilylacetylene (1.01 g, 5.05 mmol) sequentially to a 100 mL single-necked flask. React at room temperature for 6 hours under the protection of nitrogen gas. Concentrate under reduced pressure and then separate and purify by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 20 / 100) to obtain 67E (1.2 g, yield 92.3%).

[0735] LC-MS (ESI): m / z=388.2[M+H] + 。

[0736] Step 5: Add 67E (1.2 g, 3.1 mmol), methanol (30 mL), and potassium carbonate (1.3 g, 9.3 mmol) sequentially to a 50 mL single-necked flask. React at room temperature for 2 hours, filter, concentrate the filtrate under reduced pressure, and then separate and purify by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 20 / 100) to obtain 67F (0.8 g, yield 81.9%).

[0737] LC-MS (ESI): m / z = 316.1 [M+H] + 。

[0738] Step 6: 67F (0.3 g, 0.95 mmol), triethylamine (1.9 g, 19 mmol), and iodotrimethylsilane (1.9 g, 9.5 mmol) were sequentially added to a 50 mL single-neck flask, reacted at room temperature for 2 hours, concentrated under reduced pressure to obtain a crude product of 67G, which was directly used in the next step.

[0739] LC-MS (ESI): m / z = 216.1 [M+H] + 。

[0740] Step 7: 1E (273 mg, 0.95 mmol), 67G (crude product 0.8 g, 0.95 mmol), dioxane (5 mL), and DIPEA (774 mg, 6.0 mmol) were sequentially added to a 50 mL single-neck flask, reacted at 100 °C for 12 hours. After cooling to room temperature and directly concentrating the reaction solution under reduced pressure, it was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 100 / 8) to obtain 400 mg of a mixture.

[0741] The title compound 67-1 (80 mg, 18.06%, retention time: 1.855 min) and the title compound 67-2 (50 mg, 11.31%, retention time: 2.423 min) were obtained by chiral preparative separation. Chiral preparative separation method: Instrument: Waters 150MGM, chromatographic column: Chiralpak Column, mobile phase: A: carbon dioxide and B: methanol (0.1% aqueous ammonia), isocratic elution: 30% mobile phase B, flow rate: 150 mL / min, back pressure: 100 bar, column temperature: 38 °C, wavelength: 220 nm, elution time: 3.9 min.

[0742] (Compound 67-1) 1 H NMR (400 MHz, DMSO-d 6) δ7.90 - 7.83 (m, 1H), 7.46 (s, 1H), 7.09 - 7.04 (m, 1H), 4.87 - 4.79 (m, 1H), 4.81 - 4.60 (m, 2H), 4.52 - 4.35 (m, 2H), 4.08 (s, 1H), 4.04 - 3.95 (m, 1H), 3.78 - 3.65 (m, 2H), 3.51 - 3.37 (m, 2H), 3.28 - 3.15 (m, 1H), 3.07 - 2.74 (m, 5H), 2.43 - 2.16 (m, 4H), 1.86 - 1.70 (m, 2H).

[0743] LC-MS (ESI): m / z = 467.1[M + H] + 。

[0744] (Compound 67 - 2) 1 1H NMR (400 MHz, DMSO-d 6 ) δ7.96 - 7.71 (m, 1H), 7.47 (s, 1H), 7.25 - 6.78 (m, 1H), 4.88 - 4.64 (m, 3H), 4.53 - 4.36 (m, 2H), 4.08 (s, 1H), 4.04 - 3.90 (m, 1H), 3.72 (s, 2H), 3.48 - 3.39 (m, 2H), 3.27 - 3.21 (m, 1H), 3.06 - 2.75 (m, 5H), 2.40 - 2.17 (m, 4H), 1.87 - 1.72 (m, 2H).

[0745] LC-MS (ESI): m / z = 467.1[M + H] + 。

[0746] Example 63

Chem.

[0747] Step 1: To a 100 mL single-necked flask, add acetonitrile (30 mL), tert-butyl nitrite (1.5 g, 14.7 mmol), and cuprous chloride (1.2 g, 11.8 mmol) sequentially. Heat to 65 °C, and dropwise add a solution of 67C (3.0 g, 9.8 mmol) in acetonitrile (10 mL). After the addition is complete, react at 65 °C for 4 hours. After closing the heating, continue the reaction for 12 hours. Concentrate under reduced pressure and then separate and purify by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 20 / 100) to obtain 68A (0.5 g, yield 13.7%).

[0748] LC-MS (ESI): m / z=270.1[M-56+H] + 。

[0749] Step 2: To a 50 mL single-necked flask, add 68A (0.5 g, 1.5 mmol) and hydrogen chloride-dioxane solution (4N, 10 mL) sequentially. React at room temperature for 1 hour. Concentrate under reduced pressure to obtain 68B (0.5 g, yield 100.0%).

[0750] LC-MS (ESI): m / z=226.1[M+H] + 。

[0751] Step 3: To a 50 mL single-necked flask, add 1E (430 mg, 1.5 mmol), 68B (500 mg, 1.5 mmol), dioxane (5 mL), and DIPEA (774 mg, 6.0 mmol) sequentially. React at 100 °C for 12 hours. Lower the temperature to room temperature, directly concentrate the reaction solution under reduced pressure, and then separate and purify by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 100 / 8) to obtain 500 mg of the mixture.

[0752] Chiral separation yielded the title compound 68-1 (50 mg, 7.0%, retention time: 1.704 min) and the title compound 68-2 (110 mg, 15.4%, retention time: 2.183 min). Chiral separation method: Instrument: Waters 150MGM, chromatographic column: Chiralpak Column, mobile phase: A: carbon dioxide and B: methanol (0.1% aqueous ammonia), isocratic elution: 30% mobile phase B, flow rate: 120 mL / min, back pressure: 100 bar, column temperature: 25 °C, wavelength: 220 nm, elution time: 4 min.

[0753] (Compound 68-1) 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.77 - 7.73 (m, 1H), 7.48 (s, 1H), 7.21 - 7.15 (m, 1H), 4.88 - 4.81 (m, 1H), 4.80 - 4.59 (m, 2H), 4.48 - 4.33 (m, 2H), 4.09 - 3.95 (m, 1H), 3.79 - 3.68 (m, 2H), 3.47 - 3.34 (m, 2H), 3.28 - 3.17 (m, 1H), 3.07 - 2.84 (m, 3H), 2.80 - 2.67 (m, 2H), 2.42 - 2.15 (m, 4H), 1.87 - 1.67 (m, 2H).

[0754] LC-MS (ESI): m / z = 477.1 [M + H] + .

[0755] (Compound 68-2) 1 H NMR (400 MHz, DMSO-d 6) δ7.77 - 7.73 (m, 1H), 7.48 (s, 1H), 7.19 - 7.15 (m, 1H), 4.90 - 4.82 (m, 1H), 4.82 - 4.63 (m, 2H), 4.47 - 4.31 (m, 2H), 4.10 - 3.94 (m, 1H), 3.76 - 3.67 (m, 2H), 3.48 - 3.33 (m, 2H), 3.27 - 3.17 (m, 1H), 3.06 - 2.84 (m, 3H), 2.80 - 2.69 (m, 2H), 2.38 - 2.15 (m, 4H), 1.87 - 1.68 (m, 2H).

