Macrocyclic compounds, pharmaceutical compositions and applications thereof

Abstract

The present invention discloses a macrocyclic compound, a pharmaceutical composition thereof and an application thereof. Specifically, the present invention discloses a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof. The compound of the present invention shows good TRPC5 inhibitory activity.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a macrocyclic compound, a pharmaceutical composition thereof and application thereof. Background Art

[0002] Cation channels (such as transient receptor potential (TRP) cation channel subfamily C member 5 (TRPC5)) regulate the flux of calcium and sodium ions across the cell membrane. The influx of sodium and calcium causes cell depolarization. This increases the possibility that voltage-gated ion channels will reach the threshold required for activation. Therefore, the activation of non-selective cation channels can increase electrical excitability and increase the frequency of voltage-dependent events. Voltage-dependent events include but are not limited to neuronal action potentials, cardiac action potentials, smooth muscle contraction, myocardial contraction, and skeletal muscle contraction.

[0003] The calcium influx caused by the activation of non-selective cation channels (such as TRPC5) also changes the concentration of intracellular free calcium. Calcium is a ubiquitous second messenger molecule in cells, and the change of intracellular calcium levels has a profound impact on signal transduction and gene expression. Therefore, the activation of non-selective cation channels (such as TRPC5) can lead to changes in gene expression and cell phenotype. Gene expression events include but are not limited to the generation of mRNA encoding cell surface receptors, ion channels and kinases. These changes in gene expression can lead to overexcitement in the cells.

[0004] Compounds that inhibit ion channels containing TRPC5 are useful, for example, for treating disorders such as neuropsychiatric disorders, neurodegenerative disorders, renal diseases, and epileptic disorders by modulating the activity of TRPC5, which can exist in homomultimeric forms as well as heteromultimeric forms (i.e., TRPC4 and TRPC1-TRPC4-TRPC5) with other ion channels such as TRPC1 or TRPC3.

[0005] So far, only a few TRPC5 inhibitors have been developed, including Pico145 (Picomolar, selective, and subtype-specific small-molecule inhibition of TRPC1 / 4 / 5 channels. Journal of Biological Chemistry 292, 8158-8173), HC-070 (Treatment with HC-070, a potent inhibitor of TRPC4 and TRPC5, leads to anxiolytic and antidepressant effects in mice. PLOS ONE 13, e0191225.), Clemizole hydrochloride (Clemizole hydrochloride is a novel and potent inhibitor of transient receptor potential channel TRPC5. Molecular pharmacology 86, 514-521.), ML204 (Identification of ML204, a novel potent antagonist that selectively modulates native TRPC4 / C5 ion channels. Journal of Biological Chemistry 286, 33436-33446.), M084 (Identification and optimization of 2-aminobenzimidazole derivatives as novel inhibitors of TRPC4 and TRPC5 channels. British Journal of Pharmacology 172, 3495-3509.), AC1903 (Design, synthesis and characterization of novel N-heterocyclic-1-benzyl-1H-benzo[d]imidazole-2-amines as selective TRPC5 inhibitors leading to the identification of the selective compound, AC1903.Bioorganic & Medicinal Chemistry Letters 29, 155-159.), AM-12 (Natural and synthetic flavonoid modulation of TRPC5 channels. British Journal of Pharmacology 173, 562-574.) and GFB-8438 (Discovery of a Potent and Selective TRPC5 Inhibitor, Efficacious in a Focal Segmental Glomerulosclerosis Model. ACS Medicinal Chemistry Letters 10, 1579-1585.). Before Pico145 was discovered, the most potent and specific inhibitor was ML204, but a recent study showed that this is a relatively poor heteromeric TRPC5 inhibitor (Na. +Entry through heteromeric TRPC4 / C1 channels mediates (-) Englerin A-induced cytotoxicity in synovial sarcoma cells. Scientific Reports 7, 16988.). AC1903 can distinguish homologous TRPC4 and TRPC5 channels in vivo. However, its relatively low efficacy and unclear effects on different heteromeric TRPC5s limit its current use (A small-molecule inhibitor of trpc5 ionchannels suppresses progressive kidney disease in animal models. Science 358, 1332-1336). Currently, the most promising TRPC5 inhibitors for functional studies are Pico145, GFB-887 and HC-070. They are selective and subtype-specific inhibitors of homogeneous and heterogeneous TRPC5, have oral bioavailability, and are suitable for in vivo studies (Remarkable Progress with Small-Molecule Modulation of TRPC1 / 4 / 5Channels:Implications for Understanding the Channels in Health and Disease.Cells 7,52; Safety and Efficacy of GFB-887,a TRPC5Channel Inhibitor,in Patients WithFocal Segmental Glomerulosclerosis,Treatment-Resistant Minimal ChangeDisease,or Diabetic Nephropathy:TRACTION-2Trial Design.Kidney InternationalReports,10,2575-2584;Pico145-powerful new tool for TRPC1 / 4 / 5channels.Channels(Austin)11,362-364.). Summary of the invention

[0006] The technical problem to be solved by the present invention is to provide a novel macrocyclic compound, a pharmaceutical composition thereof and its application in view of the lack of TRPC5 inhibitors in the prior art. The macrocyclic compound of the present invention shows good TRPC5 inhibitory activity.

[0007] The present invention solves the above technical problems through the following methods.

[0008] The present invention provides a compound as shown in formula (I), a pharmaceutically acceptable salt thereof, an isotope compound thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof,

[0009]

[0010] in,

[0011] is a benzene ring or a 5-6 membered heteroaromatic ring having one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0012] n 1 and n 2 independently 0 or 1;

[0013] L 1 For -(CH 2 ) n -, n is 1, 2 or 3, -(CH 2 ) n 1, 2 or 3 of -CH 2 -optionally replaced by one or more selected from the following groups: -NL 1-1 -, -O- or -S-, L 1-1 H or C 1 -C 6 alkyl;

[0014] R 1 C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 8 Cycloalkyl, 3-8 membered heterocycloalkyl, 1, 2 or 3 R 1-1 Substituted C 6 -C 10 Aryl or 1, 2 or 3 R 1-2 substituted 5-10 membered heteroaryl, substituted by 1, 2 or 3 R 1-3 Substituted C 3 -C 8 Cycloalkyl or 1, 2 or 3 R 1-4Substituted 3-8 membered heterocycloalkyl, wherein, in each "5-10 membered heteroaryl" and each "3-8 membered heterocycloalkyl", the heteroatom is selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2 or 3;

[0015] R 1-1 , R 1-2 , R 1-3 and R 1-4 are independently halogen, -CN, -OH, -NR 1-1-1 R 1-1-2 , -C(=O)H, -C(=O)NR 1 -1-1 R 1-1-2 , C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C substituted by 1, 2 or 3 halogens 1 -C 6 Alkyl or C substituted by 1, 2 or 3 halogens 1 -C 6 Alkoxy;

[0016] R 1-1-1 and R 1-1-2 are independently H or C 1 -C 6 alkyl;

[0017] L 3 is the connection key;

[0018] or L 3 for

[0019] Among them, X 1 is the connecting bond, -CH 2 -、-NR X-1 -, -O- or -S-; R X-1 H or C 1 -C 6 alkyl;

[0020] C 6 -C 10 The aromatic ring or heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-10 membered heteroaromatic ring;

[0021] n 3 is 0, 1, 2, or 3;

[0022] R 2 are independently halogen, -CN, -OH, -NR 2-1 R2-2 、-C(=O)H、-C(=O)NR 2-1 R 2-2 , C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C substituted by 1, 2 or 3 halogens 1 -C 6 Alkyl or C substituted by 1, 2 or 3 halogens 1 -C 6 Alkoxy; R 2-1 and R 2-2 independently H or C 1 -C 6 alkyl;

[0023] R 3 C 1 -C 6 Alkyl, 1, 2 or 3 R 3-1 Substituted C 1 -C 6 Alkyl, 1, 2 or 3 R 3-2 Substituted C 2 -C 6 Alkenyl or 1, 2 or 3 R 3-3 Substituted C 2 -C 6 Alkynyl;

[0024] R 3-1 , R 3-2 and R 3-3 are independently deuterium, halogen, -OH, -OD, -NR 3-1-1 R 3-1-2 or -C(=O)H;

[0025] R 3-1-1 and R 3-1-2 independently H or C 1 -C 6 alkyl;

[0026] L 2 For -(CH 2 ) m -, m is 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, -(CH 2 ) m 1, 2 or 3 of -CH 2 -optionally selected from -NR L-1 -, -O-, -S-, -CH=CH-, C 3 -C 8The cycloalkylene group is replaced by one or more groups of cycloalkylene groups and 3-12-membered heterocycloalkylene groups, wherein the heteroatoms in the 3-12-membered heterocycloalkylene groups are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0027] R L-1 independently H or C 1 -C 6 alkyl.

[0028] In one embodiment of the present invention, L 2 for The a side and connected.

[0029] In one embodiment of the present invention, R 3 for

[0030] In a certain embodiment of the present invention, the isotope compound is a deuterated compound; preferably, the position of deuteration in the deuterated compound is R 3 More preferably, the position of deuteration in the deuterated compound is R 3 C 1 -C 6 Alkyl or R 3-1 The hydroxyl groups on the

[0031] In one embodiment of the present invention, each "C 2 -C 6 The "alkenyl" group may independently be vinyl, propenyl, allyl, butenyl or pentenyl, for example, vinyl,

[0032] In one embodiment of the present invention, each "C 2 -C 6 "Alkyl" may independently be ethynyl, propynyl, propargyl, butynyl or pentynyl, for example ethynyl,

[0033] In one embodiment of the present invention, is a benzene ring or a 5-6 membered heteroaromatic ring having one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0034] n 1 and n 2 independently 0 or 1;

[0035] L 1 For -(CH 2 ) n -, n is 1, 2 or 3

[0036] R 1 C 6 -C 10 Aryl, 5-10 membered heteroaryl, 1, 2 or 3 R 1-1 Substituted C 6 -C 10 Aryl or 1, 2 or 3 R 1-2 Substituted 5-10 membered heteroaryl, wherein in each "5-10 membered heteroaryl", the heteroatom is selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2 or 3;

[0037] R 1-1 and R 1-2 are independently halogen, -CN, -OH, -NR 1-1-1 R 1-1-2 , -C(=O)H, -C(=O)NR 1-1-1 R 1-1-2 , C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C substituted by 1, 2 or 3 halogens 1 -C 6 Alkyl or C substituted by 1, 2 or 3 halogens 1 -C 6 Alkoxy;

[0038] R 1-1-1 and R 1-1-2 are independently H or C 1 -C 6 alkyl;

[0039] L 3 is the connection key;

[0040] or L 3 for

[0041] Among them, X 1 and Connected, With L 2 connected;

[0042] X 1 is the connecting bond, -CH 2 -、-NR X-1 -, -O- or -S-; R X-1 H or C 1 -C 6 alkyl;

[0043] C 6-C 10 The aromatic ring or heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-10 membered heteroaromatic ring;

[0044] n 3 is 0, 1, 2, or 3;

[0045] R 2 are independently halogen, -CN, -OH, -NR 2-1 R 2-2 , -C(=O)H, -C(=O)NR 2-1 R 2-2 , C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C substituted by 1, 2 or 3 halogens 1 -C 6 Alkyl or C substituted by 1, 2 or 3 halogens 1 -C 6 Alkoxy; R 2-1 and R 2-2 are independently H or C 1 -C 6 alkyl;

[0046] R 3 C 1 -C 6 Alkyl or 1, 2 or 3 R 3-1 Substituted C 1 -C 6 Alkyl, 1, 2 or 3 R 3-2 Substituted C 2 -C 6 Alkenyl or 1, 2 or 3 R 3-3 Substituted C 2 -C 6 Alkynyl;

[0047] R 3-1 , R 3-2 and R 3-3 are independently deuterium, halogen, -OH, -OD, -NR 3-1-1 R 3-1-2 or -C(=O)H;

[0048] R 3-1-1 and R 3-1-2 are independently H or C 1 -C 6 alkyl;

[0049] L 2 For -(CH 2 )m -, m is 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, -(CH 2 ) m 1, 2 or 3 of -CH 2 -optionally selected from -NR L-1 -, -O-, -S-, -CH=CH-, C 3 -C 8 The cycloalkylene group is replaced by one or more groups of cycloalkylene groups and 3-12-membered heterocycloalkylene groups, wherein the heteroatoms in the 3-12-membered heterocycloalkylene groups are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0050] R L-1 are independently H or C 1 -C 6 alkyl.

[0051] In one embodiment of the present invention, for

[0052] L 1 -CH 2 -;

[0053] R 1 For 1 R 1-1 Substituted phenyl, R 1-1 is a halogen, and R 1-1 Located in L 1 The para or meta position of;

[0054] L 3 for X 1 is the connecting bond, -CH 2 - or O, is a benzene ring or a 5-6 membered heteroaromatic ring, n3 is 0 or 1, R 2 is halogen or C substituted by 1, 2 or 3 halogens 1 -C 6 alkyl;

[0055] L 2 Any of the following options:

[0056] I:L 2 For -(CH 2 ) m-1 -O- a 、-(CH 2 ) m-2 -O-CH 2 - a or -(CH 2 ) m-2 -NRL-1 -CH 2 - a , m is 6, 7 or 8, -(CH 2 ) m-1 -or-(CH 2 ) m-2 -1 in -CH 2 -Optionally NR L-1 or O replacement, where the a side is connected;

[0057] II:L 2 -CH 2 -(CH 2 ) m-2 -O- a , m is 5, 6 or 7, -(CH 2 ) m-2 -, at least 1 -CH 2 - is replaced by -CH=CH-, and the a side is connected;

[0058] R 3 For 1, 2 or 3 R 3-1 Substituted C 1 -C 6 Alkyl, 1, 2 or 3 R 3-2 Substituted C 2 -C 6 Alkenyl or 1, 2 or 3 R 3-3 Substituted C 2 -C 6 Alkynyl;

[0059] R 3-1 , R 3-2 and R 3-3 are independently deuterium, halogen, -OH, -OD, -NR 3-1-1 R 3-1-2 or -C(=O)H;

[0060] R 3-1-1 and R 3-1-2 Independently for C 1 -C 6 alkyl.

[0061] In one embodiment of the present invention, for

[0062] L 1 -CH 2 -;

[0063] R 1 For 1 R 1-1Substituted phenyl, R 1-1 is a halogen, and R 1-1 Located in L 1 The paraposition or metaposition of;

[0064] L 3 for X 1 is a connecting bond or -CH 2 -, is a benzene ring or a 5-6 membered heteroaromatic ring, n3 is 0 or 1, R 2 is halogen or C substituted by 1, 2 or 3 halogens 1 -C 6 alkyl;

[0065] L 2 Any of the following options:

[0066] I:L 2 For -(CH 2 ) m-1 -O- a 、-(CH 2 ) m-2 -O-CH 2 - a or -(CH 2 ) m-2 -NR L-1 -CH 2 - a , m is 6, 7 or 8, -(CH 2 ) m-1 -or-(CH 2 ) m-2 -1 in -CH 2 -Optionally NR L-1 or O replacement, where the a side is connected;

[0067] II:L 2 -CH 2 -(CH 2 ) m-2 -O- a , m is 5, 6 or 7, -(CH 2 ) m-2 -, at least 1 -CH 2 - is replaced by -CH=CH-, and the a side is connected;

[0068] R 3 For 1, 2 or 3 R 3-1 Substituted C 1 -C 6 Alkyl, 1, 2 or 3 R 3-2Substituted C 2 -C 6 Alkenyl or 1, 2 or 3 R 3-3 Substituted C 2 -C 6 Alkynyl;

[0069] R 3-1 , R 3-2 and R 3-3 Each is independently deuterium, halogen, -OH or -OD.

[0070] In one embodiment of the present invention, the compound represented by formula (I) as described above, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate,

[0071]

[0072] in,

[0073] is a benzene ring or a 5-6 membered heteroaromatic ring having one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0074] n 1 and n 2 independently 0 or 1;

[0075] L 1 For -(CH 2 ) n -, n is 1, 2 or 3, -(CH 2 ) n 1, 2 or 3 of -CH 2 -optionally replaced by one or more selected from the following groups: -NL 1-1 -, -O- or -S-, L 1-1 H or C 1 -C 6 alkyl;

[0076] R 1 C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 8 Cycloalkyl, 3-8 membered heterocycloalkyl, 1, 2 or 3 R 1-1 Substituted C 6 -C 10 Aryl, 1, 2 or 3 R 1-2 substituted 5-10 membered heteroaryl, substituted by 1, 2 or 3 R 1-3 Substituted C 3 -C 8 Cycloalkyl or 1, 2 or 3 R1-4 substituted 3-8 membered heterocycloalkyl, wherein, in each "5-10 membered heteroaryl" and each "3-8 membered heterocycloalkyl", the heteroatom is selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2 or 3,

[0077] R 1-1 , R 1-2 , R 1-3 and R 1-4 are independently halogen, -CN, -OH, -NR 1-1-1 R 1-1-2 , -C(=O)H, -C(=O)NR 1 -1-1 R 1-1-2 , C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C substituted by 1, 2 or 3 halogens 1 -C 6 Alkyl or C substituted by 1, 2 or 3 halogens 1 -C 6 Alkoxy;

[0078] R 1-1-1 and R 1-1-2 are independently H or C 1 -C 6 alkyl;

[0079] L 3 is the connection key;

[0080] or L 3 for

[0081] Among them, X 1 and Connected, With L 2 connected;

[0082] X 1 -CH 2 -、-NR X-1 -, -O- or -S-; R X-1 H or C 1 -C 6 alkyl;

[0083] C 6 -C 10 The aromatic ring or heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-10 membered heteroaromatic ring;

[0084] n3 is 0, 1, 2, or 3;

[0085] R 2 are independently halogen, -CN, -OH, -NR 2-1 R 2-2 、-C(=O)H、-C(=O)NR 2-1 R 2-2 , C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C substituted by 1, 2 or 3 halogens 1 -C 6 Alkyl or C substituted by 1, 2 or 3 halogens 1 -C 6 Alkoxy; R 2-1 and R 2-2 independently H or C 1 -C 6 alkyl;

[0086] R 3 C 1 -C 6 Alkyl or 1, 2 or 3 R 3-1 Substituted C 1 -C 6 alkyl;

[0087] R 3-1 are independently halogen, -OH, -NR 3-1-1 R 3-1-2 or -C(=O)H;

[0088] R 3-1-1 and R 3-1-2 independently H or C 1 -C 6 alkyl;

[0089] L 2 For -(CH 2 ) m -, m is 4, 5, 6, 7, 8, 9 or 10, -(CH 2 ) m 1, 2 or 3 of -CH 2 -optionally selected from -NR L-1 -, -O-, -S-, -CH=CH-, C 3 -C 8 The cycloalkylene group is replaced by one or more groups of cycloalkylene groups and 3-12-membered heterocycloalkylene groups, wherein the heteroatoms in the 3-12-membered heterocycloalkylene groups are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0090] R L-1 independently H or C 1 -C 6 alkyl.

[0091] In certain preferred embodiments of the present invention, certain groups in the compound of formula (I), its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt are defined as follows, and the unmentioned groups are the same as those described in any embodiment of the present invention (referred to as "in a certain embodiment of the present invention").

[0092] In one embodiment of the present invention,

[0093] is a benzene ring or a 5-6 membered heteroaromatic ring having one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0094] n 1 and n 2 independently 0 or 1;

[0095] L 1 For -(CH 2 ) n -, n is 1, 2 or 3

[0096] R 1 C 6 -C 10 Aryl, 5-10 membered heteroaryl, 1, 2 or 3 R 1-1 Substituted C 6 -C 10 Aryl or 1, 2 or 3 R 1-2 Substituted 5-10 membered heteroaryl, wherein in each "5-10 membered heteroaryl", the heteroatom is selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2 or 3;

[0097] R 1-1 and R 1-2 are independently halogen, -CN, -OH, -NR 1-1-1 R 1-1-2 、-C(=O)H、-C(=O)NR 1-1-1 R 1-1-2 , C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C substituted by 1, 2 or 3 halogens 1 -C 6 Alkyl or C substituted by 1, 2 or 3 halogens 1 -C 6 Alkoxy;

[0098] R 1-1-1 and R 1-1-2 independently H or C 1 -C 6 alkyl;

[0099] L 3 is the connection key;

[0100] or L 3 for

[0101] Among them, X 1 and Connected, With L 2 connected;

[0102] X 1 -CH 2 -、-NR X-1 -, -O- or -S-; R X-1 H or C 1 -C 6 alkyl;

[0103] C 6 -C 10 The aromatic ring or heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-10 membered heteroaromatic ring;

[0104] n 3 is 0, 1, 2, or 3;

[0105] R 2 are independently halogen, -CN, -OH, -NR 2-1 R 2-2 、-C(=O)H、-C(=O)NR 2-1 R 2-2 , C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C substituted by 1, 2 or 3 halogens 1 -C 6 Alkyl or C substituted by 1, 2 or 3 halogens 1 -C 6 Alkoxy; R 2-1 and R 2-2 independently H or C 1 -C 6 alkyl;

[0106] R 3 C 1 -C 6Alkyl or 1, 2 or 3 R 3-1 Substituted C 1 -C 6 alkyl;

[0107] R 3-1 are independently halogen, -OH, -NR 3-1-1 R 3-1-2 or -C(=O)H;

[0108] R 3-1-1 and R 3-1-2 independently H or C 1 -C 6 alkyl;

[0109] L 2 For -(CH 2 ) m -, m is 4, 5, 6, 7, 8, 9 or 10, -(CH 2 ) m 1, 2 or 3 of -CH 2 -optionally selected from -NR L-1 -, -O-, -S-, -CH=CH-, C 3 -C 8 The cycloalkylene group is replaced by one or more groups of cycloalkylene groups and 3-12-membered heterocycloalkylene groups, wherein the heteroatoms in the 3-12-membered heterocycloalkylene groups are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0110] R L-1 independently H or C 1 -C 6 alkyl.

[0111] In a certain embodiment of the present invention, each "5-6 membered heteroaromatic ring" can independently be a 5-6 membered heteroaromatic ring having one or more heteroatoms selected from N, O and S, and having 1 or 2 heteroatoms, such as a pyrrole ring, a thiophene ring, a furan ring, a pyrazole ring, an imidazole ring, a thiazole ring, an oxazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring, such as a pyrazole ring or an imidazole ring.

[0112] In one embodiment of the present invention, each "C 6 -C 10 The "aryl" may independently be phenyl or naphthyl.

[0113] In a certain embodiment of the present invention, each "5-10 membered heteroaryl" can independently be a 5-6 membered heteroaryl having one or more heteroatoms selected from N, O and S, and having 1 or 2 heteroatoms, such as pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, such as thiazolyl, oxazolyl or pyridinyl, and further such as

[0114] In one embodiment of the present invention, each "halogen" may independently be F, Cl, Br or I, such as F or Cl.

[0115] In one embodiment of the present invention, each "C 1 -C 6 The "alkyl" may independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0116] In one embodiment of the present invention, each "C 1 -C 6 The "alkoxy" group may independently be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy.

[0117] In a certain embodiment of the present invention, each "5-10 membered heteroaromatic ring" can independently be a 5-10 membered heteroaromatic ring having one or more heteroatoms selected from N, O and S, and having 1 or 2 heteroatoms, such as a pyrrole ring, a thiophene ring, a furan ring, a pyrazole ring, an imidazole ring, a thiazole ring, an oxazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a quinoline ring, an isoquinoline ring or an indole ring, such as a pyridine ring.

[0118] In one embodiment of the present invention, each "C 3 -C 8 The "cycloalkylene" may independently be cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene.

[0119] In a certain embodiment of the present invention, each "3-12 membered heterocycloalkylene" may independently be a 4-6 membered monocyclic heterocycloalkylene having one or two heteroatoms selected from N and O, or a 7-11 membered cyclic, bridged or spirocyclic heterocycloalkylene, preferably a 4-6 membered monocyclic heterocycloalkylene having one or two heteroatoms selected from N and O, or 1 or 2 heteroatoms, such as an azetidinylene, an oxetanylene, a tetrahydropyrrolylene, a tetrahydroimidazolylene, a tetrahydropyrazolylene, a tetrahydropyranylene, a piperidinylene, a morpholinylene or a piperazinylene.

[0120] In one embodiment of the present invention, each "C 3 -C 8 The "cycloalkyl" may independently be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0121] In a certain embodiment of the present invention, each "3-8 membered heterocycloalkyl" may independently be a 4-6 membered heterocycloalkyl having one or two heteroatoms selected from N and O, and having 1 or 2 heteroatoms, such as azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydropyranyl, piperidinyl, morpholinyl or piperazinyl.

[0122] In one embodiment of the present invention, is a benzene ring or a 5-membered heteroaromatic ring in which the heteroatom is N and the number of heteroatoms is 1, 2 or 3; preferably, is a benzene ring or a 5-membered heteroaromatic ring containing two N atoms; more preferably, It is a 5-membered heteroaromatic ring containing two N atoms.

[0123] In one embodiment of the present invention, for Preferably

[0124] In one embodiment of the present invention, L 1 exist The connection site on L 3 exist The connection sites on the 1 exist The connection site on The atoms marked with "b" are adjacent.

[0125] In one embodiment of the present invention, for For example Further example

[0126] Preferably

[0127] In one embodiment of the present invention, L 1 -CH 2 -.

[0128] In one embodiment of the present invention, R 1 is a 5-10 membered heteroaryl or is substituted by 1, 2 or 3 R 1-1 Substituted C 6 -C 10 Aryl, R 1-1 is halogen (such as F or Cl); preferably, R 1 "a 5-6 membered heteroaryl group having one or two heteroatoms selected from N, O and S" or 1 R 1-1 Substituted phenyl, R 1-1is a halogen (such as F or Cl), and R 1-1 Located in L 1 More preferably, R 1 For 1 R 1-1 Substituted phenyl, R 1-1 is a halogen (such as F or Cl), and R 1-1 Located in L 1 The counterpoint or metaposition of.

[0129] In one embodiment of the present invention, R 1 for For example

[0130] In one embodiment of the present invention, when L 3 for When X 1 exist The connection site on L 2 exist The attachment sites on the molecule are separated by one ring atom.

[0131] In one embodiment of the present invention, when L 3 for hour,

[0132] X 1 -O- or -CH 2 -, for example -O-;

[0133] n3 is 0 or 1;

[0134] R 2 is halogen or C substituted by 1, 2 or 3 halogens 1 -C 6 Alkyl groups, such as Cl, F or CF 3 ;

[0135] is a benzene ring or a 5-6 membered heteroaromatic ring, preferably a benzene ring or a "5-6 membered heteroaromatic ring in which the heteroatom is N and the number of heteroatoms is 1 or 2", for example

[0136] In one embodiment of the present invention, when L 3 for hour, for For example More example

[0137] In one embodiment of the present invention, L 2 Any of the following options:

[0138] I:L 2 For -(CH 2 ) m -, m is 6, 7 or 8, -(CH 2 ) m -1 or 2 of -CH 2 - was independently replaced by NR L-1 or O, R L-1 are independently H or C 1 -C 6 Alkyl; preferably, L 2 For -(CH 2 ) m-1 -O-、-(CH 2 ) m-2 -O-CH 2 -or-(CH 2 ) m-2 -NR L -1 -CH 2 -,-(CH 2 ) m-1 -or-(CH 2 ) m-2 -1 in -CH 2 -Optionally NR L-1 or O; more preferably, L 2 For -(CH 2 ) m-1 -O- a 、-(CH 2 ) m-2 -O-CH 2 - a or -(CH 2 ) m-2 -NR L-1 -CH 2 - a ,-(CH 2 ) m-1 -or-(CH 2 ) m-2 -1 in -CH 2 -Optionally NR L-1 or O replacement, where the a side is connected;

[0139] II:L 2 For -(CH 2 ) m -, m is 5, 6, 7, 8 or 9, -(CH 2 ) m -, at least 1 -CH 2 - is replaced by -CH=CH-; preferably, L2 For -(CH 2 ) m-1 -O-,-(CH 2 ) m-1 -, at least 1 -CH 2 - is replaced by -CH=CH-; more preferably, L 2 -CH 2 -(CH 2 ) m-2 -O-,-(CH 2 ) m-2 -, at least 1 -CH 2 - is replaced by -CH=CH-; for example, L 2 -CH 2 -(CH 2 ) m-2 -O- a ,-(CH 2 ) m-2 -, at least 1 -CH 2 - is replaced by -CH=CH-, and the a side is connected.

[0140] In one embodiment of the present invention, when L 2 When -CH=CH- is contained in the group, the configuration of -CH=CH- is Z configuration or E configuration, preferably E configuration.

[0141] In one embodiment of the present invention, L 2 For -(CH 2 ) 4 -CH=CH-CH 2 -O-、-(CH 2 ) 2 -CH=CH-CH 2 -O-、-(CH 2 ) 3 -CH=CH-CH 2 -O-、-(CH 2 ) 2 -CH=CH-CH 2 -O-CH 2 -、-(CH 2 ) 7 -O-、-(CH 2 ) 5 -O-、-(CH 2 ) 6 -O-、-(CH 2 ) 5 -O-CH 2 -、-(CH 2 ) 2 -O-(CH2 ) 2 -O-CH 2 -、-(CH 2 ) 5 -NH-CH 2 -、-(CH 2 ) 5 -N(CH 3 )-CH 2 -、-(CH 2 ) 3 -NH-(CH 2 ) 2 -O-、-(CH 2 ) 2 -CH=CH-(CH 2 ) 2 -O-, -CH 2 -CH=CH-(CH 2 ) 3 -O-、-(CH 2 ) 3 -CH=CH-(CH 2 ) 4 -O- or -(CH 2 ) 3 -CH=CH-(CH 2 ) 3 -O-; for example

[0142] Preferably

[0143] The a side and connected; e.g. The a side and connected.

[0144] In one embodiment of the present invention, R 3 for

[0145] In one embodiment of the present invention,

[0146] for

[0147] L 1 -CH 2 -;

[0148] R 1 For 1 R 1-1 Substituted phenyl, R 1-1is a halogen, and R 1-1 Located in L 1 The paraposition or metaposition of;

[0149] L 3 for X 1 For O, is a benzene ring or a 5-6 membered heteroaromatic ring, n 3 is 0 or 1, R 2 is halogen or C substituted by 1, 2 or 3 halogens 1 -C 6 alkyl;

[0150] L 2 Any of the following options:

[0151] I:L 2 For -(CH 2 ) m-1 -O- a 、-(CH 2 ) m-2 -O-CH 2 - a or -(CH 2 ) m-2 -NR L-1 -CH 2 - a , m is 6, 7 or 8, -(CH 2 ) m-1 -or-(CH 2 ) m-2 -1 in -CH 2 -Optionally NR L-1 or O replacement, where the a side is connected;

[0152] II:L 2 -CH 2 -(CH 2 ) m-2 -O- a , m is 5, 6 or 7, -(CH 2 ) m-2 -, at least 1 -CH 2 - is replaced by -CH=CH-, and the a side is connected;

[0153] R 3 For 1, 2 or 3 R 3-1 Substituted C 1 -C 6 alkyl;

[0154] R 3-1are independently halogen, -OH, -NR 3-1-1 R 3-1-2 or -C(=O)H;

[0155] R 3-1-1 and R 3-1-2 Independently for C 1 -C 6 alkyl.

[0156] In one embodiment of the present invention, the compound represented by formula (I) is any one of the following compounds:

[0157]

[0158]

[0159]

[0160]

[0161]

[0162] The present invention also provides a pharmaceutical composition comprising a substance X and a pharmaceutically acceptable excipient, wherein the substance X is a compound as shown in formula (I) as described in any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0163] The present invention also provides a use of a compound as shown in formula (I) as described in any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a TRPC5 inhibitor.

[0164] The present invention also provides a use of a compound as shown in formula (I) as described in any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a medicament for a disease associated with TRPC5; preferably, the disease associated with TRPC5 is a nervous system disease, such as depression, anxiety disorder, post-traumatic stress disorder (i.e., PTSD) or chronic kidney disease, and the chronic kidney disease is, for example, diabetic nephropathy or focal segmental glomerulosclerosis (i.e., FSGS).

[0165] The present invention also provides a use of a compound as shown in formula (I) as described in any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing a nervous system disease; preferably, the nervous system disease is depression, anxiety disorder, post-traumatic stress disorder (i.e., PTSD) or chronic kidney disease, and the chronic kidney disease is, for example, diabetic nephropathy or focal segmental glomerulosclerosis (i.e., FSGS).

[0166] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0167] The reagents and raw materials used in the present invention are commercially available.

[0168] Unless otherwise specified, the terms used in the present invention have the following meanings:

[0169] It will be understood by those skilled in the art that the structural formulas used in the present invention to describe groups are based on the conventions used in the art. It means that the corresponding group is connected to other fragments and groups in the compound through this site.

[0170] As used herein, a substituent may be preceded by a single dash "-" to indicate that the named substituent is bonded to the parent moiety through a single bond.

[0171] The term "aryl" refers to a cyclic, unsaturated, monovalent hydrocarbon group having a specified number of carbon atoms, which is monocyclic or polycyclic. When it is monocyclic, it has aromatic properties; when it is polycyclic, each monocyclic ring that makes up the polycyclic shares two atoms and one bond, and each ring has aromatic properties. "Aryl" is, for example, phenyl or naphthyl, preferably phenyl.

[0172] The term "heteroaryl" refers to a cyclic, unsaturated, monovalent group having a specified number of ring atoms (e.g., 5 to 10 members), a specified number of heteroatoms (e.g., 1, 2 or 3), and a specified type of heteroatoms (one or more of N, O and S). It is monocyclic or polycyclic, with two atoms and one bond shared between the monocyclic rings, and each ring is aromatic. An example of "heteroaryl" is pyridyl.

[0173] The term "halogen" refers to F, Cl, Br or I.

[0174] The term "alkyl" refers to a group having a specified number of carbon atoms (e.g., 1 -C 6 ). Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl and the like.

[0175] The term "alkoxy" refers to the group -OR X , where R X is alkyl as defined above.

[0176] The term "aromatic ring" satisfies the following conditions, and the rest of the definition is the same as the term "aryl group": it is connected to the rest of the molecule through two or more single bonds.

[0177] The term "heteroaromatic ring" satisfies the following conditions, and the rest of the definition is the same as the term "heteroaryl": it is connected to the rest of the molecule through two or more single bonds.

[0178] The term "cycloalkylene" refers to a group having a specified number of ring carbon atoms (e.g., C 3 -C 8 ) is a non-aromatic, saturated, divalent cyclic hydrocarbon group, and the cycloalkylene group can be monocyclic or polycyclic. Examples of cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene.

[0179] The term "heterocycloalkylene" refers to a non-aromatic saturated divalent cyclic hydrocarbon radical having a specified number of ring atoms (e.g., 3-12 members), a heteroatom selected from one or more of N, O and S, and a number of 1, 2 or 3 heteroatoms. Heterocycloalkylene can be connected to other parts of the molecule through heteroatoms or carbon atoms therein. Heterocycloalkylene includes, but is not limited to, azetidinylene, oxetanediylene, tetrahydropyrrolylene, tetrahydroimidazolylene, tetrahydropyrazolylene, tetrahydropyranylene, piperidinylene, morpholinylene or piperazinylene.