[0756] LC-MS (ESI): m / z = 477.1[M + H] + 。

[0757] Example 64

Chemical Structure

[0758] Step 1: Compound 69A (10 g, 84.6 mmol) and paraformaldehyde (25.4 g, 0.85 mol) were dissolved in acetic acid (30 mL). A 40% hydrobromic acid solution (49.2 mL, 0.85 mol) was slowly added at 0 °C, and the mixture was stirred for 30 min, heated to 80 °C and reacted for 12 h. Then it was concentrated, and compound 69B (2 g, 8%) was obtained by column chromatography (pure petroleum ether).

[0759] Step 2: Compound 69B (1.0 g, 3.3 mmol) was dissolved in ethanol (30 mL) and benzylamine (0.35 g, 3.3 mmol). After heating and refluxing for 4 h, it was passed through a silica gel plug, washed with ethyl acetate, concentrated, and compound 69C (0.6 g, 73%) was obtained by column chromatography (petroleum ether / ethyl acetate = 4 / 1).

[0760] LC-MS (ESI): m / z = 250.4[M + H] + 。

[0761] Step 3: Dissolve compound 69C (0.5 g, 2.0 mmol) in methanol (30 mL), add palladium carbon (50 mg) further, aspirate and ventilate three times with a hydrogen balloon, react at room temperature for 12 h, filter, concentrate, and obtain compound 69D (0.2 g, 62%) by column chromatography (methanol / triethylamine = 100 / 1).

[0762] LC-MS (ESI): m / z=160.2[M+H] + 。

[0763] Step 4: Dissolve compound 69D (0.2 mg, 1.3 mmol) in 1,4-dioxane (30.0 mL), add compound 1E (0.36 g, 1.3 mmol) and N,N-diisopropylethylamine (0.32 g, 2.6 mmol) further, heat to 90 °C and react for 4 h, then cool to room temperature, concentrate, and obtain compound 69 (0.1 g, 19%) by column chromatography (dichloromethane / methanol = 10 / 1).

[0764] LC-MS (ESI): m / z=411.2[M+H] + 。

[0765] 1 H NMR (400MHz,CDCl 3 ) δ 7.38 -7.32 (m,1H),7.23 -7.12 (m,2H),4.91 -4.85 (m,1H),4.78 -4.71 (m,3H),3.79 (d,2H),3.49 -3.41 (m,1H),3.27 -3.15 (m,1H),3.00 -2.94 (m,1H),2.94 -2.83 (m,5H),2.44 -2.33 (m,2H),2.25 -2.20 (m,2H),2.08 -1.99 (m,2H),1.87 -1.74 (m,2H).

[0766] Example 65

Chemical Structure

[0767] Step 1: Dissolve compound 70A (1.2 g, 5.0 mmol) in tetrahydrofuran (50 mL). Further add bis(triphenylphosphine)palladium dichloride (350.0 mg, 0.5 mmol), triethylamine (1.1 g, 10.0 mmol), trimethylsilylacetylene (650.0 mg, 6.5 mmol) and cuprous iodide (40.0 mg, 0.25 mmol). Aspirate and ventilate with nitrogen gas three times. Heat to 50 °C and react for 14 h. Then pass through a silica gel plug, wash with ethyl acetate, concentrate, and obtain compound 70B (800 mg, 76%) by column chromatography (petroleum ether / ethyl acetate = 5 / 1).

[0768] Step 2: Dissolve compound 70B (420.0 mg, 2.0 mmol) in 1,4-dioxane (30 mL). Further add 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (144.0 mg, 0.2 mmol), potassium carbonate (560.0 mg, 4.0 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (720.0 mg, 2.4 mmol) and water (6.0 mL). Aspirate and ventilate with nitrogen gas three times. Heat to 45 °C and react for 14 h. Then pass through a silica gel plug, wash with ethyl acetate, concentrate, and obtain compound 70C (400 mg, 56%) by column chromatography (dichloromethane / methanol = 20 / 1).

[0769] LC-MS (ESI): m / z = 357.2 [M+H] + 。

[0770] Step 3: Dissolve compound 70C (356.0 mg, 1.0 mmol) in dichloromethane (10 mL). Further add trifluoroacetic acid (1.2 mL). React at room temperature for half an hour, then concentrate to obtain compound 70D (150.0 mg, 78%), which was directly used in the next step.

[0771] LC-MS (ESI): m / z = 257.1 [M+H] + 。

[0772] Step 4: Compound 70D (128.1 mg, 0.5 mmol) was dissolved in 1,4-dioxane (10.0 mL), and compound 1E (172.0 mg, 0.6 mmol) was further added. After heating to 90 °C and reacting for 4 h, it was cooled to room temperature, concentrated, and compound 70E (200 mg, 79%) was obtained by column chromatography (dichloromethane / methanol = 10 / 1).

[0773] LC-MS (ESI): m / z = 508.2 [M+H] + 。

[0774] Step 5: Compound 70E (200.0 mg, 0.4 mmol) was dissolved in methanol (10.0 mL), and potassium carbonate (150.0 mg, 1.1 mmol) was further added. After reacting at room temperature for 2 h, it was concentrated, and compound 70 (110.0 mg, 62%) was obtained by column chromatography (dichloromethane / methanol = 15 / 1).

[0775] LC-MS (ESI): m / z = 436.2 [M+H] + 。

[0776] 1 1H NMR (400 MHz, CDCl 3 ) δ 8.66 (d, 1H), 7.74 - 7.72 (m, 1H), 7.35 (d, 1H), 6.75 (t, 1H), 6.57 (s, 1H), 4.47 (s, 2H), 4.06 (s, 2H), 3.87 - 3.79 (m, 2H), 3.65 - 3.57 (m, 1H), 3.40 - 3.32 (m, 1H), 3.23 (s, 1H), 3.08 - 2.98 (m, 2H), 2.71 (s, 2H), 2.43 - 2.35 (m, 2H), 2.26 - 2.18 (m, 2H), 1.96 - 1.78 (m, 2H).

[0777] Example 66

Chemical Structure

[0778] Step 1: Weigh compound 71A (5.00 g, 22.60 mmol) and dimethylphosphine oxide (2.65 g, 33.90 mmol) into a 250 mL single-neck flask, dissolve them with 1,4-dioxane (50 mL), add potassium phosphate (14.39 g, 67.80 mmol), tris(dibenzylideneacetone)dipalladium (1.03 g, 1.13 mmol), and 5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.31 g, 2.26 mmol). After the addition is complete, stir at 90 °C for 16 h. Detect the complete reaction by TLC spotting plate (petroleum ether:ethyl acetate = 5:1), add water (50 mL), stir for 5 min, extract with ethyl acetate (50 mL), separate the organic phase, dry it over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by column chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to obtain the target compound 71B (2.2 g, yield: 57%).

[0779] LCMS m / z = 172.1 [M + 1] + 。

[0780] Step 2: Weigh compound 71B (2.2 g, 12.85 mmol) into a 100 mL single-neck flask, dissolve it with acetonitrile (30 mL), add isoamyl nitrite (3.01 g, 25.70 mmol) and cuprous bromide (4.37 g, 19.22 mmol). After the addition is complete, stir at 70 °C for 12 h. Detect the complete reaction by TLC spotting plate (petroleum ether:ethyl acetate = 5:1), add water (50 mL), stir for 5 min, extract with ethyl acetate (50 mL), separate the organic phase, dry it over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to obtain the target compound 71C (0.43 g, yield: 14%).

[0781] LCMS m / z = 235.0 [M + 1] + 。

[0782] Step 3: Weigh Compound 71C (0.20 g, 0.85 mmol) and Compound 1B (0.32 g, 1.02 mmol) into a 100 mL single-neck flask, dissolve them with 1,4-dioxane (8 mL), add 2N sodium carbonate solution (2 mL) and tetrakis(triphenylphosphine)palladium (0.1 g, 0.09 mmol). After the addition is complete, stir at 90 °C for 16 h. Detect the complete reaction by TLC spotting plate (petroleum ether:ethyl acetate = 5:1). Add water (20 mL), stir for 5 min, extract with ethyl acetate (20 mL), separate the organic phase, dry it over anhydrous sodium sulfate, concentrate it under reduced pressure, and purify the crude product by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain the target compound 71E (1.0 g, yield: 58%).

[0783] LCMS m / z=338.1[M+1] + 。

[0784] Step 4: Weigh Compound 71E (0.20 g, 0.59 mmol) into a 100 mL single-neck flask, dissolve it with dichloromethane (6 mL), add trifluoroacetic acid (2 mL), and stir for 2 h after the addition is complete. Concentrate the organic phase under reduced pressure until the liquid stops dripping to obtain the target compound 71F (0.20 g, crude product).

[0785] LCMS m / z=238.1[M+1] + 。

[0786] Step 5: Add Compound 1E (150 mg, 0.52 mmol), Compound 71F (150 mg, 0.62 mmol), and 1,4-dioxane (10 mL) to a 100 mL single-neck flask and dissolve them. Then add N,N-diisopropylethylamine (0.16 g, 1.56 mmol). After the addition is complete, protect the system with nitrogen gas, stir at 90 °C for 16 h, concentrate the reaction solution under reduced pressure to obtain a crude product, and separate it by preparative HPLC to obtain the title compound 71 (110 mg, 43%).

[0787] Fractionation method: Instrument: Waters 2767 Fractionation Liquid Phase, Chromatographic Column: SunFire@Prep C18 (19 mm × 250 mm). Dissolve the sample in DMF, filter it through a 0.45 μm filter to prepare the sample solution. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: Acetonitrile, Mobile phase B: Water (containing 5 mM aqueous ammonia); b. Gradient elution, the content of mobile phase A is 40% - 70%; c. Flow rate is 15 mL / min; d. Elution time is 20 min, retention time: 11.20 min.

[0788] LCMS m / z = 489.2 [M + 1] + 。

[0789] 1 H NMR (400 MHz, DMSO - d 6 ) δ 8.99 (t, 1H), 7.79 (t, 1H), 7.38 (s, 2H), 4.84 (t, 1H), 4.48 (s, 2H), 3.99 (t, 2H), 3.75 (d, 2H), 3.48 - 3.39 (m, 1H), 3.26 - 3.18 (m, 1H), 2.98 - 2.84 (m, 2H), 2.70 (s, 2H), 2.42 - 2.30 (m, 2H), 2.24 - 2.18 (m, 2H), 1.86 - 1.76 (m, 2H), 1.73 (s, 3H), 1.70 (s, 3H).

[0790] Example 67

Chemical Structure

[0791] Step 1: Add 65H (90 mg, 0.49 mmol) and dioxane (6 mL) to a 50 mL single - necked flask and dissolve. Add piperazine (84 mg, 0.98 mmol), and stir at 90 °C for 3 h. Add water (5 mL) to the reaction solution, extract with ethyl acetate (3 × 10 mL), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain the target compound 72A (60 mg, crude product), which was directly used in the next - step reaction.

[0792] LCMS m / z = 191.2 [M+1] + 。

[0793] Step 2: Add 1E (60 mg, 0.21 mmol) and dioxane (6 mL) to a 50 mL single-neck flask and dissolve. Sequentially add 72A (60 mg, 0.32 mmol) and N,N-diisopropylethylamine (68 mg, 0.53 mmol), and stir at 95 °C overnight. Concentrate the reaction solution and purify by SFC to obtain the target compound 72 (9 mg, yield: 10%).

[0794] Fractionation method: Instrument: SFC Prep150, Chromatographic column: SunFire silica (19 mm × 250 mm). Dissolve the sample in MeOH, filter through a 0.45 μm filter to prepare the sample solution. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: CO2, Mobile phase B: methanol / acetonitrile (7:3); b. Elute at a uniform concentration, and the content of mobile phase B is 35%; c. Flow rate is 40 mL / min; d. Elution time is 15 min.

[0795] LCMS m / z = 442.31 [M+1] + 。

[0796] 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.36 (s, 1H), 4.81 (s, 1H), 3.84 - 3.69 (m, 10H), 3.26 - 3.20 (m, 4H), 3.04 - 3.02 (m, 2H), 2.98 - 2.83 (m, 2H), 2.40 - 2.26 (m, 2H), 2.22 - 2.16 (m, 2H), 1.83 - 1.71 (m, 2H).

[0797] Example 68

Chemical Structure

[0798] Step 1: Methanol (10 mL), 67D (0.5 g, 1.20 mmol), and palladium carbon (100 mg) were sequentially added to a 50 mL single-necked flask, and the mixture was subjected to a hydrogenation reaction at room temperature for 16 hours. After filtration of the filtrate and concentration under reduced pressure, 73A (0.31 g, yield 88.9%) was obtained.

[0799] LC-MS (ESI): m / z = 292.1 [M+H] + 。

[0800] Step 2: 73A (0.31 g, 1.07 mmol) and hydrogen chloride-dioxane solution (4N, 15 mL) were sequentially added to a 50 mL single-necked flask, and the mixture was reacted at room temperature for 1 hour. After concentration under reduced pressure, 73B (0.25 g, yield 100.0%) was obtained.

[0801] LC-MS (ESI): m / z = 192.1 [M+H] + 。

[0802] Step 3: 1E (287 mg, 1.0 mmol), 73B (250 mg, 1.07 mmol), dioxane (10 mL), and DIPEA (774 mg, 6.0 mmol) were sequentially added to a 50 mL single-necked flask, and the mixture was reacted at 100 °C for 12 hours. After cooling to room temperature and directly concentrating the reaction solution under reduced pressure, separation and purification were carried out by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 100 / 8) to obtain 350 mg of a mixture.