[0180] The term "cycloalkyl" refers to a cycloalkyl radical having a specified number of ring carbon atoms (e.g., C 3 -C 8 ), a saturated cyclic group whose ring atoms consist only of carbon atoms. Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0181] The term "heterocycloalkyl" refers to a saturated cyclic group having a specified number of ring atoms (e.g., 3-8 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (1, 2, or 3 of N, O, and S). Heterocycloalkyl includes, but is not limited to, azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydropyranyl, piperidinyl, morpholinyl, or piperazinyl.

[0182] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention and a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent.

[0183] The term "isotopic compound" refers to a compound in which one or more atoms have an isotopic abundance different from its natural abundance. For example, one or more atoms in the compound are replaced by an atom with a lower mass number than occurs naturally - a hydrogen atom in the compound is replaced by deuterium, for example -OD is a hydrogen atom in a hydroxyl group replaced by deuterium.

[0184] The term "alkenyl" refers to a group having the specified number of carbon atoms (e.g., C 2 ~C 6 ) is a linear or branched, unsaturated, monovalent hydrocarbon group having one or more (e.g., 1, 2, or 3) carbon-carbon sp 2 Double bond. Alkenyl groups include but are not limited to: vinyl, wait.

[0185] The term "alkynyl" refers to a radical having the specified number of carbon atoms (e.g., C 2 ~C 6 ) is a linear or branched, unsaturated, monovalent hydrocarbon group having one or more (e.g., 1, 2, or 3) carbon-carbon sp 3 triple bond. Alkynyl groups include but are not limited to: ethynyl, wait.

[0186] The term "solvate" refers to a substance formed by the combination of a compound of the present invention and a stoichiometric or non-stoichiometric solvent. The solvent molecules in the solvate may exist in an ordered or non-ordered arrangement. The solvent includes, but is not limited to, water, methanol, ethanol, etc.

[0187] The "pharmaceutically acceptable salt" and "solvate" in the term "pharmaceutically acceptable salt solvate" as described above refer to substances prepared from the compounds of the present invention and relatively non-toxic, pharmaceutically acceptable acids or bases; and formed in combination with stoichiometric or non-stoichiometric solvents.

[0188] The term "pharmaceutically acceptable excipients" refers to excipients and additives used in the production of drugs and the preparation of prescriptions, and is all substances contained in drug preparations except the active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2015 Edition) Part IV, or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0189] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) ameliorating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0190] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0191] The positive and progressive effect of the present invention is that the macrocyclic compounds described in the present invention show good TRPC5 inhibitory activity. DETAILED DESCRIPTION

[0192] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0193] NMR test method in the following examples:

[0194] NMR spectra were recorded on a Bruker AVANCE IIIHD 400 MHz instrument using TopSpin 3.2pl6 software. Chemical shifts are given in parts per million (ppm) downfield from the internal reference trimethylsilane, in units of δ.

[0195] Selected data are reported as follows: Chemical shift (multiplicity, coupling constant (J), number of hydrogens). Abbreviations are as follows: s (singlet), d (doublet), t (triplet), q (quartet), spt (septet), m (multiplet), br (broad).

[0196] Preparation of intermediates

[0197]

[0198] Preparation of Intermediate 2-amino-7-[(4-chlorophenyl)methyl]-1,6-dihydropurin-6-one JD-350103

[0199]

[0200] 2-Amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-1,6-dihydropurin-6-one JD-350101 (10.0 g, 35.3 mmol, 1.00 eq) was dissolved in dimethyl sulfoxide (70.0 mL), 1-chloro-4-(chloromethyl)benzene JD-350102 (7.11 g, 44.1 mmol, 1.25 eq) was added, and the mixture was reacted at 50° C. for 16 hours, and then heated under N 2 Under the protection of the atmosphere, the reaction was continued at 70°C for 3 hours. The reaction mixture was cooled to room temperature, the mixture was filtered, the filter cake was washed with water (200 mL) and ethanol (50.0 mL), and the filter cake was concentrated to obtain 2-amino-7-[(4-chlorophenyl)methyl]-1,6-dihydropurin-6-one JD-350103 (3.50 g, 36.0% yield, crude product) as a white solid.

[0201] LC-MS [M+H] + =276.1.

[0202] Preparation of intermediate 7-[(4-chlorophenyl)methyl]-1,2,3,6-tetrahydropurine-2,6-dione JD-350104

[0203]

[0204] 2-amino-7-[(4-chlorophenyl)methyl]-1,6-dihydropurine-6-one JD-350103 (3.5 g, 12.70 mmol, 1.00 eq) was dissolved in AcOH (20 mL), and a solution of sodium nitrite (551 mg, 7.98 mmol, 1.10 eq) dissolved in water (4.00 mL) was added dropwise to the mixture at 50° C., and the mixture was reacted at 50° C. for 3 hours. Water (100 mL) was added to the reaction mixture, the mixture was filtered, and the filter cake was concentrated to obtain 7-[(4-chlorophenyl)methyl]-1,2,3,6-tetrahydropurine-2,6-dione JD-350104 (1.20 g, 34.2% yield, crude product) as a white solid.

[0205] LC-MS [M+H] + =277.0.

[0206] Preparation of intermediate 7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-350105

[0207]

[0208] 7-[(4-chlorophenyl)methyl]-1,2,3,6-tetrahydropurine-2,6-dione JD-350104 (100 mg, 361 μmol, 1.00 eq) was dissolved in DMF (3.00 mL), DBU (55.0 mg, 361 μmol, 54.5 uL, 1.00 eq) and SEM-Cl (60.3 mg, 361 μmol, 64.0 uL, 1.00 eq) were added, and the mixture was reacted at room temperature for 16 hours. The reaction mixture was concentrated to obtain a residue. The residue was purified by preparative thin layer chromatography (silica, petroleum ether / ethyl acetate = 3 / 1) to give 7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-350105 (20.0 mg, 13.6% yield) as a white solid.

[0209] LC-MS [M+H] + =407.1.

[0210] Preparation of Intermediate 8-chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-350106

[0211]

[0212] 7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-350105 (2.50 g, 6.14 mmol, 1.00 eq) was dissolved in THF (15.0 mL), NCS (1.23 g, 9.22 mmol, 1.50 eq) was added, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was quenched by adding water (50.0 mL) at room temperature, and then extracted with ethyl acetate (40.0 mL, 20.0 mL*2). The collected organic phases were concentrated under reduced pressure to give 8-chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-350106 (3.00 g, crude) as a yellow oil.

[0213] Preparation of intermediate 8-chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1-(2,2,3,3-tetramethyl-4-oxa-3-silaheptan-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-350108

[0214]

[0215] 8-Chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-350106 (5.21 g, 11.8 mmol, 1.00 eq) was dissolved in DMF (14.0 mL) and K 2 CO 3 (3.26 g, 23.6 mmol, 2.00 eq), 7-bromo-2,2,3,3-tetramethyl-4-oxa-3-sila-heptane JD-350107 (4.48 g, 17.71 mmol, 1.50 eq), the mixture was reacted at 70°C for 16 hours. The reaction mixture was quenched by adding water (50.0 mL) at room temperature, and then extracted with ethyl acetate (40.0 mL, 20.0 mL*2). The collected organic phases were concentrated under reduced pressure to give 8-chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1-(2,2,3,3-tetramethyl-4-oxa-3-silahept-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD001-8 (7.24 g, 99.9% yield) as a crude yellow oil.

[0216] LC-MS[MH] + =612.2.

[0217] Preparation of intermediate 7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1-(2,2,3,3-tetramethyl-4-oxa-3-silaheptan-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501010

[0218]

[0219] 8-Chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1-(2,2,3,3-tetramethyl-4-oxa-3-silaheptan-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-350108 (7.24 g, 11.8 mmol, 1.00 eq) was dissolved in DMF (50.0 mL), and K 2 CO 3(3.26 g, 23.6 mmol, 2.00 eq), 3-(prop-2-enyloxy)phenol JD-350109 (1.95 g, 13.0 mmol, 1.10 eq), the mixture was reacted at 80°C for 16 hours. The reaction mixture was quenched by adding water (200 mL) at room temperature, and then extracted with ethyl acetate (180 mL, 60.0 mL*3). The collected organic phase was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to give 7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1-(2,2,3,3-tetramethyl-4-oxa-3-silaheptan-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501010 (5.00 g, yield 45.45%, purity 78%) as a yellow oil.

[0220] Preparation of intermediate 7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501011

[0221]

[0222] 7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1-(2,2,3,3-tetramethyl-4-oxa-3-silahep-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501010 (3.00 g, 4.12 mmol, 1.00 eq) was dissolved in ethanol (20.0 mL), hydrochloric acid (12.0 M, 3.00 mL) was added, and the mixture was reacted at 80° C. for 16 hours. The reaction mixture was concentrated to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 50 / 1 to 2 / 1) to give 7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501011 (1.00 g, 50.21% yield) as a yellow solid.

[0223] LC-MS[MH] + =483.1.

[0224] Preparation of Intermediate 3-(Propan-2-enyloxy)phenol JD-350109C

[0225]

[0226] Resorcinol JD-350109A (5.00 g, 45.4 mmol, 7.58 mL, 1.00 eq) was dissolved in acetonitrile (50 mL), and 3-bromoprop-1-ene JD-350109B (5.49 g, 45.41 mmol, 1.00 eq) and K 2 CO 3 (12.6 g, 90.8 mmol, 2.00 eq), the mixture was reacted at 80 ° C for 16 hours. TLC (Plate 1: petroleum ether: ethyl acetate = 2: 1, Rf = 0.51) showed that the starting material was completely consumed, and a new major spot with less polarity was detected. The reaction mixture was quenched with water (100 mL), extracted with ethyl acetate (60.0 mL, 30.0 mL * 2), and the organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 50 / 1-2 / 1) to obtain 3-(prop-2-enyloxy)phenol JD-350109C (1.00 g, 6.66 mmol, 14.7% yield) as a yellow oil.

[0227] 1 H NMR: (400MHz, CDCl 3 -d6)δ=7.18-7.06(m,1H),6.51(ddd,J=0.8,2.2,8.3Hz,1H),6.46-6.41(m,2H),6.1 3-5.96(m,1H),5.41(qd,J=1.6,17.3Hz,1H),5.33-5.23(m,1H),4.56-4.45(m,2H).

[0228] Preparation of intermediate 3-chloro-5-[(prop-2-enyloxy)methyl]phenol JD-3501004C

[0229]

[0230] 5-Chloro-3-hydroxybenzene-1-carboxaldehyde JD-3501004A (3 g, 19.16 mmol, 1 eq) was dissolved in dichloromethane (30 mL) and propylene propoxy (trimethyl) silane JD-3501004B (3.00 g, 22.99 mmol, 3.87 mL, 1.2 eq) were added at 0 °C. 3 SiH (2.67g, 22.99mmol, 3.67mL, 1.2eq) and TMSOT f(425.88 mg, 1.92 mmol, 346.24 μL, 0.1 eq), the mixture was reacted at 10 ° C for 0.5 hours. TLC (petroleum ether: ethyl acetate = 3:1) showed that the H-1 reactant was consumed and a new spot was formed. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 0 / 1-100 / 1) to obtain 3-chloro-5-[(prop-2-enyloxy)methyl]phenol JD-3501004C (2 g, 10.07 mmol, yield 52.54%) as a colorless oil.

[0231] Preparation of Intermediate 3-(7-bromo-2,5-dioxahept-1-yl)phenol JD-3501009D

[0232]

[0233] Step 1 Preparation of 8-bromo-2,2-dimethyl-3,6-dioxa-2-silaoctane JD-3501009B

[0234]

[0235] 2-[(2-bromoethyl)oxy]ethan-1-ol JD-3501009A (1.0 g, 5.92 mmol, 1.00 eq) was dissolved in dichloromethane (15.0 mL), imidazole (805.57 mg, 11.83 mmol, 2 eq) and TMSCl (1.09 g, 10.06 mmol, 1.28 mL, 1.7 eq) were added, and the mixture was reacted at 25 ° C for 2 hours. TLC (petroleum ether: ethyl acetate = 1: 1) showed that the starting material was completely consumed and a new spot was formed. The reaction mixture was diluted with water (10 mL), extracted with dichloromethane (45 mL, 15 mL * 3), and the collected organic phase was concentrated under reduced pressure to obtain 8-bromo-2,2-dimethyl-3,6-dioxa-2-silaoctane JD-3501009B (1.0 g, crude product) as a colorless oil.

[0236] Step 2 Preparation of 3-(7-bromo-2,5-dioxahept-1-yl)phenol JD-3501009D

[0237]

[0238] 8-Bromo-2,2-dimethyl-3,6-dioxa-2-silaoctane JD-3501009B (0.2 g, 1.64 mmol, 1 eq) was dissolved in dichloromethane (10 mL), 3-hydroxybenzaldehyde JD-3501009C (592.52 mg, 2.46 mmol, 1.5 eq) was added, and then Et 3 SiH (228.51 mg, 1.97 mmol, 313.89 μL, 1.2 eq) and TMSOT f (36.40 mg, 163.77 μmol, 29.59 μL, 0.1 eq), the mixture was reacted at 10 ° C for 0.5 hours. TLC (petroleum ether: ethyl acetate = 1: 1) showed that the starting material was completely consumed and a new spot was formed. The reaction mixture was concentrated under reduced pressure to give 3-(7-bromo-2,5-dioxahept-1-yl)phenol JD-3501009D (400 mg, crude product) as a colorless oil.

[0239] Preparation of intermediate [(5-bromopentyl)(methyl)amino]methanoic acid-2-methylpropan-2-yl ester JD-3501011C

[0240]

[0241] (Methylamino)methanoic acid-2-methylpropane-2-yl ester JD-3501011B (2.00 g, 15.3 mmol, 1.00 eq) was dissolved in tetrahydrofuran (20.0 mL). NaH (915 mg, 22.9 mmol, 60% purity, 1.50 eq) was added to the reaction mixture at 0°C. The reaction mixture was reacted at 0-10°C for 1 hour. 1,5-dibromopentane JD-3501011A (7.01 g, 30.5 mmol, 4.13 mL, 2.00 eq) was added to the reaction mixture at 25°C for 2 hours. TLC (plate 1: petroleum ether: ethyl acetate = 10: 1, Rf = 0.50) showed that the starting material was completely consumed, and a new major spot with less polarity was detected. The reaction mixture was quenched by adding water (50.0 mL) at 0-10°C, and then extracted with ethyl acetate (50.0 mL, 25.0 mL*2). The collected organic layer was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to obtain [(5-bromopentyl)(methyl)amino]methane acid-2-methylpropan-2-yl ester JD-3501011C (2.00 g, 7.14 mmol, yield 46.81%) as a colorless oil.

[0242] 1H NMR (400MHz, CHLOROFORM-d) δ = 3.41 (t, J = 6.8 Hz, 2H), 3.21 (t, J = 7.1 Hz, 2H), 2. 84(s,3H),1.89(td,J=7.0,14.5Hz,2H),1.58-1.51(m,2H),1.49-1.39(m,11H).

[0243] Preparation of intermediate 2-chloro-5-(prop-2-enyloxy)phenol JD-3501013B

[0244]

[0245] 3-(Propan-2-enyloxy)phenol JD-350109C (200 mg, 1.33 mmol, 1.00 eq) was dissolved in dichloromethane (3.00 mL), sulfuryl chloride JD-3501013A (216 mg, 1.60 mmol, 160 μL, 1.20 eq) was added, and the mixture was reacted at 25°C for 16 hours. TLC (Plate 1: petroleum ether: ethyl acetate = 5:1, Rf = 0.65) showed that the starting material was completely consumed, and a major new spot with less polarity was detected. The reaction mixture was concentrated to obtain a residue. The residue was subjected to preparative thin layer chromatography (SiO 2 , petroleum ether / ethyl acetate = 3 / 1) to give 2-chloro-5-(prop-2-enyloxy)phenol JD-3501013B (0.05 g, 271 μmol, yield 20.3%) as a yellow oil.

[0246] 1 H NMR: (400MHz, CHLOROFORM-d) δ = 7.19 (d, J = 8.9Hz, 1H), 6.62 (d, J = 2.6Hz, 1H), 6.48 (dd, J = 2.7, 8.8Hz, 1H), 6.03 (tdd, J = 5.3, 11.0, 16.8Hz, 1H), 5.41 (br d, J=17.3Hz, 1H), 5.30 (br d, J=10.5Hz, 1H), 4.50 (br d, J=4.9Hz, 2H).

[0247] Preparation of intermediate 4-chloro-3-(prop-2-enyloxy)phenol JD-3501014B

[0248]

[0249] Compound JD-3501014A (5.00 g, 34.6 mmol, 1.00 eq) was dissolved in acetonitrile (40 mL), and 3-bromoprop-1-ene JD-350109B (6.28 g, 51.9 mmol, 1.50 eq) and K 2 CO 3 (9.56g, 69.2mmol, 2.00eq), the mixture was reacted at 80℃ for 4 hours. TLC (Plate1: petroleum ether: ethyl acetate = 2:1, Rf = 0.45) showed that 1 / 4 of the starting material remained, and a new spot with less polarity was detected. The reaction mixture was quenched with water (150mL), extracted with ethyl acetate (80.0mL, 40.0mL*2), the organic phase was separated, washed with NaCl (30mL, aq), and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1-2 / 1) to obtain 4-chloro-3-(prop-2-enyloxy)phenol JD-3501014B (1.90 g, 10.29 mmol, 29.6% yield) as a yellow oil.

[0250] 1H NMR (400MHz, CHLOROFORM-d) δ = 4.56 (dt, J = 5.10, 1.52Hz, 2H) 5.18 (br s,1H)5.32(dq,J=10.55,1.32Hz,1H)5.46(dq,J=17.26,1.54Hz,1H)6.05(ddt,J=17.26,10.44 ,5.16,5.16Hz,1H)6.38(dd,J=8.50,2.75Hz,1H)6.47(d,J=2.63Hz,1H)7.19(d,J=8.50Hz,1H).