[0803] The title compound 73-1 (91 mg, 20.6%, retention time: 1.472 min) and the title compound 73-2 (63 mg, 14.3%, retention time: 1.770 min) were obtained by chiral preparative separation. Chiral preparative separation method: Instrument: Waters 150MGM, chromatographic column: Chiralpak Column, mobile phase: A: carbon dioxide and B: methanol (0.1% aqueous ammonia), isocratic elution: 30% mobile phase B, flow rate: 100 mL / min, back pressure: 100 bar, column temperature: 25 °C, wavelength: 220 nm, elution time: 4.2 min.

[0804] (Compound 73-1) 1 1H NMR (400 MHz, DMSO-d 6 ) δ 7.79 - 7.67 (m, 1H), 7.44 (s, 1H), 7.06 - 6.94 (m, 1H), 6.68 - 6.55 (m, 1H), 4.89 - 4.80 (m, 1H), 4.79 - 4.62 (m, 2H), 4.50 - 4.34 (m, 2H), 4.06 - 3.92 (m, 1H), 3.79 - 3.65 (m, 2H), 3.50 - 3.37 (m, 1H), 3.36 - 3.32 (m, 1H), 3.28 - 3.16 (m, 1H), 3.06 - 2.81 (m, 3H), 2.79 - 2.63 (m, 2H), 2.41 - 2.25 (m, 2H), 2.25 - 2.14 (m, 2H), 1.89 - 1.71 (m, 2H).

[0805] LC-MS (ESI): m / z = 443.2 [M + H] + .

[0806] (Compound 73 - 2) 1 1H NMR (400 MHz, DMSO-d 6 ) δ 7.84 - 7.64 (m, 1H), 7.44 (s, 1H), 7.15 - 6.83 (m, 1H), 6.80 - 6.46 (m, 1H), 4.87 - 4.81 (m, 1H), 4.80 - 4.62 (m, 2H), 4.50 - 4.31 (m, 2H), 4.04 - 3.94 (m, 1H), 3.76 - 3.68 (m, 2H), 3.50 - 3.38 (m, 1H), 3.36 - 3.31 (m, 1H), 3.28 - 3.16 (m, 1H), 3.05 - 2.82 (m, 3H), 2.81 - 2.64 (m, 2H), 2.43 - 2.25 (m, 2H), 2.25 - 2.14 (m, 2H), 1.85 - 1.71 (m, 2H).

[0807] LC-MS (ESI): m / z = 443.2 [M + H] + .

[0808] Example 69 [Chemical Structure]

[0809] Step 1: To a 250 mL single-necked flask, add N,N-dimethylformamide (50 mL), 74A (5.0 g, 35.97 mmol), tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (7.77 g, 35.97 mmol), and potassium hydroxide (6.05 g, 107.85 mmol) sequentially. After reacting at 100 °C for 16 hours, filter, add ethyl acetate (100 mL) to the filtrate, wash with water (50 mL × 3), wash with saturated brine (100 mL × 1), dry the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and then separate and purify by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (v / v) = 20 / 100) to obtain 74B (0.5 g, yield 4.4%).

[0810] LC-MS (ESI): m / z = 316.2[M+H] + 。

[0811] Step 2: To a 50 mL single-necked flask, add 74B (0.5 g, 1.59 mmol), dichloromethane (15 mL), and triethylamine (3.21 g, 31.8 mmol) sequentially. Dropwise add iodotrimethylsilane (3.18 g, 15.9 mmol) at 0 °C, react at room temperature for 1 hour, concentrate under reduced pressure to obtain crude product 74C (4.5 g, yield 100.0%).

[0812] LC-MS (ESI): m / z = 216.2[M+H] + 。

[0813] Step 3: To a 50 mL single-necked flask, add 1E (456 mg, 1.59 mmol), crude product 74C (4.5 g, 1.59 mmol), dioxane (10 mL), and DIPEA (1.03 g, 8.0 mmol) sequentially. React at 100 °C for 12 hours. Lower the temperature to room temperature, directly concentrate the reaction solution under reduced pressure, and then separate and purify by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 100 / 10) to obtain 450 mg of a mixture.

[0814] By chiral separation, the title compound 74-1 (112 mg, 15.1%, retention time: 0.925 min) and the title compound 74-2 (86 mg, 11.6%, retention time: 1.896 min) were obtained. Chiral separation method: Instrument: Waters 150MGM, chromatographic column: Chiralpak Column, mobile phase: A: carbon dioxide and B: isopropyl alcohol (0.1% aqueous ammonia), isocratic elution: 70% mobile phase B, flow rate: 100 mL / min, back pressure: 100 bar, column temperature: 25 °C, wavelength: 220 nm, elution time: 5.1 min.

[0815] (Compound 74-1) 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.46 (s, 1H), 7.35 - 7.31 (m, 1H), 7.14 - 7.09 (m, 1H), 6.89 - 6.84 (m, 1H), 4.88 - 4.79 (m, 1H), 4.78 - 4.60 (m, 2H), 4.51 - 4.39 (m, 1H), 4.10 - 4.00 (m, 1H), 3.97 - 3.88 (m, 1H), 3.77 - 3.66 (m, 2H), 3.52 - 3.36 (m, 1H), 3.29 - 3.16 (m, 1H), 3.16 - 3.02 (m, 2H), 3.00~2.81 (m, 2H), 2.79 - 2.62 (m, 2H), 2.44 - 2.25 (m, 2H), 2.25 - 2.14 (m, 2H), 1.88 - 1.69 (m, 2H).

[0816] LC-MS (ESI): m / z = 467.1 [M + H] + .

[0817] (Compound 74-2) 1 H NMR (400 MHz, DMSO-d 6) δ 7.46 (s,1H),7.40 - 7.30 (m,1H),7.14 - 7.10 (m,1H),6.88 - 6.84 (m,1H),4.88 - 4.79 (m,1H),4.79 - 4.60 (m,2H),4.51 - 4.38 (m,1H),4.12 - 3.98 (m,1H),3.95 - 3.87 (m,1H),3.79 - 3.65 (m,2H),3.52 - 3.38 (m,1H),3.28 - 3.17 (m,1H),3.15 - 3.02 (m,2H),3.01 - 2.83 (m,2H),2.79 - 2.61 (m,2H),2.45 - 2.25 (m,2H),2.24 - 2.13 (m,2H),1.87 - 1.67 (m,2H).

[0818] LC - MS (ESI): m / z = 467.1[M + H] + .

[0819] Example 70 [Chemical formula]

[0820] Step 1: 47B (10.0 g, 29.8 mmol) and hydrogen chloride - 1,4 - dioxane (100 mL) were sequentially added to a 250 mL single - necked flask. After reacting at room temperature for 1 hour, it was concentrated, and then saturated aqueous sodium bicarbonate solution (100 mL) was added to adjust the pH > 7. It was extracted with dichloromethane (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 75A (7.0 g, 99.8%).

[0821] LC - MS (ESI): m / z = 236.1[M + H] + .

[0822] Step 2: 75A (3.5 g, 14.9 mmol), absolute ethanol (40 mL), paraformaldehyde (3.5 g) and sodium cyanoborohydride (1.88 g, 29.8 mmol) were sequentially added to a 50 mL single-necked flask, reacted at room temperature for 12 h, concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 90 / 10) to obtain 75B (2.5 g, 67.6%).