[0251] Preparation of intermediate 5-fluoro-3-(prop-2-enyloxy)phenol JD-3501015B

[0252]

[0253] 5-Fluorobenzene-1,3-diphenol JD-3501015A (1.00 g, 7.81 mmol, 75.8 mL, 1.00 eq) was dissolved in acetonitrile (10 mL), and 3-bromoprop-1-ene JD-350109B (1.42 g, 11.71 mmol, 1.5 eq) and K 2 CO 3(2.16 g, 15.6 mmol, 2.00 eq), the mixture was reacted at 80 ° C for 5 hours. TLC (Plate 1: petroleum ether: ethyl acetate = 2: 1, Rf = 0.51) showed that the starting material was completely consumed, and a new major spot with less polarity was detected. The reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (10.0 mL), and the organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1-2 / 1) to obtain 5-fluoro-3-(prop-2-enyloxy)phenol JD-3501015B (400 mg, 2.38 mmol, 30.5% yield) as a yellow oil.

[0254] 1 H NMR (400MHz, CHLOROFORM-d) δ = 6.30-6.15 (m, 3H), 6.04 (tdd, J = 5.3, 10.6, 17.2Hz, 1H), 5.42 (qd, J=1.5, 17.3Hz, 1H), 5.32 (qd, J=1.3, 10.5Hz, 1H), 4.53-4.48 (m, 2H).

[0255] Preparation of intermediate 4-fluoro-3-(prop-2-enyloxy)phenol JD-3501016B

[0256]

[0257] 4-Fluorobenzene-1,3-diphenol JD-3501016A (5.00 g, 39.0 mmol, 1.00 eq) was dissolved in acetonitrile (40 mL), and 3-bromoprop-1-ene JD-350109B (7.08 g, 58.55 mmol, 1.50 eq) and K 2 CO 3 (10.8g, 78.1mmol, 2.00eq), the mixture was reacted at 80℃ for 16 hours. TLC (Plate1: petroleum ether: ethyl acetate = 2:1, Rf = 0.41) showed that 1 / 4 of the starting material remained, and a new spot with less polarity was detected. The reaction mixture was quenched with water (150mL), extracted with ethyl acetate (150.0mL, 75.0mL*2), the organic phase was collected and washed with NaCl (50mL, aq), and the organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 50 / 1-2 / 1) to obtain 4-fluoro-3-(prop-2-enyloxy)phenol JD-3501016B (2.10 g, 12.5 mmol, 32.0% yield) as a dark brown oil.

[0258] 1 H NMR (400MHz, CHLOROFORM-d) δ = 4.56 (dt, J = 5.38, 1.31Hz, 2H) 5.30 (dd, J = 10.51, 1.25Hz, 1H) 5.42 (dq, J = 17.26, 1.46Hz, 1H) 6.05 (d dt,J=17.23,10.60,5.35,5.35Hz,1H)6.33(dt,J=8.76,3.13Hz,1H)6.50(dd,J=7.00,2.88Hz,1H)6.92(dd,J=10.88,8.76Hz,1H).

[0259] Preparation of Intermediate 5-(Trifluoromethyl)benzene-1,3-diphenol JD-3501018B

[0260]

[0261] 3-Methoxy-5-(trifluoromethyl)phenol JD-3501018A (100 mg, 520 μmol, 1.00 eq) was dissolved in hydrogen iodide (2.00 mL) and reacted at 80°C for 16 hours. TLC (Plate 1: petroleum ether: ethyl acetate = 3:1, Rf = 0.39) showed that the starting material was completely consumed and a new spot with greater polarity was detected. The reaction mixture was concentrated to obtain a residue. The residue was subjected to preparative thin layer chromatography (SiO 2 , petroleum ether / ethyl acetate = 3 / 1) to obtain 5-(trifluoromethyl)benzene-1,3-diol JD-3501018B (40.0 mg, 225 μmol, yield 43.2%) as a white solid.

[0262] 1 H NMR (400MHz, CHLOROFORM-d) δ = 6.68 (d, J = 1.8 Hz, 2H), 6.52 (t, J = 2.1 Hz, 1H), 5.25 (br s, 2H).

[0263] Preparation of intermediate trifluoromethanesulfonic acid-6,6-difluoro-2,2-dimethyl-3,3-diphenyl-4-oxa-3-silaheptan-7-yl ester JD-3501028C

[0264]

[0265] Step 1 Preparation of 2,2-difluoro-3-{[(2-methylpropan-2-yl)diphenylsilyl]oxy}propan-1-ol JD-3501028B

[0266]

[0267] 2,2-Difluoropropane-1,3-diol (5.00 g, 44.6 mmol, 1.00 eq) and imidazole (9.11 g, 134 mmol, 3.00 eq) were dissolved in DMF (50.0 mL) at 0 °C. TBDPSCl (18.4 g, 66.9 mmol, 17.1 mL, 1.50 eq) was added dropwise to the mixture, and the mixture was reacted at 25 °C for 16 hours. Thin layer chromatography (plate 1: petroleum ether: ethyl acetate = 2: 1, Rf = 0.36) showed that the raw material was retained and two new spots were detected. Water (50.0 mL) was added to quench the reaction mixture, and then extracted with ethyl acetate (50.00 mL, 25.0 mL*2), and the organic phase was washed with sodium chloride (5.00 mL, aq), collected and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 50 / 1 to 2 / 1) to give 2,2-difluoro-3-{[(2-methylpropan-2-yl)diphenylsilyl]oxy}propan-1-ol JD-3501028B (5.00 g, 14.27 mmol, 31.98% yield) as a yellow oil.

[0268] Step 2 Preparation of trifluoromethanesulfonic acid-6,6-difluoro-2,2-dimethyl-3,3-diphenyl-4-oxa-3-silaheptan-7-yl ester JD-3501028C

[0269]

[0270] 2,2-Difluoro-3-{[(2-methylpropan-2-yl)diphenylsilyl]oxy}propan-1-ol JD-3501028B (2.00 g, 5.71 mmol, 1.00 eq) was dissolved in dichloromethane (20.0 mL), 2,6-dimethylpyridine (1.83 g, 17.12 mmol, 1.99 mL, 3.00 eq) and Tf2O (3.22 g, 11.4 mmol, 1.88 mL, 2.00 eq) were added at 10°C, and the mixture was reacted at 25°C for 2 hours. The reaction mixture was quenched by adding water (20.0 mL), then extracted with dichloromethane (20.0 mL, 10.0 mL*2), the collected organic layer was washed with sodium chloride (2.00 mL, aq), and the organic phase was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 50 / 1 to 2 / 1) to give trifluoromethanesulfonic acid-6,6-difluoro-2,2-dimethyl-3,3-diphenyl-4-oxa-3-silaheptan-7-yl ester JD-3501028C (2.50 g, 5.18 mmol, yield 90.79%) as a yellow solid.

[0271] Example 1 Preparation of (10E)-21-[(4-chlorophenyl)methyl]-18-(3-hydroxypropyl)-2,8-dioxa-16,18,21,22-tetraazatetracyclo[14.5.2.13,7.020,23]twenty-tetra-1(22),3(4),5,7(24),10,20(23)-hexaene-17,19-dione JD-3501001

[0272]

[0273] Step 1 Preparation of 7-[(4-chlorophenyl)methyl]-3-(hex-5-enyl)-1-(3-hydroxypropyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501001-3

[0274]

[0275] 7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501011 (200 mg, 414 μmol, 1.00 eq) was dissolved in DMF (2.00 mL), 6-bromohex-1-ene JD-3501001-2 (101 mg, 621 μmol, 83.0 uL, 1.50 eq), Cs 2 CO 3 (270 mg, 828 μmol, 2.00 eq), the mixture was reacted at 100 ° C for 3 hours. The reaction mixture was quenched by adding water (20 mL) at room temperature, and then extracted with ethyl acetate (10 mL). The collected organic phase was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative thin layer chromatography (silica, petroleum ether / ethyl acetate = 1 / 1) to obtain 7-[(4-chlorophenyl)methyl]-3-(hex-5-enyl)-1-(3-hydroxypropyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501001-3 (120 mg, 51.28% yield) as a colorless oil.

[0276] LC-MS [M+H] + =565.2.

[0277] Step 2 Preparation of (10E)-21-[(4-chlorophenyl)methyl]-18-(3-hydroxypropyl)-2,8-dioxa-16,18,21,22-tetraazatetracyclo[14.5.2.13,7.020,23]twenty-tetra-1(22),3(4),5,7(24),10,20(23)-hexaene-17,19-dione JD-3501001

[0278]

[0279] 7-[(4-chlorophenyl)methyl]-3-(hex-5-enyl)-1-(3-hydroxypropyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501001-3 (100 mg, 177 μmol, 1.00 eq) was dissolved in dichloromethane (5.00 mL), HG-II (11.1 mg, 17.7 μmol, 0.10 eq) was added, and the mixture was reacted at room temperature for 16 hours. The reaction mixture was concentrated to obtain a residue. The residue was purified by preparative thin layer chromatography (silica, petroleum ether / ethyl acetate = 1 / 1) to obtain a crude product. The crude product was purified by prep-HPLC (column: Welch UlC18150*25mm*5mm; mobile phase: [water (TFA)-acetonitrile]; B%: 52%-82%, 10 min) to give (10E)-21-[(4-chlorophenyl)methyl]-18-(3-hydroxypropyl)-2,8-dioxa-16,18,21,22-tetraazatetracyclo[14.5.2.13,7.020,23]twenty-tetra-1(22),3(4),5,7(24),10,20(23)-hexaene-17,19-dione JD-3501001 (15.5 mg, 16.1% yield, purity 98.4%) as a white solid.

[0280] LC-MS [M+H] + =537.4.

[0281] 1 H NMR:EC7857-131-P1C(400MHz,DMSO-d 6)δ=7.52-7.39(m,4H),7.31(t,J=8.2Hz,1H),6.96(t,J=2.1Hz,1H),6.89-6.74(m,2H),5.52(br s,2H),5.40(s,2H),4.61(br s,2H),4.45(br s,1H),3.92(br t,J=7.3Hz,2H),3.82(br t,J=7.6Hz,2H),3.43(brt,J=6.0Hz,2H),2.06(br d,J=12.4Hz,2H),1.74-1.61(m,4H),1.30(br d,J=6.5Hz,2H).

[0282] Referring to the preparation method of Example 1, the following Examples 2 and 3 were prepared:

[0283] Example 2 Preparation of (13E)-22-[(4-chlorophenyl)methyl]-8-(3-hydroxypropyl)-2,16-dioxa-4,8,10,22-tetraazatetracyclo[15.3.1.13,6.05,10]twenty-1(20),3(4),5(6),13,17(21),18-hexaene-7,9-dione JD-3501002

[0284]

[0285] The intermediate 7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501011 and 4-bromobut-1-ene JD-3501002A were used by the method of step 2 of Example 1 to obtain (13E)-22-[(4-chlorophenyl)methyl]-8-(3-hydroxypropyl)- Hydroxypropyl)-2,16-dioxa-4,8,10,22-tetraazatetracyclo[15.3.1.13,6.05,10]twenty-1(20),3(4),5(6),13,17(21),18-hexaene-7,9-dione JD-3501002 (2.42 mg, 4.71 μmol, yield 12.6%, purity 99.5%) was a white solid.

[0286] LC-MS [M+H] + =509.2.

[0287] 1 H NMR:EC7857-131-P1C(400MHz,MeOD-d 6)δ=7.47(d,J=8.5Hz,2H),7.37(d,J=8.4Hz,2H),7.23(t,J=8.2Hz,1H),6.90( t,J=2.2Hz,1H),6.79(dd,J=1.5,8.0Hz,1H),6.72(dd,J=1.6,8.4Hz,1H),5.72 -5.60(m,1H),5.59-5.49(m,1H),5.44(s,2H),4.55(d,J=6.8Hz,2H),4.16-4. 05(m,4H),3.62(t,J=6.4Hz,2H),2.49-2.38(m,2H),1.88(quin,J=6.7Hz,2H).

[0288] Example 3 Preparation of (10E)-20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501003

[0289]

[0290] The intermediate 7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501011 and 5-bromopent-1-ene JD-3501003A were used by the method of step 2 of Example 1 to obtain (10E)-20-[(4-chlorophenyl)methyl]-17-(3- Hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]tris-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501003 (7.86 mg, 14.7 μmol, yield 16.2%, purity 97.7%) was a white solid.

[0291] LC-MS [M+H] + =523.1.

[0292] 1 H NMR:EC7857-131-P1C(400MHz,MeOD-d 6)δ=7.83(s,1H),7.44(s,4H),7.27(t,J=8.2Hz,1H),6.86-6.76(m,2H),6.09-5.93(m,1H),5.66(td,J=5.7,15.6Hz,1H),5.42(s,2H),4.70(br d,J=5.3Hz,2H),4.45(t,J=5.2Hz,1H),4.00-3.86(m,4H),3.43(q,J=6.1Hz,2H),2.07(br s,2H),1.78-1.64(m,4H).

[0293] Example 4 Preparation of (11E)-5-chloro-20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-2,9-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,11,19(22)-hexaene-16,18-dione JD-3501004

[0294]

[0295] Step 1 Preparation of 7-[(4-chlorophenyl)methyl]-8-({3-chloro-5-[(prop-2-enyloxy)methyl]phenyl}oxy)-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1-(2,2,3,3-tetramethyl-4-oxa-3-silaheptan-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501004-1

[0296]

[0297] 8-Chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1-(2,2,3,3-tetramethyl-4-oxa-3-silaheptan-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-350108 (1.9 g, 3.10 mmol, 1 eq) was dissolved in DMF (20 mL), and K 2 CO 3 (855.73 mg, 6.19 mmol, 2 eq) and 3-chloro-5-[(prop-2-enyloxy)methyl]phenol JD-3501004C (737.98 mg, 3.72 mmol, 1.2 eq), the mixture was reacted at 80°C for 16 hours. LC-MS showed that the starting material remained 11%, and 87% of the target compound was detected (LC-MS [M+H] +=775.2). The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (60 mL, 20 ml*3), and the organic phase was collected and concentrated under reduced pressure to obtain 7-[(4-chlorophenyl)methyl]-8-({3-chloro-5-[(prop-2-enyloxy)methyl]phenyl}oxy)-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1-(2,2,3,3-tetramethyl-4-oxa-3-silaheptan-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501004-1 (3.30 g, crude product) as a yellow oil.

[0298] LC-MS [M+H] + =775.2.

[0299] Step 2 Preparation of 7-[(4-chlorophenyl)methyl]-8-({3-chloro-5-[(prop-2-enyloxy)methyl]phenyl}oxy)-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501004-2

[0300]

[0301] 7-[(4-chlorophenyl)methyl]-8-({3-chloro-5-[(prop-2-enyloxy)methyl]phenyl}oxy)-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1-(2,2,3,3-tetramethyl-4-oxa-3-silaheptan-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501004-1 (3 g, 3.87 mmol, 1 eq) was dissolved in ethanol (30 mL), hydrochloric acid (3 mL, 12 M) was added, and the mixture was reacted at 80°C for 16 hours. LC-MS analysis showed that the starting material was completely consumed, and a major peak with the required mass was detected (LC-MS [M+H] + =531.1). The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 0 / 1 ~ 100 / 1) to give 7-[(4-chlorophenyl)methyl]-8-({3-chloro-5-[(prop-2-enyloxy)methyl]phenyl}oxy)-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501004-2 (0.9 g, 1.37 mmol, yield 35.48%, purity 81%) as a white solid.

[0302] LC-MS [M+H] + =531.1.

[0303] Step 3 Preparation of 3-(but-3-enyl)-7-[(4-chlorophenyl)methyl]-8-({3-chloro-5-[(prop-2-enyloxy)methyl]phenyl}oxy)-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501004-4

[0304]

[0305] 7-[(4-chlorophenyl)methyl]-8-({3-chloro-5-[(prop-2-enyloxy)methyl]phenyl}oxy)-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501004-2 (300 mg, 564.56 μmol, 1 eq) was dissolved in DMF (5.0 mL) and Cs 2 CO 3 (367.89 mg, 1.13 mmol, 2 eq) and 4-bromobut-1-ene JD-3501004-3 (91.46 mg, 677.47 μmol, 68.77 μL, 1.2 eq), the mixture was reacted at 80 ° C for 2 hours. LC-MS analysis showed that the starting material was completely consumed and a main peak meeting the required mass was detected (LC-MS [M+H] + =586.2). The reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (15 mL, 5 ml*3), and the organic phase was collected and concentrated under reduced pressure to obtain 3-(but-3-enyl)-7-[(4-chlorophenyl)methyl]-8-({3-chloro-5-[(prop-2-enyloxy)methyl]phenyl}oxy)-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501004-4 (450 mg, crude product) as a black oil.

[0306] LC-MS [M+H] + =586.2.

[0307] Step 4 Preparation of (11E)-5-chloro-20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-2,9-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,11,19(22)-hexaene-16,18-dione JD-3501004

[0308]

[0309] 3-(But-3-enyl)-7-[(4-chlorophenyl)methyl]-8-({3-chloro-5-[(prop-2-enyloxy)methyl]phenyl}oxy)-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501004-4 (110 mg, 187.88 μmol, 1 eq) was dissolved in dichloromethane (10.00 mL), HG-II (35.32 mg, 56.36 μmol, 0.3 eq) was added, and the mixture was reacted at 25°C for 16 hours. LC-MS showed that compound JD-3501004-4 was completely consumed, and a main peak was detected (LC-MS [M+H] + =557.2) met the requirements. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative high performance liquid chromatography (TFA conditions; chromatographic column: Agela DuraShell C18 150*25mm*5um; mobile phase: [water (NH3H2O)-ACN]; gradient: 57%-87% B / min) to obtain JD-3501004 (26 mg, 46.64 μmol, yield 24.83%) as a white solid.