[0823] LC-MS (ESI): m / z=250.2[M+H] + 。

[0824] Step 3: 75B (2.5 g, 10.0 mmol), ethyl acetate (50 mL) and palladium carbon (10%, 0.5 g) were sequentially added to a 100 mL single-necked flask, hydrogenated and reduced at room temperature for 12 h, filtered, and the filtrate was concentrated under reduced pressure to obtain 75C (2.2 g, 100%).

[0825] LC-MS (ESI): m / z=220.2[M+H] + 。

[0826] Step 4: 75C (2.2 g, 10.0 mmol), methanol (20 mL) and aqueous hydrochloric acid solution (3 M, 10 mL) were sequentially added to a 100 mL single-necked flask, sodium nitrite (693 mg, 10.0 mmol) was added at -5 °C, and immediately bis(pinacolato)diboron (5.1 g, 20.1 mmol) was added, reacted at room temperature for 1 h, saturated sodium hydrogen carbonate was added to adjust the pH>7, extracted with dichloromethane (100 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 90 / 10) to obtain 75D (2.0 g, 63.1%).

[0827] LC-MS (ESI): m / z=317.2[M+H] + 。

[0828] Step 5: Under the protection of nitrogen gas, 1E (907 mg, 3.16 mmol), 75D (1.0 g, 3.16 mmol), water (4 mL), 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (224 mg, 0.32 mmol), and potassium carbonate (1.3 g, 9.48 mmol) were sequentially added to a 100 mL single-necked flask. 1,4-Dioxane (20 mL) was added and dissolved, and the temperature was raised to 100 °C and reacted for 5 hours. After cooling the temperature to room temperature, the reaction solution was directly concentrated under reduced pressure and then separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 90 / 10) to obtain a mixture of compounds 75-1 and 75-2 (200 mg, 13.8%).

[0829] The title compound 75-1 (81 mg, 5.6%, retention time: 0.885 min) and the title compound 75-2 (74 mg, 5.1%, retention time: 1.795 min) were obtained by chiral preparative separation.

[0830] Chiral preparative separation method: Instrument: Waters 150MGM, chromatographic column: Chiralpak Column, mobile phase: A: carbon dioxide and B: isopropyl alcohol (0.1% aqueous ammonia), isocratic elution: 70% mobile phase B, flow rate: 100 mL / min, back pressure: 100 bar, column temperature: 25 °C, wavelength: 220 nm, elution time: 5.1 min.

[0831] (Compound 75-1) 1 H NMR (400MHz,DMSO-d 6) δ 7.84 - 7.79 (m, 1H), 7.75 (s, 1H), 7.64 - 7.61 (m, 1H), 6.98 - 6.89 (m, 1H), 4.93 - 4.83 (m, 1H), 4.31 - 4.23 (m, 1H), 3.96 - 3.89 (m, 1H), 3.84 - 3.73 (m, 3H), 3.66 - 3.51 (m, 1H), 3.40 - 3.31 (m, 1H), 3.22 - 3.09 (m, 2H), 3.02 - 2.94 (m, 1H), 2.91 - 2.71 (m, 3H), 2.47 - 2.32 (m, 2H), 2.31 - 2.24 (m, 2H), 2.23 (s, 3H), 2.11 - 2.02 (m, 1H), 1.90 - 1.77 (m, 2H), 1.75 - 1.66 (m, 1H).

[0832] LC - MS (ESI): m / z = 456.2 [M + H] + .

[0833] (Compound 75 - 2) 1 H NMR (400 MHz, DMSO - d 6 ) δ 7.83 - 7.80 (m, 1H), 7.75 (s, 1H), 7.64 - 7.61 (m, 1H), 6.98 - 6.91 (m, 1H), 4.93 - 4.86 (m, 1H), 4.30 - 4.23 (m, 1H), 3.99 - 3.87 (m, 1H), 3.85 - 3.73 (m, 3H), 3.63 - 3.52 (m, 1H), 3.38 - 3.31 (m, 1H), 3.21 - 3.11 (m, 2H), 3.02 - 2.93 (m, 1H), 2.91 - 2.71 (m, 3H), 2.46 - 2.32 (m, 2H), 2.31 - 2.24 (m, 2H), 2.23 (s, 3H), 2.14 - 1.99 (m, 1H), 1.89 - 1.78 (m, 2H), 1.75 - 1.66 (m, 1H).

[0834] LC - MS (ESI): m / z = 456.2 [M + H] + .

[0835] Example 71 [Chemical formula]

[0836] Step 1: Under the protection of nitrogen gas, compound 76A (2.00 g, 7.02 mmol), [1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]boronic acid (2.28 g, 7.37 mmol), potassium carbonate (1.94 g, 14.04 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (770 mg, 1.05 mmol) were added to a reaction flask, tetrahydrofuran (40 mL) and water (8 mL) were added, and after replacing with nitrogen gas, the temperature was raised to 75 °C and reacted for 16 h. The disappearance of the raw materials was detected by TLC, diluted with water (100 mL), and extracted three times with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated in vacuo to obtain a crude product, which was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 0 - 95 / 5) to obtain the target compound 76B (1.00 g, 41.9%).

[0837] LC-MS (ESI): m / z = 254.60 [M - 56 + H] + 。

[0838] 1 H NMR (400 MHz, CDCl 3 ) δ 8.71 (s, 2H), 7.21 - 7.20 (m, 1H), 4.16 - 4.15 (m, 2H), 3.64 - 3.61 (m, 2H), 2.69 - 2.68 (m, 2H), 1.49 (s, 9H).

[0839] Step 2: Compound 76B (1.00 g, 2.94 mmol), 1-(trimethylsilyl)propyne (660 mg, 5.88 mmol), potassium carbonate (1.02 g, 7.35 mmol), cuprous iodide (112 mg, 0.59 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (160 mg, 0.44 mmol) were added to a reaction flask, a 1,4-dioxane (20 mL) solution was added, after purging with nitrogen gas, the temperature was raised to 85 °C and reacted for 16 h. The disappearance of the raw materials was detected by TLC, diluted with water (100 mL), and extracted three times with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate and then concentrated in vacuo to obtain a crude product, and the crude product was purified three times by column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 0 - 95 / 5) to obtain the target compound 76C (200 mg, 22.7%).

[0840] LC-MS (ESI): m / z = 244.10[M - 56 + H] + 。

[0841] Step 3: Compound 76C (200 mg, 0.67 mmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (2 mL) was added, and stirred at 0 °C for 30 min. After detecting the disappearance of the raw materials by TLC, the reaction solution was concentrated at room temperature to obtain a crude product 76D (230 mg), which was directly used in the reaction of the next step.