[0310] LC-MS [M+H] + =557.2.

[0311] 1 H NMR: EC7857-76-P1A1 (400 MHz, CHLOROFORM-d) δ = 7.36 (d, J = 1.50 Hz, 4 H), 7.27 (s, 1H), 7.14-7.17 (m, 1 H), 5.71-5.81 (m, 1 H), 5.50 (dt, J = 15.26, 4.69 Hz,1 H),5.40(s,2 H),4.49(s,2 H),4.46(t,J=5.25 Hz,1 H),3.98-4.03(m,2 H),3.92-3.98(m,2H),3.80(br d,J=4.13 Hz,2 H),3.41-3.49(m,3H),2.31-2.41(m,2 H), 1.68-1.76 (m, 2H).

[0312] Example 5 Preparation of 21-[(4-chlorophenyl)methyl]-18-(3-hydroxypropyl)-2,8-dioxa-16,18,21,22-tetraazatetracyclo[14.5.2.13,7.020,23]twenty-tetra-1(22),3(4),5,7(24),20(23)-pentaene-17,19-dione JD-3501005

[0313]

[0314] Lindlar reagent (0.1 g, 18.62 μmol, 5% purity, 0.1 eq) was dissolved in ethyl acetate (10.0 mL) and added to a mixture of (10E)-21-[(4-chlorophenyl)methyl]-18-(3-hydroxypropyl)-2,8-dioxa-16,18,21,22-tetraazatetracyclo[14.5.2.13,7.020,23]twenty-tetra-1(22),3(4),5,7(24),10,20(23)-hexaene-17,19-dione JD-3501001 (0.01 g, 18.62 μmol, 1 eq) dissolved in ethyl acetate. The suspension was degassed and purged with hydrogen three times. The mixture was stirred under hydrogen (15 psi) at room temperature for 0.5 hours. The mixture was filtered and the filtrate was concentrated to obtain a residue. The residue was purified by prep-HPLC (column: Welch UlC18 150*25mm*5mm; mobile phase: [water (TFA)-acetonitrile]; B%: 58%-88%, 10 min) to give 21-[(4-chlorophenyl)methyl]-18-(3-hydroxypropyl)-2,8-dioxa-16,18,21,22-tetraazatetracyclo[14.5.2.13,7.020,23]twenty-tetra-1(22),3(4),5,7(24),20(23)-pentaene-17,19-dione JD-3501005 (4.62 mg, 45.57% yield, purity 99.6%) as a white solid.

[0315] LC-MS [M+H] + =539.4.

[0316] 1 H NMR:EC7857-131-P1C(400MHz,DMSO-d 6 )δ=7.48(d,J=8.0Hz,2H),7.40-7.30(m,3H),6.97(s,1H),6.89(br d,J=7.9Hz,1H),6.79(br d,J=8.8Hz,1H),5.41(s,2H),4.20(br t,J=5.6Hz,2H),4.13(br t,J=7.4Hz,2H),3.95-3.89(m,2H),3.54(t,J=5.2Hz,2H),1.91(br s,2H),1.51-1.24(m,10H).

[0317] Referring to the preparation method of Example 5, the following Examples 6 and 7 were prepared

[0318] Example 6 Preparation of 22-[(4-chlorophenyl)methyl]-8-(3-hydroxypropyl)-2,16-dioxa-4,8,10,22-tetraazatetracyclo[15.3.1.13,6.05,10]triacontac-1(20),3(4),5(6),17(21),18-pentaene-7,9-dione JD-3501006

[0319]

[0320] Using Example 2 as a raw material and the method of Example 5, 22-[(4-chlorophenyl)methyl]-8-(3-hydroxypropyl)-2,16-dioxa-4,8,10,22-tetraazatetracyclo[15.3.1.13,6.05,10]twenty-1(20),3(4),5(6),17(21),18-pentaene-7,9-dione JD-3501006 (3.00 mg, 5.87 μmol, yield 9.96%, purity 100%) was obtained as a white solid.

[0321] LC-MS [M+H] + =511.2.

[0322] 1 H NMR:EC7857-131-P1C(400MHz,MeOD-d 6 )δ=7.53-7.46(m,2H),7.41-7.35(m,2H),7.27(t,J=8.3Hz,1H),7.08(t,J=2.3Hz,1H),6.83-6.77(m,1H),6.73(td,J=1.2,8. 4Hz,1H),5.46(s,2H),4.13-4.06(m,4H),4.02(t,J=5.9Hz,2H),3.60(t,J=6.4Hz,2H),1.96-1.76(m,6H),1.31-1.23(m,2H).

[0323] Example 7 Preparation of 20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501007

[0324]

[0325] Using Example 3 as a raw material and the method of Example 5, 20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]twenty-three-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501007 (10.9 mg, 20.6 μmol, yield 21.6%, purity 99.5%) was obtained as a white solid.

[0326] LC-MS [M+H] + =525.3.

[0327] 1 H NMR:EC7857-131-P1C(400MHz,MeOD-d 6 )δ=7.94(s,1H),7.45(s,4H),7.28(t,J=8.3Hz,1H),6.84(dd,J=1.3,8.4Hz,1H),6.76(dd,J=1.9,8.3Hz, 1H),5.44(s,2H),4.47(t,J=5.3Hz,1H),4.21-4.10(m,2H),3.98-3.87(m,4H),3.46-3.40(m,2H),1.78(br d,J=2.4Hz,2H),1.74-1.62(m,4H),1.48-1.35(m,4H).

[0328] Example 8 Preparation of 5-chloro-20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-2,9-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501008

[0329]

[0330] Using compound example 4 as raw material, the method of example 5 was used to obtain 5-chloro-20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-2,9-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]twenty-three-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501008 (13 mg, 22.42 μmol, yield 24.99%, purity 96.47%) as a white solid.

[0331] LC-MS [M+H] +=559.2.

[0332] 1 H NMR:EC12163-80-PJH(400MHz,DMSO-d 6 )δ=7.35-7.51(m,6H),7.19-7.25(m,1H),5.36-5.45(m,2H),4.39-4.49(m,3H),3.83-3 .97(m,4H),3.41-3.47(m,4H),1.59-1.75(m,4H),1.43-1.52(m,2H),1.31-1.42(m,2H).

[0333] Example 9 Preparation of 20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-15,17,20,21-tetraaza-2,9,12-trioxatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501009

[0334]

[0335] Step 1 Preparation of 8-chloro-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501009-1

[0336]

[0337] 8-Chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silanahex-1-yl)-1-(2,2,3,3-tetramethyl-4-oxa-3-silanahept-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-350108 (1 g, 1.63 mmol, 1 eq) was dissolved in ethanol (10 mL), hydrochloric acid (1 mL) was added, and the mixture was reacted at 80°C for 16 hours. LC-MS showed that the starting material was completely consumed, and a main peak with the required mass was detected (LC-MS [MH] - = 368.9). The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to obtain compound 6A8-chloro-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501009-1 (400 mg, 769.23 μmol, yield 47.21%, purity 71%) as a white solid.

[0338] LC-MS [MH]-=368.9.

[0339] Step 2 Preparation of 20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-15,17,20,21-tetraaza-2,9,12-trioxatetracyclo[13.5.2.13,7.019,22]triacontria-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501009

[0340]

[0341] 8-Chloro-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501009-1 (100 mg, 270.85 μmol, 1 eq) was dissolved in DMF (5.0 mL) and K 2 CO 3 (74.87 mg, 541.71 μmol, 2 eq) and 3-(7-bromo-2,5-dioxahept-1-yl)phenol JD-3501007D (89.43 mg, 325.03 μmol, 1.2 eq), the mixture was reacted at 80 ° C for 16 hours. LC-MS showed several new peaks, among which 7% of compound JD-3501009-1 and 33% of the target compound were detected (LC-MS [M+H] + =527.4). The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (15 mL, 5 mL*3), and the collected organic phase was concentrated under reduced pressure to obtain a residue, which was purified by preparative high performance liquid chromatography (TFA conditions; chromatographic column: Welch xestimate C18 150*25mm*5um; mobile phase: [water (TFA)-ACN]; gradient: 35%-65% B, 10 minutes) to obtain 20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-15,17,20,21-tetraaza-2,9,12-trioxatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501009 (40 mg, 75.62 μmol, yield 27.92%, purity 99.625%) as a white solid.

[0342] LC-MS [M+H] + =527.4.

[0343] 1H NMR: EC12163-13-P1A1 (400MHz, DMSO-d6) δ = 7.50-7.57 (m, 1H), 7.33-7.42 (m, 5H), 7.16-7.23 (m ,1H),7.02(d,J=7.50Hz,1H),5.36-5.43(m,2H),4.46-4.50(m,2H),4.08-4.13(m,2H),3.94(br t,J=7.25Hz,2H),3.62(br t,J=4.25Hz,2H),3.44-3.51(m,6H),3.43(br s,1H),1.71(quin,J=6.82Hz,2H).

[0344] Example 10 Preparation of 20-[(4-chlorophenyl)methyl]-6-fluoro-17-(3-hydroxypropyl)-2-oxa-9,15,17,20,21-pentazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501010

[0345]

[0346] Step 1 Preparation of 5-({7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-2,6-dioxy-1-(2,2,3,3-tetramethyl-4-oxa-3-silanheptan-7-yl)purin-8-yl}oxy)-2-fluorobenzoic acid methyl ester JD-3501010-2

[0347]

[0348] 8-Chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1-(2,2,3,3-tetramethyl-4-oxa-3-silaheptan-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-350108 (2.00 g, 3.26 mmol, 1.00 eq) was dissolved in DMF (3 mL) and K 2 CO 3(901 mg, 6.52 mmol, 2.00 eq) and methyl 2-fluoro-5-hydroxybenzoate JD-3501010-1 (81.95 mg, 325.03 μmol, 66.74 μL, 1.2 eq), the mixture was reacted at 80° C. for 16 hours. LC-MS showed that compound JD-350108 was completely consumed, and a main peak with the expected mass was detected (LC-MS [M+Na] = 769.3). The reaction mixture was diluted with water (20 mL, 10 mL*2), extracted with ethyl acetate (20 mL, 10 mL*2), the organic phase was collected and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5-({7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-2,6-dioxy-1-(2,2,3,3-tetramethyl-4-oxa-3-silanheptan-7-yl)purin-8-yl}oxy)-2-fluorobenzoic acid methyl ester JD-3501010-2 (2.50 g, crude) as a yellow oil.

[0349] LC-MS [M+Na] = 769.3.

[0350] Step 2 Preparation of ethyl 5-({7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-2,6-dioxy-3H-purin-8-yl}oxy)-2-fluorobenzoate JD-3501010-3

[0351]

[0352] 5-({7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silanahex-1-yl)-2,6-dioxy-1-(2,2,3,3-tetramethyl-4-oxa-3-silanahept-7-yl)purin-8-yl}oxy)-2-fluorobenzoic acid methyl ester JD-3501010-2 (1.50 g, 2.01 mmol, 1.00 eq) was dissolved in ethanol (15 mL), hydrochloric acid (12 M, 2 mL, 12.0 eq) was added, and the mixture was reacted at 80 ° C for 16 hours. LC-MS showed that the starting material was completely consumed, and a main peak with the required mass was detected (LC-MS [M+H] + =517.1). The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (10 mL), and the organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was subjected to preparative thin layer chromatography (SiO 2, petroleum ether / ethyl acetate = 1 / 1) to give 5-({7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-2,6-dioxy-3H-purin-8-yl}oxy)-2-fluorobenzoic acid ethyl ester JD-3501010-3 (400 mg, 774 μmol, yield was 38.6%) as a white solid.

[0353] LC-MS [M+H] + =517.1.

[0354] Step 3 Preparation of ethyl 5-({7-[(4-chlorophenyl)methyl]-3-(2,2-dimethyl-4-oxydecan-5-aza-3-oxadecan-10-yl)-1-(3-hydroxypropyl)-2,6-dioxydecan-8-yl}oxy)-2-fluorobenzoate JD-3501010-5

[0355]

[0356] 5-({7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-2,6-dioxy-3H-purin-8-yl}oxy)-2-fluorobenzoic acid ethyl ester JD-3501010-3 (400 mg, 773 μmol, 1.00 eq) was dissolved in DMF (2 mL), and [(5-bromopentyl)amino]methane acid-2-methylpropan-2-yl ester JD3501010-4 (247 mg, 929 μmol, 1.20 eq) and Cs 2 CO 3 (504 mg, 1.55 mmol, 2.00 eq), the mixture was reacted at 80 ° C for 3 hours. LC-MS showed that the starting material was completely consumed, and a main peak with a quality that met the requirements was detected (LC-MS [M] = 702.2). The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (10 mL), and the organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative thin layer chromatography (silica, petroleum ether / ethyl acetate = 1 / 1). Preparative thin layer chromatography (silica, petroleum ether / ethyl acetate = 1 / 1) was used to give ethyl 5-({7-[(4-chlorophenyl)methyl]-3-(2,2-dimethyl-4-oxyylidene-5-aza-3-oxadecan-10-yl)-1-(3-hydroxypropyl)-2,6-dioxyylidenepurin-8-yl}oxy)-2-fluorobenzoate JD-3501010-5 (250 mg, 356 μmol, 46.0% yield) as a colorless oil.

[0357] LC-MS [M] = 702.2.

[0358] Step 4 Preparation of 5-({7-[(4-chlorophenyl)methyl]-3-(2,2-dimethyl-4-oxydecan-5-aza-3-oxadecan-10-yl)-1-(3-hydroxypropyl)-2,6-dioxydecan-8-yl}oxy)-2-fluorobenzoic acid JD-3501010-6

[0359]

[0360] Ethyl 5-({7-[(4-chlorophenyl)methyl]-3-(2,2-dimethyl-4-oxyylidene-5-aza-3-oxadecan-10-yl)-1-(3-hydroxypropyl)-2,6-dioxyylidenepurin-8-yl}oxy)-2-fluorobenzoate JD-3501010-5 (250 mg, 356 μmol, 1.00 eq) was dissolved in a mixed solution of methanol (2.00 mL), tetrahydrofuran (2.00 mL), and water (2 mL), and LiOH.H2O (22.4 mg, 534 μmol, 1.50 eq) was added, and the mixture was reacted at 25°C for 1 hour. LC-MS showed that the starting material was completely consumed, and a main peak with the required mass was detected (LC-MS [M] = 674.2). The reaction mixture was quenched by adding potassium hydrogen sulfate (10 mL, aq) at 25°C, and then extracted with ethyl acetate (5.00 mL). The organic phase was collected and concentrated under reduced pressure to obtain 5-({7-[(4-chlorophenyl)methyl]-3-(2,2-dimethyl-4-oxygen-5-aza-3-oxadecan-10-yl)-1-(3-hydroxypropyl)-2,6-dioxypurin-8-yl}oxy)-2-fluorobenzoic acid JD-3501010-6 (250 mg, crude product) as a white solid.

[0361] LC-MS [M] = 674.2.

[0362] Step 5 Preparation of 5-{[3-(5-aminopentyl)-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-2,6-dioxypurin-8-yl]oxy}-2-fluorobenzoic acid JD-3501010-7

[0363]

[0364] 5-({7-[(4-chlorophenyl)methyl]-3-(2,2-dimethyl-4-oxydecan-5-aza-3-oxadecan-10-yl)-1-(3-hydroxypropyl)-2,6-dioxydecan-8-yl}oxy)-2-fluorobenzoic acid JD-3501010-6 (250 mg, 301 μmol, 1.00 eq) was dissolved in ethyl acetate (3.00 mL), HCl / EtOAc (4 M, 2 mL) was added, and the mixture was reacted at 25°C for 3 hours. LC-MS showed that the starting material was completely consumed, and a main peak with a satisfactory mass was detected (LC-MS [M] = 574.0). The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*25mm*5um; mobile phase: [water (HCl)-ACN]; B%: 15%-45%, 10 min) to give 5-{[3-(5-aminopentyl)-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-2,6-dioxypurin-8-yl]oxy}-2-fluorobenzoic acid JD-3501010-7 (0.1 g, 174.22 μmol, yield 46.98%) as a white solid.

[0365] LC-MS [M] = 574.0.

[0366] Step 6 Preparation of 20-[(4-chlorophenyl)methyl]-6-fluoro-17-(3-hydroxypropyl)-2-oxa-9,15,17,20,21-pentazatetracyclo[13.5.2.13,7.019,22]triacontria-1(21),3(23),4,6,19(22)-pentaene-8,16,18-trione JD-3501010-8

[0367]

[0368] 5-{[3-(5-aminopentyl)-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-2,6-dioxypurin-8-yl]oxy}-2-fluorobenzoic acid JD-3501010-7 (100 mg, 164 μmol, 1.00 eq, HCl) was dissolved in dichloromethane (5 mL), and DIEA (63.51 mg, 491.43 μmol, 85.60 μL, 3 eq) and T were added respectively. 3P (0.39 g, 612.86 μmol, 364.83 μL, purity 50%, 3.74 eq), the mixture was stirred at 80 ° C for 12 hours. LC-MS showed that the starting material was completely consumed, and a main peak with a satisfactory mass was detected (LC-MS [M] = 556.1). The reaction mixture was quenched by adding water (20 mL) at 25 ° C, extracted with ethyl acetate (10 mL), and the organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; B%: 27%-57%, 10 minutes) to obtain 20-[(4-chlorophenyl)methyl]-6-fluoro-17-(3-hydroxypropyl)-2-oxa-9,15,17,20,21-pentazatetracyclo[13.5.2.13,7.019,22]twenty-three-1(21),3(23),4,6,19(22)-pentaene-8,16,18-trione JD-3501010-8 (10.25 mg, 17.88 μmol, yield 10.92%, purity 97%) as a white solid.