[0842] LC-MS (ESI): m / z = 200.20[M + H] + 。

[0843] Step 4: Compound 1E (130 mg, 0.45 mmol) and compound 76D (230 mg, 0.63 mmol) were dissolved in 1,4-dioxane (6 mL), and N,N-diisopropylethylamine (350 mg, 2.71 mmol) was added. After the addition was completed, the temperature was raised to 85 °C under the protection of nitrogen gas and stirred for 16 h. After the reaction was completed, the temperature was lowered to room temperature, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (dichloromethane / methanol (v / v) = 100 / 0 - 90 / 10) and then further purified by prep.HPLC (fractionation method: instrument: waters 2767 preparative liquid phase, chromatographic column: SunFire@Prep C18 (19 mm × 250 mm), the sample was dissolved in DMF, filtered through a 0.45 μm filter, the sample solution was prepared, and the conditions for preparative chromatography were: a. The composition of mobile phases A and B: mobile phase A: acetonitrile, mobile phase B: water (containing 5 mM aqueous ammonia), b. Gradient elution, the content of mobile phase A was 30% - 95%, c. The flow rate was 15 mL / min. d. The elution time was 15 min, and the retention time was 6.0 min) to obtain the target compound 76 (48 mg, 23.6%).

[0844] 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 2H), 7.34 (s, 1H), 7.29 (s, 1H), 4.85 - 4.82 (m, 1H), 4.46 (s, 2H), 3.98 - 3.95 (m, 2H), 3.75 - 3.74 (m, 2H), 3.47 - 3.39 (m, 1H), 3.26 - 3.19 (m, 1H), 2.98 - 2.92 (m, 1H), 2.89 - 2.84 (m, 1H), 2.65 (s, 2H), 2.43 - 2.30 (m, 2H), 2.22 - 2.18 (m, 2H), 2.12 (s, 3H), 1.83 - 1.73 (m, 2H).

[0845] LCMS m / z = 451.2 [M + H] + 。

[0846] Example 72

Chemical Structure

[0847] Step 1: Dissolve compound 65H (0.5 g, 2.72 mmol) in glacial acetic acid (20 mL), add thionyl chloride (10 mL), stir at 60 °C overnight. After the reaction is completed, cool to room temperature, add ethyl acetate (50 mL) to dilute the reaction system, adjust the pH of the reaction system to neutral with saturated aqueous sodium bicarbonate solution, extract with ethyl acetate (50 mL × 3), dry the organic phase over anhydrous sodium sulfate, filter and concentrate. The residue is separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 0 - 80 / 20) to obtain compound 77A (100 mg, 26%).

[0848] LCMS (ESI): m / z = 141.1 [M + H] + 。

[0849] Step 2: Under the protection of nitrogen gas, dissolve compound 42C (238 mg, 0.71 mmol), 77A (100 mg, 0.71 mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (51 mg, 0.07 mmol) and sodium carbonate (226 mg, 2.13 mmol) in a mixed solvent of 1,4-dioxane / water (10 mL / 2 mL), heat to 90 °C and react for 18 h. After the reaction is completed, cool to room temperature, filter through diatomaceous earth, wash with ethyl acetate, concentrate the filtrate, and separate and purify the obtained residue by column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 0 - 90 / 10) to obtain the target compound 77B (102 mg, 45%).

[0850] LCMS (ESI): m / z = 258.1 [M + H - 56] + 。

[0851] Step 3: Compound 77B (102 mg, 0.33 mmol) was dissolved in a mixed solvent of dichloromethane / trifluoroacetic acid (6 mL / 2 mL), stirred at room temperature for 1 h, and directly spin-dried to obtain the trifluoroacetate salt of compound 77C, which was directly used in the reaction of the next step (111 mg).

[0852] LCMS (ESI): m / z = 214.1 [M+H] + 。

[0853] Step 4: The trifluoroacetate salt compound of compound 77C (111 mg) was dissolved in 1,4-dioxane (5 ml), 1E (95 mg, 0.33 mmol) and diisopropylethylamine (128 mg, 0.99 mmol) were added, and the reaction system was placed in an oil bath at 100 °C and reacted for 15 h. After the reaction was completed, it was cooled to room temperature, the reaction was monitored by LCMS, and directly spin-dried after the reaction was completed. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 100 / 0 - 80 / 20) to obtain a mixture of compound 77-1 and 77-2 (50 mg, 33%). Further chiral resolution was carried out to obtain compound 77-1 (26 mg, retention time: 1.891 s) and compound 77-2 (21.6 mg, retention time: 2.901 s).

[0854] Chiral separation method: Instrument: Waters 150Prep-SFC E, chromatographic column: Chiralcel Cellulose-2 column, mobile phase: A: carbon dioxide and B: methanol (0.1% aqueous ammonia), gradient elution, B 40%, flow rate: 100 mL / min, back pressure: 100 bar, column temperature: 25 °C, wavelength: 220 nm, elution time: 7.0 min.

[0855] (Compound 77-1) 1 H NMR (400MHz,CDCl 3) δ 8.23 (s,1H),6.78 (s,1H),5.67 (s,1H),5.09 (d,1H),4.07 - 3.92 (m,1H),3.89 - 3.73 (m,4H),3.67 (s,1H),3.61 - 3.53 (m,1H),3.49 - 3.44 (m,2H),3.40 (d,1H),3.31 (d,1H),3.23 (t,2H),3.16 (s,1H),3.11 - 2.92 (m,3H),2.85 (d,1H),2.36 (d,2H),2.23 - 2.15 (m,2H),1.97 - 1.89 (m,2H).

[0856] LCMS (ESI): m / z = 465.2[M + H] + .

[0857] (Compound 77 - 2) 1 H NMR (400MHz, CDCl 3 ) δ 8.23 (s,1H),6.78 (s,1H),5.83 (s,1H),5.09 (d,1H),4.06 - 3.90 (m,1H),3.89 - 3.73 (m,4H),3.67 (s,1H),3.57 (d,1H),3.46 (s,2H),3.43 - 3.28 (m,2H),3.23 (s,2H),3.18 - 2.96 (m,4H),2.87 (d,1H),2.41 - 2.31 (m,1H),2.28 - 2.15 (m,3H),1.99 - 1.83 (m,2H).

[0858] LCMS (ESI): m / z = 465.2[M + H] + .

[0859] Example 73 [Chemical Structure]

[0860] Step 1: 75A (3.5 g, 14.89 mmol) was dissolved in dichloromethane (35 mL), triethylamine (4.5 g, 44.67 mmol) and acetic anhydride (1.5 g, 14.89 mmol) were added, and after reacting at room temperature for 1 hour, water (50 mL) was added. The mixture was extracted with dichloromethane (50 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 91 / 9) to obtain 78A (3.2 g, 77.6%).

[0861] LC-MS (ESI): m / z = 278.1[M+H] + 。

[0862] Step 2: Compound 78A (3.2 g, 11.55 mmol) was dissolved in ethyl acetate (50 mL), palladium carbon (10%, 0.5 g) was added, and the temperature was raised to 50 °C under a hydrogen gas atmosphere and reacted for 12 hours. After the reaction was completed, it was directly filtered, and the filtrate was concentrated under reduced pressure to obtain 78B (2.8 g, 98.2%).