[0369] LC-MS [M] = 556.1.

[0370] 1 H NMR:(400 MHz, DMSO-d6)δ=8.68-7.91(m,2H),7.55-7.29(m,6H),5.52-5.38(m,2H),4.51-4.40(m,1H),4.01-3.85(m,4H),3.53-3.39(m,2H),3.24(br d,J=4.8 Hz,1H),3.00-2.84(m,1H),1.78

[0371] -1.57(m,5H),1.51(br d,J=3.4 Hz,2H),1.30-1.14(m,1H).

[0372] Step 7 Preparation of 20-[(4-chlorophenyl)methyl]-6-fluoro-17-(3-hydroxypropyl)-2-oxa-9,15,17,20,21-pentazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501010

[0373]

[0374] 20-[(4-chlorophenyl)methyl]-6-fluoro-17-(3-hydroxypropyl)-2-oxa-9,15,17,20,21-pentaazatetracyclo[13.5.2.13,7.019,22]triacontria-1(21),3(23),4,6,19(22)-pentaene-8,16,18-trione JD-3501010-8 (5.00 mg, 8.99 μmol, 1.00 eq) was dissolved in tetrahydrofuran (2 mL), and BH 3 .THF (1 M, 8.99 μL, 1.00 eq), the mixture was reacted at 10°C for 2 hours. LC-MS showed that the starting material was completely consumed, and a main peak with a satisfactory mass was detected (LC-MS [M] = 542.2). The reaction mixture was quenched by adding methanol (3 mL) at 0°C, the mixture was stirred at room temperature for 5 minutes, and the mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (chromatographic column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; gradient: 37%-67% B, 10 minutes) to give 20-[(4-chlorophenyl)methyl]-6-fluoro-17-(3-hydroxypropyl)-2-oxa-9,15,17,20,21-pentazatetracyclo[13.5.2.13,7.019,22]twenty-three-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501010 (1.18 mg, 1.90 μmol, yield 21.2%, purity 87.4%) as a yellow solid.

[0375] LC-MS [M] = 542.2.

[0376] 1 H NMR: (400MHz, DMSO-d 6 )δ=8.30(t,J=2.3Hz,1H),8.18(d,J=2.4Hz,1H),8.15(d,J=2.3Hz,1H),7.46(s,4H),6.17-6.0 3(m,1H),5.71-5.56(m,1H),5.45(s,2H),4.79(brd,J=5.1Hz,2H),4.00-3.86(m,4H),3.43(br s,2H),2.08(br s,2H),1.80-1.62(m,4H).

[0377] Example 11 Preparation of 5-chloro-20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-9-methyl-2-oxa-9,15,17,20,21-pentazatetracyclo[13.5.2.13,7.019,22]tris-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501011

[0378]

[0379] Step 1 Preparation of [(5-{8-chloro-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-2,6-dioxypurin-3-yl}pentyl)(methyl)amino]methane acid-2-methylpropane-2-yl ester JD-3501011-1

[0380]

[0381] 8-Chloro-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501009-1 (0.55 g, 1.49 mmol, 1.00 eq) was dissolved in DMF (3.00 mL) and Cs 2 CO 3 (971 mg, 2.98 mmol, 2.00 eq) and [(5-bromopentyl)amino]methanoic acid-2-methylpropan-2-yl ester JD3501010C (501 mg, 1.79 mmol, 1.20 eq), the mixture was reacted at 80° C. for 4 hours. LC-MS showed that the starting material was completely consumed, and a main peak with the required mass was detected (LC-MS [M-Boc] = 468.1). The reaction mixture was quenched by adding water (10 mL) at 25°C, extracted with ethyl acetate (8 mL, 4 mL*2), and the organic phase was collected and concentrated under reduced pressure to give [(5-{8-chloro-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-2,6-dioxypurin-3-yl}pentyl)(methyl)amino]methane-2-methylpropan-2-yl ester JD-3501011-1 (1.00 g, crude) as an off-white solid.

[0382] LC-MS [M-Boc] = 468.1.

[0383] Step 2 Preparation of [(5-{8-[(3-chloro-5-formylphenyl)oxy]-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-2,6-dioxypurin-3-yl}pentyl)(methyl)amino]methanoic acid-2-methylpropan-2-yl ester JD-3501011-2

[0384]

[0385] Dissolve [(5-{8-chloro-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-2,6-dioxypurin-3-yl}pentyl)(methyl)amino]methanoic acid-2-methylpropan-2-yl ester JD-3501011-1 (1.00 g, 1.76 mmol, 1.00 eq) in DMF (10.0 mL), add K 2 CO 3 (486 mg, 3.52 mmol, 2.00 eq) and 5-chloro-3-hydroxybenzene-1-carboxaldehyde JD-3501004A (413 mg, 2.64 mmol, 1.50 eq), the mixture was reacted at 80°C for 16 hours. LC-MS showed that the starting material was completely consumed, and a main peak with the required mass was detected (LC-MS [M] = 688.1). The reaction mixture was extracted with water (100 mL) and ethyl acetate (60.0 mL, 30.0 mL*2). The organic phase was separated and washed with sodium chloride (20.0 mL, aq), and the organic phase was collected and concentrated under reduced pressure to give [(5-{8-[(3-chloro-5-formylphenyl)oxy]-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-2,6-dioxypurin-3-yl}pentyl)(methyl)amino]methane-2-methylpropan-2-yl ester JD-3501011-2 (0.70 g, 884.41 μmol, yield 50.28%, purity 87%) as a yellow oil.

[0386] LC-MS [M] = 688.1.

[0387] Step 3 Preparation of 5-chloro-3-({7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-3-[5-(methylamino)pentyl]-2,6-dioxypurin-8-yl}oxy)benzene-1-carboxaldehyde JD-3501011-3

[0388]

[0389] [(5-{8-[(3-chloro-5-formylphenyl)oxy]-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-2,6-dioxypurin-3-yl}pentyl)(methyl)amino]methanoic acid-2-methylpropan-2-yl ester JD-3501011-2 (800 mg, 116.18 μmol, 1.00 eq) was dissolved in dichloromethane (3.00 mL), HCl / dioxane (4 M, 1.50 mL) was added, and the mixture was reacted at 25° C. for 2 hours. LC-MS showed that the starting material was completely consumed, and a main peak with the required mass was detected (LC-MS [M+Na] = 590.3). The reaction mixture was concentrated under reduced pressure to give 5-chloro-3-({7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-3-[5-(methylamino)pentyl]-2,6-dioxoylidenepurin-8-yl}oxy)benzene-1-carbaldehyde JD-3501011-3 (50.0 mg, 85.0 μmol, yield 73.1%) as a white solid.

[0390] LC-MS [M+Na] = 590.3.

[0391] Step 4 Preparation of 5-chloro-20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-9-methyl-2-oxa-9,15,17,20,21-pentazatetracyclo[13.5.2.13,7.019,22]triacontria-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501011

[0392]

[0393] 5-Chloro-3-({7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-3-[5-(methylamino)pentyl]-2,6-dioxypurin-8-yl}oxy)benzene-1-carboxaldehyde JD-3501011-3 (50.0 mg, 85.0 μmol, 1.00 eq) was dissolved in methanol (5.00 mL), TEA (17.2 mg, 170 μmol, 23.6 μL, 2.00 eq) was added at 25 °C, the mixture was reacted for 0.5 h, and NaBH 3 CN (10.7 mg, 170 μmol, 2.00 eq), the reaction mixture was kept at the temperature for 3 hours, then AcOH (5.10 mg, 84.96 μmol, 4.86 μL, 1.00 eq) was added to the reaction mixture, and the mixture was reacted at 25°C for 13 hours. LCMS showed that 48% of the starting material remained. A new peak was shown on LC-MS, and 34% of the desired compound was detected (LC-MS [M+H]+ =573.0). The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: water xbridge 150*25mm 10um; mobile phase: [water (NH 4 HCO 3 )-ACN]; gradient: 59%-89%, B over 18 min) to give 5-chloro-20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-9-methyl-2-oxa-9,15,17,20,21-pentazatetracyclo[13.5.2.13,7.019,22]twenty-three-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501011 (0.008 g, 13.83 μmol, yield 16.28%, purity 99%) as a white solid.

[0394] LC-MS [M+H] + =573.0.

[0395] 1 H NMR (400 MHz, DMSO-d 6 )δppm 1.28(br dd,J=14.76,6.00Hz,4H)1.57(br d,J=5.88Hz,2H)1.70(quin,J=6.85Hz,2H)2.12-2.25(m,5H)3.41-3.47(m,4H)3.84-3.98(m,4H)4.47(br t,J=5.00Hz,1H)5.42(s,2H)7.16(s,1H)7.23(s,1H)7.34(s,1H)7.37-7.45(m,4H).

[0396] Example 12 Preparation of 20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-2,8-dioxa-11,15,17,20,21-pentazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501012

[0397]

[0398] Step 1 Preparation of [(3-{8-chloro-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-2,6-dioxypurin-3-yl}propyl)amino]methane-2-methylpropane-2-yl ester JD-3501012-2

[0399]

[0400] 8-Chloro-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501009-1 (500 mg, 1.35 mmol, 1.00 eq) was dissolved in DMF (5.00 mL) and Cs 2 CO 3 (883 mg, 2.71 mmol, 2.00 eq) and [(3-bromopropyl)amino]methanoic acid-2-methylpropan-2-yl ester JD-3501012-1 (387 mg, 1.63 mmol, 1.20 eq), the mixture was reacted at 80 ° C for 1 hour. LCMS showed that the starting material was completely consumed, and a main peak with the expected mass was detected (LC-MS [M + H] + =526.1). The reaction mixture was quenched by adding water (20.0 mL) at room temperature, then extracted with ethyl acetate (10.0 mL), and the organic phase was collected and concentrated under reduced pressure to obtain [(3-{8-chloro-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-2,6-dioxypurin-3-yl}propyl)amino]methane-2-methylpropan-2-yl ester JD-3501012-2 (700 mg, crude product) as a yellow oil.

[0401] LC-MS [M+H] + =526.1.

[0402] Step 2 Preparation of [(3-{7-[(4-chlorophenyl)methyl]-8-[(3-hydroxyphenyl)oxy]-1-(3-hydroxypropyl)-2,6-dioxypurin-3-yl}propyl)amino]methane-2-methylpropane-2-yl ester JD-3501012-4

[0403]

[0404] Dissolve 2-methylpropan-2-yl [(3-{8-chloro-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-2,6-dioxypurin-3-yl}propyl)amino]methane JD-3501012-2 (200 mg, 380 μmol, 1.00 eq) in acetonitrile (2.00 mL) and add K 2 CO 3 (105 mg, 760 μmol, 2.00 eq) and m-diphenol JD-3501012-3 (62.8 mg, 570 μmol, 95.1 μL, 1.50 eq) were added and the mixture was reacted at 80 °C for 2 hours. LCMS showed that the starting material was completely consumed and a main peak with the expected mass was detected (LC-MS [M+H]+ =600.3). The reaction mixture was quenched by adding water (20.0 mL) at room temperature, then extracted with ethyl acetate (10.0 mL), and the organic phase was collected and concentrated under reduced pressure to obtain [(3-{7-[(4-chlorophenyl)methyl]-8-[(3-hydroxyphenyl)oxy]-1-(3-hydroxypropyl)-2,6-dioxypurin-3-yl}propyl)amino]methane-2-methylpropan-2-yl ester JD-3501012-4 (300 mg, crude product) as a yellow oil.

[0405] LC-MS [M+H] + =600.3.

[0406] Step 3 Preparation of ({3-[8-({3-[(2-bromoethyl)oxy]phenyl}oxy)-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-2,6-dioxypurin-3-yl]propyl}amino)methane-2-methylpropane-2-yl ester JD-3501012-6

[0407]

[0408] Dissolve 2-methylpropan-2-yl [(3-{7-[(4-chlorophenyl)methyl]-8-[(3-hydroxyphenyl)oxy]-1-(3-hydroxypropyl)-2,6-dioxypurin-3-yl}propyl)amino]methane JD-3501012-4 (200 mg, 333 μmol, 1.00 eq) in acetonitrile (3.00 mL) and add K 2 CO 3 (92.1 mg, 667 μmol, 2.00 eq) and 1,2-dibromoethane JD-3501012-5 (75.1 mg, 400 μmol, 30.2 μL, 1.20 eq), the mixture was reacted at 80 ° C for 16 hours. LCMS showed that the raw material was completely consumed and a main peak with the expected mass was detected (LC-MS [M-Boc] = 600.3). The reaction mixture was quenched by adding water (20.0 mL) at room temperature, and then extracted with ethyl acetate (10.0 mL), and the organic phase was collected and concentrated under reduced pressure. The residue was subjected to preparative thin layer chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 2) was purified to give ({3-[8-({3-[(2-bromoethyl)oxy]phenyl}oxy)-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-2,6-dioxypurin-3-yl]propyl}amino)methane-2-methylpropan-2-yl ester JD-3501012-6 (120 mg, 170 μmol, yield 50.9%) as a white solid.

[0409] LC-MS [M-Boc] = 600.3.

[0410] Step 4 Preparation of 3-(3-aminopropyl)-8-({3-[(2-bromoethyl)oxy]phenyl}oxy)-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501012-7

[0411]

[0412] 2-Methylpropan-2-yl ({3-[8-({3-[(2-bromoethyl)oxy]phenyl}oxy)-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-2,6-dioxypurin-3-yl]propyl}amino)methane JD-3501012-6 (100 mg, 141 μmol, 1.00 eq) was dissolved in dichloromethane (2.00 mL), HCl / dioxane (4 M, 1 mL) was added, and the mixture was reacted at 25° C. for 2 hours. LCMS showed that the starting material was completely consumed, and a main peak with the expected mass was detected (LC-MS [M+H] + =608.2). The reaction mixture was concentrated to give 3-(3-aminopropyl)-8-({3-[(2-bromoethyl)oxy]phenyl}oxy)-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501012-7 (100 mg, crude) as a white solid.

[0413] LC-MS [M+H] + =608.2.

[0414] Step 5 Preparation of 20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-2,8-dioxa-11,15,17,20,21-pentazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501012

[0415]

[0416] 3-(3-aminopropyl)-8-({3-[(2-bromoethyl)oxy]phenyl}oxy)-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501012-7 (50.0 mg, 82.4 μmol, 1.00 eq) was dissolved in acetonitrile (5.00 mL) and K 2 CO 3(45.6 mg, 330 μmol, 4.00 eq), the mixture was reacted at 50° C. for 16 hours. LC-MS showed that 32% of the starting material remained, and 42% of the desired compound was detected (LC-MS [M+H] + =526.3). The reaction mixture was quenched by adding water (20.0 mL) at room temperature, then extracted with ethyl acetate (10.0 mL), and the organic phase was collected and concentrated under reduced pressure to obtain a residue. The organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Welch Xtfdel C18 150*25mm*5mm; mobile phase: [water (TFA)-ACN]; gradient: 20%-50% B, 10% / 10min) to give 20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-2,8-dioxa-11,15,17,20,21-pentazatetracyclo[13.5.2.13,7.019,22]twenty-three-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501012 (12.4 mg, 22.6 μmol, yield 27.4%, purity 95.4%) as a white solid.

[0417] LC-MS [M+H] + =526.3.

[0418] 1 H NMR: (400MHz, DMSO-d6)δ=8.74(br s,2H),7.70(s,1H),7.54(s,4H),7.45(t,J=8.2Hz,1H),7.06-7.00(m,1H),6.96(dd,J=1.9,8.4Hz,1H),5.51(s,2H),4.63-4.44(m,3H),4.07(br t,J=6.8Hz,2H),4.00(br t,J=7.3Hz,2H),3.52(br d,J=2.5Hz,2H),3.36(br s,2H),3.21(br t,J=6.0Hz,2H),2.04(br t,J=6.7Hz,2H),1.82-1.72(m,2H).

[0419] Example 13 Preparation of (10E)-4-chloro-20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501013

[0420]

[0421] Step 1 Preparation of 7-[(4-chlorophenyl)methyl]-8-{[2-chloro-5-(prop-2-enyloxy)phenyl]oxy}-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-1-(2,2,3,3-tetramethyl-4-oxa-3-silanheptan-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501013-1

[0422]

[0423] 8-Chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1-(2,2,3,3-tetramethyl-4-oxa-3-silaheptan-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-350108 (2 g, 3.26 mmol, 1 eq) was dissolved in DMF (20 mL) and Cs 2 CO 3 (2.12 g, 6.52 mmol, 2 eq) and 2-chloro-5-(prop-2-enyloxy)phenol JD-3501013B (721.97 mg, 3.91 mmol, 1.2 eq), the mixture was reacted at 80 ° C for 5 hours. LC-MS showed that the starting material was completely consumed and a major peak with the desired mass was detected (LC-MS [MH] - =763.1). The reaction mixture was quenched with water (20 mL), and then extracted with ethyl acetate (20 mL, 10 mL*2). The collected organic phase was washed with NaCl (4 mL, aq.) and concentrated under reduced pressure to give 7-[(4-chlorophenyl)methyl]-8-{[2-chloro-5-(prop-2-enyloxy)phenyl]oxy}-3-(5,5-dimethyl-2-oxa-5-silanahex-1-yl)-1-(2,2,3,3-tetramethyl-4-oxa-3-silanahept-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501013-1 (3 g, crude product) as a yellow oil.

[0424] LC-MS[MH] - =763.1.