[0863] LC-MS (ESI): m / z = 248.2[M+H] + 。

[0864] Step 3: 78B (2.5 g, 10.12 mmol), methanol (20 mL), and aqueous hydrochloric acid solution (3 M, 10 mL) were sequentially added to a 100 mL single-necked flask. Sodium nitrite (698 mg, 10.12 mmol) was added at -5 °C, and immediately bis(pinacolato)diboron (5.1 g, 20.24 mmol) was added, and the mixture was reacted at room temperature for 1 hour. After monitoring the completion of the reaction by TLC, saturated sodium bicarbonate was added to adjust the pH > 7, and the mixture was extracted with dichloromethane (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 91 / 9) to obtain 78C (2.5 g, 71.8%).

[0865] LC-MS (ESI): m / z = 345.2 [M+H] + 。

[0866] Step 4: 1E (907 mg, 3.16 mmol), 78C (1.1 g, 3.16 mmol), 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (224 mg, 0.32 mmol), and potassium carbonate (1.3 g, 9.48 mmol) were sequentially added to a 100 mL single-necked flask. A mixed solvent of 1,4-dioxane (20 mL) and water (4 mL) was added to dissolve them. The temperature was raised to 100 °C under the protection of nitrogen gas and reacted for 5 hours. After cooling to room temperature, the reaction solution was directly concentrated under reduced pressure and then separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 91 / 9) to obtain a mixture (250 mg) of 78-1 and...

Claims

1. A compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 【Chemical 1】 wherein Cy is selected from Cy1, Cy2, a 5-membered monocyclic heteroaryl group, or an 8- to 10-membered bicyclic heteroaryl group, and the monocyclic heteroaryl group and the bicyclic heteroaryl group are optionally further substituted with 1 to 3 R's, 【Chemical 2】 and Cy2 is optionally substituted with 1 to 3 R's, L is -(L １ )n-(L ２ )m-and L １ is -NR １ -, -CR ２ =N-, -CR ２ =CR ２ - or -CR ２ R ２ -, and L ２ is 【Chemical Formula 3】 C １－４ an alkylene group, C ２－４ an alkenylene group, C ２－４ an alkynylene group, CO, O, NR Ｌ２ , C ３－５ a cycloalkylene group, a 6- to 9-membered arylene group, a 5- to 6-membered heteroarylene group containing 1 to 3 heteroatoms selected from N, S, O, a 5-membered monocycloheteroalkylene group containing 1 to 3 heteroatoms selected from N, S, O, a 7- to 8-membered monocycloheteroalkylene group containing 1 to 3 heteroatoms selected from N, S, O, a 5- to 10-membered fused-ring heteroalkylene group containing 1 to 3 heteroatoms selected from N, S, O, a 6- to 10-membered bridged-ring heteroalkylene group containing 1 to 3 heteroatoms selected from N, S, O, a 7- to 12-membered spiro-ring heteroalkylene group containing 1 to 3 heteroatoms selected from N, S, O, and the alkylene group, alkenylene group, alkynylene group, cycloalkylene group, arylene group, heteroarylene group, monocycloheteroalkylene group, fused-ring heteroalkylene group, bridged-ring heteroalkylene group and spiro-ring heteroalkylene group are optionally substituted with 1 to 3 groups selected from halogen, =O, CN, C １－４ an alkyl group, C １－４ an alkoxy group, OH and NH ２ and are substituted with 1 to 3 groups selected from R Ｌ２ is H, C １－４ an alkyl group or C ３－６ a cycloalkyl group, X １ 、 X ２ is independently CR Ｘ１ or N, and Each R Ｘ１ independently is H, halogen, C １－４ alkyl group, C １－４ haloalkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group or -SO ２ NH ２ or R Ｘ１ and R １ , R Ｘ１ and R ２ , or R Ｘ１ and R ３ and the atoms linked thereto together form a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from C ３－８ cycloalkyl group, N, S, O, a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, O, and the cycloalkyl group, heterocycloalkyl group and heteroaryl group are optionally halogen, =O, CN, C １－４ alkyl group, C １－４ alkoxy group, OH and NH ２ substituted with 1 to 3 groups selected from Each R is independently H, halogen, cyano group, C １－４ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, C ３－８ cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, Si, P, -SO ２ NH ２ , -NHSO ２ NH ２ , -NHCONH ２ , -NHCOC １－４ alkyl group, -CONHC １－４ alkyl group, -NHSO ２ C １－４ alkyl group, -SO ２ NH C １－４ alkyl group, -SO ２ C １－４ alkyl group, -P(O)(C １－４ alkyl group) ２ , -SCF ３ , -SF ５ or -C １－４ haloalkyl group, and the cycloalkyl group and heterocycloalkyl group are optionally substituted with 1 to 3 groups selected from halogen, =O, CN, C １－４ alkyl group, C １－４ alkoxy group, OH, -C(O)C １－４ alkyl group and NH ２ selected from or two adjacent Rs, R and R Ｘ１ and the atoms linked thereto together form a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from C ３－８ cycloalkyl group, N, S, O, P, B, a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, O, provided that the cycloalkyl group, heterocycloalkyl group and heteroaryl group are optionally halogen, =O, CN, C １－４ alkyl group, C １－４ alkoxy group, OH, -C(O)C １－４ alkyl group and NH ２ substituted with 1 to 3 groups selected from and R １ is H, C １－４ alkyl group, C １－４ haloalkyl group or C ３－６ cycloalkyl group, and R ２ is H, C １－４ alkyl group, C １－４ haloalkyl group, C １－４ alkoxy group, -NHC １－４ alkyl group or C ３－６ cycloalkyl group, and R ３ is H, halogen, =O, CN, C １－４ alkyl group or C １－４ alkoxy group, and n is 0, 1, 2, 3, or 4, m is 0, 1, 2, or 3, provided that the compound is 【Chemical Formula 4】 not a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

2. Each L ２ is independently CO, O, NR Ｌ２ , C １－４ alkylene group, C ２－４ alkenylene group, C ２－４ alkynylene group, 【Chemical Formula 5】 selected from R Ｌ２ is H, C １－４ an alkyl group or C ３－６ a cycloalkyl group, and Each R Ｘ１ is independently H, halogen, C １－４ alkyl group or C １－４ haloalkyl group, or R Ｘ１ and R １ , R Ｘ１ and R ２ , or R Ｘ１ and R ３ and the atoms linked thereto together form a 5- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from C ３－６ cycloalkyl group, N, S, O, a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, O, and the cycloalkyl group, heterocycloalkyl group and heteroaryl group are optionally halogen, =O, CN, C １－４ alkyl group, C １－４ alkoxy group, OH and NH ２ substituted with 1 to 3 groups selected from Each R is independently H, halogen, cyano group, C １－４ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, C ３－６ cycloalkyl group, N, S, O, Si, P, a 4- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected therefrom, -SO ２ NH ２ , -NHSO ２ NH ２ , -NHSO ２ C １－４ alkyl group, -SO ２ NH C １－４ alkyl group, SO ２ C １－４ alkyl group, -P(O)(C １－２ alkyl) ２ , SCF ３ , SF ５ or C １－４ haloalkyl group, and the cycloalkyl group and heterocycloalkyl group are optionally substituted with 1 to 3 groups selected from halogen, =O, CN, C １－４ alkyl group, C １－４ alkoxy group, OH, -C(O)C １－４ alkyl group and NH ２ or two adjacent Rs, R and R Ｘ１ and the atoms to which they are attached together form a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from C ３－６ cycloalkyl group, N, S, O, P, B, and the cycloalkyl group and heterocycloalkyl group are optionally substituted with 1 to 3 groups selected from halogen, =O, CN, C １－４ alkyl group, C １－４ alkoxy group, OH, -C(O)C １－４ alkyl group and NH ２ selected therefrom, R １ is H, C １－４ an alkyl group or C １－４ a haloalkyl group, and R ２ is H, C １－４ alkyl group, C １－４ haloalkyl group or C １－４ alkoxy group, and R ３ is H, halogen, =O, CN or C １－４ alkyl group, n is 0, 1, 2, 3, or 4, m is 0, 1, or 2, the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to Claim 1.