[0425] Step 2 Preparation of 7-[(4-chlorophenyl)methyl]-8-{[2-chloro-5-(prop-2-enyloxy)phenyl]oxy}-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501013-2

[0426]

[0427] 7-[(4-chlorophenyl)methyl]-8-{[2-chloro-5-(prop-2-enyloxy)phenyl]oxy}-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1-(2,2,3,3-tetramethyl-4-oxa-3-silaheptan-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501013-1 (3 g, 3.94 mmol, 1 eq) was dissolved in ethanol (20 mL), hydrochloric acid (12 M, 3 mL, 9.14 eq) was added, and the mixture was reacted at 80 ° C for 16 hours. LC-MS showed that the starting material was completely consumed and the desired mass was detected (LC-MS [MH] - =517.0). The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 50 / 1 ~ 2 / 1) and the residue was purified to obtain 7-[(4-chlorophenyl)methyl]-8-{[2-chloro-5-(prop-2-enyloxy)phenyl]oxy}-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501013-2 (1.1 g, 2.13 mmol, 54.00% yield) as a white solid.

[0428] LC-MS[MH] - =517.0.

[0429] Step 3 Preparation of 7-[(4-chlorophenyl)methyl]-8-{[2-chloro-5-(prop-2-enyloxy)phenyl]oxy}-1-(3-hydroxypropyl)-3-(pent-4-enyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501013-4

[0430]

[0431] 7-[(4-chlorophenyl)methyl]-8-{[2-chloro-5-(prop-2-enyloxy)phenyl]oxy}-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501013-2 (0.5 g, 966.44 μmol, 1 eq) was dissolved in DMF (10 mL) and Cs 2 CO 3 (472.33 mg, 1.45 mmol, 1.5 eq) and 5-bromopent-1-ene JD-3501013-3 (216.04 mg, 1.45 mmol, 1.5 eq), the mixture was reacted at 80 ° C for 2 hours. LC-MS showed that the starting material was completely consumed and the desired mass was detected (LC-MS [MH] -=585.0). The reaction mixture was quenched with water (10 mL), and then extracted with ethyl acetate (10 mL, 50 mL*2). The collected organic phase was washed with NaCl (2 mL, aq.) and concentrated under reduced pressure to obtain a residue. The residue was subjected to preparative thin layer chromatography (SiO 2 , petroleum ether: ethyl acetate = 1.5: 1) to obtain 7-[(4-chlorophenyl)methyl]-8-{[2-chloro-5-(prop-2-enyloxy)phenyl]oxy}-1-(3-hydroxypropyl)-3-(pent-4-enyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501013-4 (0.4 g, 683.20 μmol, yield 70.69%) as a white solid.

[0432] LC-MS[MH] - =585.0.

[0433] Step 4 Preparation of (10E)-4-chloro-20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501013

[0434]

[0435] 7-[(4-chlorophenyl)methyl]-8-{[2-chloro-5-(prop-2-enyloxy)phenyl]oxy}-1-(3-hydroxypropyl)-3-(pent-4-enyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501013-4 (0.1 g, 170.80 μmol, 1 eq) was dissolved in dichloromethane (30 mL), HG-II (Hoveyda-Grubbs 2nd generation catalyst, 32.11 mg, 51.24 μmol, 0.3 eq) was added, and the mixture was reacted at 25 °C for 16 hours. LC-MS showed that the starting material was completely consumed and the desired mass was detected (LC-MS [MH] - =585.1). The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative thin layer chromatography (SiO 2, petroleum ether: ethyl acetate = 1: 1) to obtain the residue. The residue was purified by high performance liquid chromatography (chromatographic column: Phenomenex lunaC18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 69%-99%, 10min) to obtain (10E)-4-chloro-20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]twenty-three-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501013 (9.64mg, 17.29μmol, yield 10.13%) as a white solid.

[0436] LC-MS[MH] - =585.1.

[0437] 1H NMR:EC12352-36-P1A(400MHz,DMSO-d6)δppm 1.64-1.78(m,4H)2.07(br s,2H)3.43(brd,J=5.50Hz,2H)3.87-3.99(m,4H)4.45(t,J=5.19Hz,1H)4.71(br d,J=5.50Hz,2H)5.45(s,2H)5.65(dt,J=15.60,5.58Hz,1H)5.94-6.05(m, 1H)6.85(dd,J=8.88,2.75Hz,1H)7.42-7.48(m,5H)7.95(d,J=2.88Hz,1H).

[0438] Example 14 Preparation of (14E)-19-chloro-23-[(4-chlorophenyl)methyl]-8-(3-hydroxypropyl)-2,17-dioxa-4,8,10,23-tetraazatetracyclo[16.3.1.13,6.05,10]triacontac-1(22),3(4),5(6),14,18(19),20-hexaene-7,9-dione JD-3501014

[0439]

[0440] The intermediate 8-chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1-(2,2,3,3-tetramethyl-4-oxa-3-silahep-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-350108 and the intermediate 4-chloro-3-(prop-2-enyloxy)phenol JD-3501014B were used to synthesize (14E)-19- Chloro-23-[(4-chlorophenyl)methyl]-8-(3-hydroxypropyl)-2,17-dioxa-4,8,10,23-tetraazatetracyclo[16.3.1.13,6.05,10]triacontac-1(22),3(4),5(6),14,18(19),20-hexaene-7,9-dione JD-3501014 (0.034 g, 59.17 μmol, yield 34.64%, purity 97%) was a white solid.

[0441] LC-MS [M+H] + =557.0.

[0442] 1 H NMR (400 MHz, DMSO-d 6 )δppm 1.66-1.79(m,4H)2.02-2.12(m,2H)3.43(br t,J=6.44Hz,2H)3.88-4.03(m,4H)4.82(br d,J=5.50Hz,2H)5.43(s,2H)5.62-5.78(m,1H)6.02(br dd,J=14.38,7.50Hz,1H)6.85-6.96(m,1H)7.37-7.52(m,5H)7.96(d,J=2.75Hz,1H).

[0443] Example 15 Preparation of (10E)-20-[(4-chlorophenyl)methyl]-5-fluoro-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501015

[0444]

[0445] The intermediate 8-chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1-(2,2,3,3-tetramethyl-4-oxa-3-silaheptan-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-350108 and 5-fluoro-3-(prop-2-enyloxy)phenol JD-3501015B were prepared by the method of Example 10 to give (10E)-20-[( JD-3501015 (20.0 mg, 35.5 μmol, yield 16.8%, purity 96%) was a white solid.

[0446] LC-MS [MH]-=541.3.

[0447] 1 H NMR:EC7857-186-P1C(400MHz,DMSO-d 6 )δ=7.76(s,1H),7.45(s,4H),6.83(td,J=2.0,9.4Hz,1H),6.73-6.65(m,1 H),6.14-5.97(m,1H),5.65(td,J=5.8,15.6Hz,1H),5.42(s,2H),4.73(br d,J=5.6Hz,2H),4.44(t,J=5.3Hz,1H),3.94(td,J=7.5,17.1Hz,4H),3.45-3.41(m,2H),2.07(br s,2H),1.78-1.64(m,4H).

[0448] Example 16 Preparation of (10E)-20-[(4-chlorophenyl)methyl]-6-fluoro-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501016

[0449]

[0450] The intermediate 8-chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1-(2,2,3,3-tetramethyl-4-oxa-3-silaheptan-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-350108 and the intermediate 4-fluoro-3-(prop-2-enyloxy)phenol JD-3501016B were prepared by the method of Example 10 to obtain (10E)-20-[( JD-3501016 (0.043 g, 79.33 μmol, yield 45.14%, purity 99.8%) was a white solid.

[0451] LC-MS [MH]-=541.6.

[0452] 1 H NMR (400 MHz, DMSO-d 6 )δppm 1.62-1.80(m,4H)2.07(br s,2H)3.43(br t,J=6.25Hz,2H)3.84-4.00(m,4H)4.78(br d,J=5.63Hz,2H)5.42(s,2H)5.68(dt,J=15.35,5.77Hz,1H)5.98-6.10(m,1H)6.84(dt,J=8 .82,3.22Hz,1H)7.25(dd,J=10.88,9.01Hz,1H)7.44(s,4H)7.94(dd,J=7.50,2.88Hz,1H).

[0453] Example 17 Preparation of Compound (14E)-23-[(4-chlorophenyl)methyl]-8-(3-hydroxypropyl)-2,17-dioxa-4,8,10,20,23-pentazatetracyclo[16.3.1.13,6.05,10]triacontac-1(22),3(4),5(6),14,18(19),20-hexaene-7,9-dione JD-3501017

[0454]

[0455] Step 1 Preparation of compound 7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-8-[(5-hydroxypyridin-3-yl)oxy]-1-(2,2,3,3-tetramethyl-4-oxa-3-silanheptan-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501017-2

[0456]

[0457] 8-Chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1-(2,2,3,3-tetramethyl-4-oxa-3-silaheptan-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD001-8 (1.6 g, 2.61 mmol, 1.00 eq) was dissolved in DMF solution, and K 2 CO 3 (540.48 mg, 3.91 mmol, 1.5 eq) and pyridine-3,5-diol JD-3501017-1 (347.57 mg, 3.13 mmol, 1.2 eq) were heated at 80 °C under N 2 The reaction was carried out under atmosphere protection for 16 hours. LCMS analysis showed that the starting material was completely consumed, and a main peak with the desired mass was detected (LC-MS [M+H] + =688.4). The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (45 mL, 15 mL*3). The collected organic phase was concentrated under reduced pressure to obtain 7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silanahex-1-yl)-8-[(5-hydroxypyridin-3-yl)oxy]-1-(2,2,3,3-tetramethyl-4-oxa-3-silanahept-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501017-2 (1.80 g, crude product) as a brown oil.

[0458] LC-MS [M+H] + =688.4.

[0459] Step 2 Preparation of compound 7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-8-{[5-(prop-2-enyloxy)pyridin-3-yl]oxy}-1-(2,2,3,3-tetramethyl-4-oxa-3-silanheptan-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501017-3

[0460]

[0461] 7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-8-[(5-hydroxypyridin-3-yl)oxy]-1-(2,2,3,3-tetramethyl-4-oxa-3-silaheptan-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501017-2 (1.2 g, 1.74 mmol, 1 eq) was dissolved in DMF solution, and K 2 CO 3 (481.86 mg, 3.49 mmol, 2 eq) and 3-bromopropane-1-ene JD-350109B (253.07 mg, 2.09 mmol, 1.2 eq) were heated at 80 °C under N 2 The reaction was carried out for 2 hours under the protection of the atmosphere. LCMS showed that the starting material was completely consumed, and a main peak with the desired mass was detected (LC-MS [M] = 728.5). The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (60 mL, 20 mL * 3), and the collected organic phase was concentrated under reduced pressure to obtain 7-[(4-chlorophenyl) methyl] -3- (5,5-dimethyl-2-oxa-5-silanahex-1-yl) -8-{[5-(prop-2-enyloxy) pyridin-3-yl] oxy} -1- (2,2,3,3-tetramethyl-4-oxa-3-silanahept-7-yl) -1,2,3,6-tetrahydropurine-2,6-dione JD-3501017-3 (1.70 g, crude product) as a brown oil.

[0462] LC-MS [M] = 728.5.

[0463] Step 3 Preparation of compound 7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-8-{[5-(prop-2-enyloxy)pyridin-3-yl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501017-4

[0464]

[0465] 7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-8-{[5-(prop-2-enyloxy)pyridin-3-yl]oxy}-1-(2,2,3,3-tetramethyl-4-oxa-3-silaheptan-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501017-3 (1.2 g, 1.65 mmol, 1 eq) was dissolved in ethanol solution (16 mL), hydrochloric acid (1.6 mL, 1 M) was added, and the mixture was heated at 80 °C under N2 The reaction was carried out under atmosphere protection for 16 hours. LC-MS analysis showed that the starting material was completely consumed and a main peak meeting the required mass was detected (LC-MS [M+H] + =484.2). The reaction mixture was concentrated to obtain a residue, which was purified by column chromatography (SiO 2 , dichloromethane:methanol=10 / 1) to obtain 7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-8-{[5-(prop-2-enyloxy)pyridin-3-yl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501017-4 (500 mg) as a transparent oil.

[0466] LC-MS [M+H] + =484.2.

[0467] Step 4 Preparation of compound 7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-3-(pent-4-enyl)-8-{[5-(prop-2-enyloxy)pyridin-3-yl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501017-5

[0468]

[0469] 7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-8-{[5-(prop-2-enyloxy)pyridin-3-yl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501017-4 (400 mg, 826.61 μmol, 1.00 eq) was dissolved in DMF solution (4.0 mL), and Cs 2 CO 3 (403.99 mg, 1.24 mmol, 1.5 eq) and 5-bromopent-1-ene JD-3501003A (147.83 mg, 991.93 μmol, 117.32 μL, 1.2 eq), the mixture was reacted at 80 ° C for 1 hour. LC-MS showed that compound JD-3501017-4 was completely consumed, and a main peak with the required mass was detected (LC-MS [M+H] + =552.8). The reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (15 mL, 5 mL*3), and the collected organic phase was concentrated under reduced pressure to obtain a residue, which was subjected to preparative thin layer chromatography (SiO 2, petroleum ether: ethyl acetate = 3: 1) to obtain 7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-3-(pent-4-enyl)-8-{[5-(prop-2-enyloxy)pyridin-3-yl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501017-5 (190 mg) as a yellow oil.

[0470] LC-MS [M+H] + =552.8.

[0471] Step 5 Preparation of compound (14E)-23-[(4-chlorophenyl)methyl]-8-(3-hydroxypropyl)-2,17-dioxa-4,8,10,20,23-pentazatetracyclo[16.3.1.13,6.05,10]triacontac-1(22),3(4),5(6),14,18(19),20-hexaene-7,9-dione JD-3501017

[0472]

[0473] 7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-3-(pent-4-enyl)-8-{[5-(prop-2-enyloxy)pyridin-3-yl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501017-5 (190 mg, 344.19 μmol, 1 eq) was dissolved in DCM (10.00 mL), HG-II (64.70 mg, 103.26 μmol, 0.3 eq) was added, and the mixture was reacted at 25°C for 1 hour. LC-MS showed that compound JD-3501017-5 was completely consumed, and a main peak with the required mass was detected (LC-MS [M+H] + =524.4). The reaction mixture was diluted with water (10 mL), extracted with dichloromethane (45 mL, 15 mL*3), and the collected organic phase was concentrated under reduced pressure to obtain a residue. The residue was subjected to preparative thin layer chromatography (SiO 2 , petroleum ether / ethyl acetate = 0 / 1) to obtain (14E)-23-[(4-chlorophenyl)methyl]-8-(3-hydroxypropyl)-2,17-dioxa-4,8,10,20,23-pentazatetracyclo[16.3.1.13,6.05,10]triacontac-1(22),3(4),5(6),14,18(19),20-hexaene-7,9-dione JD-3501017 (190 mg, 319.10 μmol, yield 88%, purity 99.729%) as a white solid.

[0474] LC-MS [M+H] + =524.4.

[0475] 1 H NMR: EC7857-53-P1A1 (400MHz, CHLOROFORM-d) δ = 8.50-8.57 (m, 1H), 8.11-8.44 (m, 2H), 7.33 -7.49(m,4H),5.98-6.10(m,1H),5.71(dt,J=15.57,5.60Hz,1H),5.41-5.49(m,2H),4.80(br d,J=5.50Hz,2H),4.20(br t,J=5.94Hz,2H),4.02-4.11(m,2H),3.55(br t,J=5.38Hz,2H),2.12-2.22(m,2H),1.79-1.98(m,4H).

[0476] Referring to the preparation method of Example 17, the following Example 18 was prepared

[0477] Example 18 Preparation of (10E)-20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-5-(trifluoromethyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501018

[0478]

[0479] The intermediate 8-chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1-(2,2,3,3-tetramethyl-4-oxa-3-silaheptan-7-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-350108 and the intermediate 5-(trifluoromethyl)benzene-1,3-diphenol JD-3501018B were used by the method of Example 17 to obtain (10E)-20-[( JD-3501018 (27.89 mg, 47.19 μmol, yield 29.21%) was a white solid.

[0480] LC-MS [M+H] + =591.5.

[0481] 1H NMR:EC12352-43-P1A(400MHz,CHLOROFORM-d)δppm 1.85-1.92(m,4H)2.11-2.18(m,2H)3.53(t,J=5.44Hz,2H)4.04-4.10(m,2H)4.19(t,J=5.88Hz,2H)4.74(br d,J=5.38Hz,2H)5.43(s,2H)5.68-5.77(m,1H)5.92-6.01(m,1H)6.97(s,1H)7.12(s,1H)7.33-7.38(m,2H)7.43-7.47(m,2H)8.06(s,1H).

[0482] Example 19 Preparation of 23-[(4-chlorophenyl)methyl]-8-(3-hydroxypropyl)-2,17-dioxa-4,8,10,20,23-pentazatetracyclo[16.3.1.13,6.05,10]tricosyl-1(22),3(4),5(6),18(19),20-pentaene-7,9-dione JD-3501019

[0483]

[0484] (14E)-23-[(4-chlorophenyl)methyl]-8-(3-hydroxypropyl)-2,17-dioxa-4,8,10,20,23-pentazatetracyclo[16.3.1.13,6.05,10]triacontac-1(22),3(4),5(6),14,18(19),20-hexaene-7,9-dione JD-3501017 (100 mg, 190.85 μmol, 1 eq) was dissolved in ethyl acetate (10.0 mL) and added to a mixture of Lindlar reagent (0.1 g, 18.62 μmol, 5% purity, 0.1 eq) dissolved in ethyl acetate (40.0 mL). The suspension was subjected to H 2 Degassing and purging were performed 3 times. The mixture was reacted under H2 (15 psi) at 25°C for 0.5 hours. LC-MS showed that 43% of compound JD-3501017 remained, and 22% of the compound was detected (LC-MS [M+H] +=526.4). The mixture was filtered and the filtrate was concentrated to obtain a residue. The residue was purified by preparative high performance liquid chromatography (chromatographic column: Welch xestimate C18 150*25mm*5um; mobile phase: [water (TFA)-ACN]; gradient: 35%-65% B, 10 minutes) to obtain 23-[(4-chlorophenyl)methyl]-8-(3-hydroxypropyl)-2,17-dioxa-4,8,10,20,23-pentazatetracyclo[16.3.1.13,6.05,10]twenty-three-1(22),3(4),5(6),18(19),20-pentaene-7,9-dione JD-3501019 (5 mg, 9.51 μmol, yield 4.98%, purity 93.276%) as a white solid.