3. The compound has the structure of Formula II, 【Chemical Formula 6】 wherein L is [Chemical Formula 7] selected from one of the following structures X １ 、 X ２ is independently CR Ｘ１ or N, and Each R Ｘ１ is independently H, halogen, C １－４ alkyl group or C １－４ haloalkyl group, or R Ｘ１ and R １ , R Ｘ１ and R ２ , or R Ｘ１ and R ３ and the atoms linked thereto together form a 5- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from C ３－６ cycloalkyl group, N, S, O, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, O, and the cycloalkyl group, heterocycloalkyl group and heteroaryl group are optionally halogen, =O, CN, C １－４ alkyl group, C １－４ alkoxy group, OH and NH ２ substituted with 1 to 3 groups selected from Each R is independently H, halogen, cyano group, C １－４ alkyl group, C ２－４ alkynyl group, C ３－６ cycloalkyl group, a 4- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, Si, P, -SO ２ NH ２ , -NHSO ２ C １－４ alkyl group, -SO ２ NH C １－４ alkyl group, SO ２ C １－４ alkyl group, -P(O)(CH ３ ) ２ , SCF ３ , SF ５ or C １－４ haloalkyl group, and the cycloalkyl group and heterocycloalkyl group are optionally substituted with 1 to 3 groups selected from halogen, =O, CN, C １－４ alkyl group, C １－４ alkoxy group, OH, -C(O)C １－４ alkyl group and NH ２ , or two adjacent Rs, R and R Ｘ１ and the atoms connected thereto together form a 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from C ３－６ cycloalkyl group, N, S, O, P, B, and the cycloalkyl group and heterocycloalkyl group are optionally substituted with 1 to 3 groups selected from halogen, =O, CN, C １－４ alkyl group, C １－４ alkoxy group, OH, -C(O)C １－４ alkyl group and NH ２ selected from R １ is H or C １－４ an alkyl group or C １－４ a haloalkyl group, and R ２ is H, C １－４ an alkyl group or C １－４ a haloalkyl group, and R ３ is H, halogen, =O, CN or C １－４ alkyl group, the compound according to claim 2, its stereoisomer or pharmaceutically acceptable salt.

4. Cy is a 5-membered monocyclic heteroaryl group, a 5-membered heteroaryl group-fused benzene ring, a 5-membered heteroaryl group-fused 5-membered heteroaryl group, a 5-membered heteroaryl group-fused 6-membered heteroaryl group, a 5-membered heteroaryl group-fused 4-membered cycloalkyl group, a 5-membered heteroaryl group-fused 5-membered cycloalkyl group, a 5-membered heteroaryl group-fused 6-membered cycloalkyl group, a 5-membered heteroaryl group-fused 4-membered heterocycloalkyl group, a 5-membered heteroaryl group-fused 5-membered heterocycloalkyl group, a 5-membered heteroaryl group-fused 6-membered heterocycloalkyl group, a 6-membered heteroaryl group-fused benzene ring, a 6-membered heteroaryl group-fused 5-membered heteroaryl group, a 6-membered heteroaryl group-fused 6-membered heteroaryl group, a 6-membered heteroaryl group-fused 4-membered cycloalkyl group, a 6-membered heteroaryl group-fused 5-membered cycloalkyl group, a 6-membered heteroaryl group-fused 6-membered cycloalkyl group, a 6-membered heteroaryl group-fused 4-membered heterocycloalkyl group, a 6-membered heteroaryl group-fused 5-membered heterocycloalkyl group, a 6-membered heteroaryl group-fused 6-membered heterocycloalkyl group, which are optionally further substituted with 1 to 3 R's, or Cy is selected from 【Chemical 8】 the following structure, which is optionally further substituted with 1 to 3 R's, the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to Claim 1.

5. L is 【Chemical Formula 9】 selected from X １ 、X ２ is independently CR Ｘ１ or N, and Each R Ｘ１ is independently H, F, Cl, a methyl group, an ethyl group, or R Ｘ１ and R ３ and the atoms linked thereto together form a C ５ cycloalkyl group, a C ６ cycloalkyl group, a 5-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, or a 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O. R ３ is H, F, Cl, =O, CN, C １－３ is an alkyl group, Each R is independently H, F, Cl, a methyl group, an ethyl group, acetylene, propyne, or two adjacent Rs and the atoms to which they are attached together form a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, or a cyclohexenyl group, and the cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, or cyclohexenyl group is optionally substituted with one to three groups selected from F, Cl, =O, CN, a methyl group, an ethyl group, a methoxy group, an ethoxy group, OH, and NH ２ The compound, stereoisomer, or pharmaceutically acceptable salt according to claim 3, which is substituted with one to three groups selected from

6. 【Fig. 10】 is 【Chemical 11】 selected from the following structure, the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to Claim 1.

7. The compound, its stereoisomer or pharmaceutically acceptable salt as described in Table 1 of the specification.

8. The compound, its stereoisomer or pharmaceutically acceptable salt according to Claim 7, wherein the compound is selected from one of the structures in Table 2.

9. A pharmaceutical composition or pharmaceutical preparation containing the compound, its stereoisomer or pharmaceutically acceptable salt according to any one of Claims 1 to 8, a pharmaceutically acceptable carrier and / or excipient.

10. The pharmaceutical composition or pharmaceutical preparation according to Claim 9, containing 1 to 1500 mg of the compound, its stereoisomer or pharmaceutically acceptable salt according to any one of Claims 1 to 8, a pharmaceutically acceptable carrier and / or excipient.

11. Use of the compound, its stereoisomer or pharmaceutically acceptable salt according to any one of Claims 1 to 8 in the manufacture of a medicament for treating / preventing a PDE4B-mediated disease.

12. A method for treating a mammalian disease, the method comprising administering to a subject a therapeutically effective amount of the compound, its stereoisomer or pharmaceutically acceptable salt according to any one of Claims 1 to 8, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and the disease is preferably cancer, COPD, idiopathic pulmonary fibrosis or interstitial lung disease.

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