[0485] LC-MS [M+H] + =526.4.

[0486] δ=8.32(s,1H),7.96-8.25(m,2H),7.38(br d,J=8.38Hz,2H),7.27(br d,J=8.50Hz,2H),5.38(s,2H),4.07-4.21(m,4H),3.88-4.01(m,2H),3.65(q,J=7.00Hz,1H),3.46(br t,J=5.50Hz,2H),1.80-1.89(m,4H),1.39-1.52(m,4H),1.17(t,J=7.00Hz,2H).

[0487] Example 20 Preparation of 4-chloro-20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501020

[0488]

[0489] Example 13 The method of Example 5 was used to obtain 4-chloro-20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501020 (20.05 mg, 35.84 μmol, 49.94% yield) as a white solid.

[0490] LC-MS [M+H]+ =561.1.

[0491] 1 H NMR:EC12352-41-P1B(400MHz,CHLOROFORM-d)δppm 1.45-1.61(m,4H)1.86-1.97(m,6H)3.50-3.57(m,2H)4.00-4.07(m,2H)4.13-4.27(m,4H)5.52( s,2H)6.77(dd,J=8.88,2.88Hz,1H)7.31-7.37(m,3H)7.50-7.66(m,2H)8.17(d,J=2.88Hz,1H).

[0492] Example 21 Preparation of 6-chloro-20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501021

[0493]

[0494] Example 14 The method of Example 5 was used to obtain chloro-20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501021 (0.033 g, 58.59 μmol, yield 21.77%, purity 99.32%) as a white solid.

[0495] LC-MS [M+H] + =559.2.

[0496] 1 H NMR (400 MHz, DMSO-d 6 )δppm 1.38-1.48(m,4H)1.63-1.74(m,4H)1.80(br s,2H)3.43(br s,2H)3.83-3.99(m,4H)4.20-4.33(m,2H)5.43(s,2H)6.91(dd,J=8.76,2.63Hz,1H)7.37-7.51(m,5H)8.11(d,J=2.50Hz,1H).

[0497] Example 22 Preparation of 20-[(4-chlorophenyl)methyl]-6-fluoro-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501022

[0498]

[0499] Example 15 The method of Example 5 was used to obtain 20-[(4-chlorophenyl)methyl]-6-fluoro-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501022 (0.016 g, 29.32 μmol, yield 10.57%, purity 99.5%) as a white solid.

[0500] LC-MS [M+H] + =543.2.

[0501] 1 H NMR (400 MHz, DMSO-d 6 )δppm 1.42(br s,4H)1.62-1.73(m,4H)1.80(br s,2H)3.43(br t,J=6.44Hz,3H)3.84-3.96(m,4H)4.21-4.30(m,2H)5.43(s,2H)6.87(dt,J=8.72,3 .14Hz,1H)7.26(dd,J=11.01,9.01Hz,1H)7.45(s,4H)8.08(dd,J=7.50,2.75Hz,1H).

[0502] Example 23 Preparation of 20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-5-(trifluoromethyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]tris-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501023

[0503]

[0504] Example 18 The method of Example 5 was used to obtain 20-[(4-chlorophenyl)methyl]-17-(3-hydroxypropyl)-5-(trifluoromethyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501023 (40.81 mg, 68.82 μmol, yield 40.67%) as a white solid.

[0505] LC-MS [M+H] + =593.1.

[0506] 1 H NMR:EC12352-46-P1B(400MHz,CHLOROFORM-d)δppm 1.46-1.59(m,5H)1.81-1.85(m,2H)1.88-1.97(m,4H)3.54(br t,J=5.44Hz,2H)4.00-4.07(m,2H)4.17-4.25(m,4H)5.45(s,2H)6.98(s,1H)7.07(s,1H)7.32-7.38(m,2H)7.45(d,J=8.38Hz,2H)8.22(s,1H).

[0507] Example 24 Preparation of (10E)-20-[(4-chlorophenyl)methyl]-17-(2,3-dihydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501024

[0508]

[0509] Step 1 Preparation of 8-chloro-7-[(4-chlorophenyl)methyl]-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501024-2

[0510]

[0511] 8-Chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-350106 (2.69 g, 6.09 mmol, 1 eq) was dissolved in DMF (20 mL) and K 2 CO 3 The mixture was heated at 80 °C under N 2 The reaction was carried out for 16 hours under the protection of the atmosphere. LC-MS showed that the starting material was completely consumed, and a main peak with the desired mass was detected (LC-MS [M + Na] = 577.3). The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (15 mL, 5 mL * 2), and the collected organic phase was concentrated under reduced pressure to obtain 8-chloro-7-[(4-chlorophenyl) methyl] -1-[(2,2-dimethyl-1,3-dioxolane-4-yl) methyl] -3-(5,5-dimethyl-2-oxa-5-silanhexane-1-yl) -1,2,3,6-tetrahydropurine-2,6-dione JD-3501024-2 (1.70 g, crude product) as a yellow oil.

[0512] LC-MS [M+Na] = 577.3.

[0513] Step 2 Preparation of 7-[(4-chlorophenyl)methyl]-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-3-(5,5-dimethyl-2-oxa-5-silan-1-yl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501024-3

[0514]

[0515] 8-Chloro-7-[(4-chlorophenyl)methyl]-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501024-2 (3.4 g, 6.12 mmol, 1 eq) was dissolved in DMF (30 mL), and K 2 CO 3 The mixture was heated at 80 °C under N2 The reaction was carried out for 16 hours under atmosphere protection. LC-MS showed that the starting material was completely consumed, and a main peak with a satisfactory quality was detected (LC-MS [M] = 669.3). The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (40 mL, 20 mL * 2), and the collected organic phase was concentrated under reduced pressure to obtain 7-[(4-chlorophenyl) methyl]-1-[(2,2-dimethyl-1,3-dioxolane-4-yl) methyl]-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-8-{[3-(prop-2-enyloxy) phenyl] oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501024-3 (4 g, crude product) as a yellow oil.

[0516] LC-MS [M] = 669.3.

[0517] Step 3 Preparation of 7-[(4-chlorophenyl)methyl]-1-(2,3-dihydroxypropyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501024-4

[0518]

[0519] 7-[(4-chlorophenyl)methyl]-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-3-(5,5-dimethyl-2-oxa-5-silan-1-yl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501024-3 (4 g, 5.98 mmol, 1 eq) was dissolved in ethanol (30 mL) and hydrochloric acid (1.49 mL, 1 eq, 4 M) was added. The mixture was reacted at 80° C. for 16 hours. LC-MS showed that the starting material was completely consumed and a main peak with the required mass was detected (LC-MS [M+H] + =499.3). The reaction mixture was quenched by adding water (30 mL) at 25°C, then extracted with ethyl acetate (40 mL), and the collected organic phase was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 2) to obtain 7-[(4-chlorophenyl)methyl]-1-(2,3-dihydroxypropyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501024-4 (1.48 g, 2.97 mmol, yield 49.63%) as a white solid.

[0520] LC-MS [M+H] +=499.3.

[0521] Step 4 Preparation of 7-[(4-chlorophenyl)methyl]-1-(2,3-dihydroxypropyl)-3-(pent-4-enyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501024-5

[0522]

[0523] 7-[(4-chlorophenyl)methyl]-1-(2,3-dihydroxypropyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501024-4 (0.5 g, 1.00 mmol, 1 eq) was dissolved in DMF (4 mL) and Cs 2 CO 3 (326.53 mg, 1.00 mmol, 1 eq) and 5-bromopent-1-ene JD-3501003A (224.03 mg, 1.50 mmol, 1.5 eq), the mixture was reacted at 80 ° C for 1 hour. LC-MS showed that the starting material was completely consumed, and a main peak with the required mass was detected (LC-MS [M] = 607.4). The reaction mixture was quenched with water (30 mL) at 25 ° C, and then extracted with ethyl acetate (30 mL), and the collected organic phase was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 2) to obtain 7-[(4-chlorophenyl)methyl]-1-(2,3-dihydroxypropyl)-3-(pent-4-enyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501024-5 (0.412 g, 726.59 μmol, yield 72.50%) as a yellow oil.

[0524] LC-MS [M] = 607.4.

[0525] Step 5 Preparation of (10E)-20-[(4-chlorophenyl)methyl]-17-(2,3-dihydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501024

[0526]

[0527] 7-[(4-chlorophenyl)methyl]-1-(2,3-dihydroxypropyl)-3-(pent-4-enyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501024-5 (0.38 g, 670.16 μmol, 1 eq) was dissolved in DCM (19 mL), (125.98 mg, 201.05 μmol, 0.3 eq) was added, and the mixture was reacted at 25 ° C for 16 hours. LC-MS showed that the starting material was completely consumed, and a main peak with the required mass was detected (LC-MS [M+H] + =539.5). The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 2) and the obtained crude product was purified by high performance liquid chromatography (chromatographic column: Welch xestimate C18150*25mm*5um; mobile phase: [water (TFA)-ACN]; B%: 38%--68%, 10 minutes) to obtain (10E)-20-[(4-chlorophenyl)methyl]-17-(2,3-dihydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]twenty-three-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501024 (24.58 mg, 45.60 μmol, 6.81% yield) as a white solid.

[0528] LC-MS [M+H] + =539.5.

[0529] 1 H NMR:EC12149-18-p1m1(400MHz,DMSO-d 6 )δppm 1.74(br d,J=6.63Hz,2H)2.02-2.15(m,2H)3.76-3.85(m,2H)3.91-4.06(m,3H)4.51(t,J=5.75Hz,1H)4.65(d,J=5.38Hz,1H)4.71(br d,J=5.50Hz,2H)5.43(s,2H)5.58-5.77(m,1H)5.95-6.11(m,1H)6.76-6.88(m,2H)7.28(t,J=8.19Hz,1H)7.45(s,4H)7.84(t,J=2.31Hz,1H).

[0530] Referring to the preparation method of Example 24, the following Example 25 was prepared

[0531] Example 25 Preparation of (10E)-20-[(4-chlorophenyl)methyl]-17-[2-(dimethylamino)ethyl]-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501025

[0532]

[0533] The intermediate 8-chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-350106 and (2-iodoethyl)dimethylamine were used according to the method of Example 24 to obtain (10E)-20-[(4-chlorophenyl)methyl]-17-[2-(dimethylamino)ethyl]-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501025.

[0534] LC-MS [M+H] + =536.3.

[0535] 1 H NMR:EC7857-37-P1A1(400MHz,DMSO-d 6 )δ=7.79-7.86(m,1H),7.39-7.49(m,4H),7.21-7.31(m,1H),6.78-6.83(m,2H),5.94-6.07(m,1H),5.61(s,1H),5.39-5 .47(m,2H),4.66-4.74(m,2H),3.89-4.02(m,4H),2.40-2.44(m,2H),2.17(s,6H),2.02-2.12(m,2H),1.66-1.78(m,2H).

[0536] Example 26 Preparation of (10E)-20-[(4-chlorophenyl)methyl]-17-(3-hydroxybutyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501026

[0537]

[0538] Step 1 Preparation of 3-{7-[(4-chlorophenyl)methyl]-2,6-dioxy-8-{[3-(prop-2-enyloxy)phenyl]oxy}-3H-purin-1-yl}propanal JD-3501026-1

[0539]

[0540] 7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501011 (0.05 g, 103.54 μmol, 1 eq) was dissolved in dichloromethane (3 mL), DMP (52.70 mg, 124.25 μmol, 38.47 uL, 1.2 eq) was added, and the mixture was reacted at 25 ° C for 16 hours. LC-MS showed that the starting material was completely consumed, and a main peak meeting the required mass was detected (LC-MS [M+H] + =481.1). The reaction mixture was concentrated under reduced pressure to obtain 3-{7-[(4-chlorophenyl)methyl]-2,6-dioxyylidene-8-{[3-(prop-2-enyloxy)phenyl]oxy}-3H-purin-1-yl}propanal JD-3501026-1 (0.06 g, crude product) as a yellow solid.

[0541] LC-MS [M+H] + =481.1.

[0542] Step 2 Preparation of 7-[(4-chlorophenyl)methyl]-1-(3-hydroxybutyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501026-2

[0543]

[0544] 3-{7-[(4-chlorophenyl)methyl]-2,6-dioxy-8-{[3-(prop-2-enyloxy)phenyl]oxy}-3H-purin-1-yl}propanal JD-3501026-1 (0.06 g, crude product) was dissolved in tetrahydrofuran (3 mL), MeMgBr (3 M, 436.68 uL, 1.5 eq) was added to the mixture at 0°C, and the mixture was stirred at 0°C for 0.5 hours. LC-MS showed that the starting material was completely consumed, and a main peak with the required mass was detected (LC-MS [M+H] +=497.2). The reaction mixture was quenched with water (20 mL) at 0°C, then extracted with ethyl acetate (20 mL, 10 mL*2), the organic phase was washed with NaCl (5 mL, aq), the organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was subjected to preparative thin layer chromatography (SiO 2 , petroleum ether / ethyl acetate = 1:2) to obtain 7-[(4-chlorophenyl)methyl]-1-(3-hydroxybutyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501026-2 (0.18 g, 356.78 μmol, yield 40.85%, purity 98.5%) as a yellow solid.

[0545] LC-MS [M+H] + =497.2.

[0546] Step 3 Preparation of 7-[(4-chlorophenyl)methyl]-1-(3-hydroxybutyl)-3-(pent-4-enyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501026-3

[0547]

[0548] 7-[(4-chlorophenyl)methyl]-1-(3-hydroxybutyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501026-2 10 (0.18 g, 362.22 μmol, 1 eq) was dissolved in DMF (3 mL) and Cs 2 CO 3 (236.03 mg, 724.43 μmol, 2 eq) and 5-bromopent-1-ene JD-3501003A (80.97 mg, 543.32 μmol, 1.5 eq), the mixture was reacted at 80 ° C for 2 hours. LC-MS showed that the starting material was completely consumed, and a main peak with the required mass was detected (LC-MS [M] = 565.2). The reaction mixture was quenched with water (10 mL) at 0 ° C, extracted with ethyl acetate (6 mL, 3 mL * 2), and the organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative thin layer chromatography (SiO 2, petroleum ether / ethyl acetate = 1:2) to obtain 7-[(4-chlorophenyl)methyl]-1-(3-hydroxybutyl)-3-(pent-4-enyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501026-3 (0.11 g, 190.78 μmol, yield 52.67%, purity 98%) as an off-white solid.

[0549] LC-MS [M] = 565.2.

[0550] Step 4 Preparation of (10E)-20-[(4-chlorophenyl)methyl]-17-(3-hydroxybutyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501026

[0551]

[0552] 7-[(4-chlorophenyl)methyl]-1-(3-hydroxybutyl)-3-(pent-4-enyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501026-3 (0.11 g, 194.67 μmol, 1 eq) was dissolved in dichloromethane (5.5 mL), HG-II (12.20 mg, 19.47 μmol, 0.1 eq) was added, and the mixture was reacted at 25 °C for 16 hours. LC-MS showed that the starting material was completely consumed, and a main peak with the required mass was detected (LC-MS [M] = 537.1). The reaction mixture was quenched with water (100 mL), extracted with dichloromethane (60 mL, 30 mL*2), and the organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2The residue was purified by preparative high performance liquid chromatography (chromatographic column: Welch xestimate C18 150*25mm*5um; mobile phase: [water (TFA)-ACN]; B%: 51%-81%, 10 min) to obtain (10E)-20-[(4-chlorophenyl)methyl]-17-(3-hydroxybutyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]twenty-three-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501026 (0.022 g, 38.51 μmol, yield 19.78%, purity 94%) as a white solid.

[0553] LC-MS [M] = 537.1.

[0554] 1 H NMR (400 MHz, DMSO-d 6 )δppm 1.08(d,J=6.13Hz,3H)1.52-1.64(m,2H)1.67-1.78(m,2H)2.02-2.11(m,2H)3. 59-3.69(m,1H)3.83(ddd,J=12.60,9.04,5.75Hz,1H)3.92-4.05(m,3H)4.70(br d,J=5.63Hz,2H)5.42(s,2H)5.61-5.71(m,1H)5.95-6.06(m,1H)6.77-6. 84(m,2H)7.27(t,J=8.19Hz,1H)7.41-7.48(m,4H)7.83(t,J=2.25Hz,1H).

[0555] Example 27 Preparation of (10E)-20-[(4-chlorophenyl)methyl]-17-(3-hydroxy-2-methylpropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501027

[0556]

[0557] The intermediate 8-chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-350106 and 3-bromo-2-methylpropan-1-ol were used in the manner of Example 24 to obtain (10E)-20-[(4-chlorophenyl)methyl]-17-(3-hydroxy-2-methylpropan-1-ol. JD-3501027 (5.41 mg, 10.1 μmol, 18.0% yield, 100% purity) was obtained as a white solid.

[0558] LC-MS [M] = 537.4.

[0559] 1 H NMR:EC12163-217-P1A1(400MHz,DMSO-d 6 )δ=8.23(t,J=2.19Hz,1H),7.42-7.52(m,4H),7.31(t,J=8.25Hz,1H),6.72-6.92(m,2H),5.53-5.70(m,2H),5.4 3(s,2H),4.37-4.45(m,1H),4.07-4.19(m,2H),3.73-3.93(m,4H),3.20-3.31(m,2H),2.54-2.62(m,2H),2.48(br s, 2H), 1.94-2.10 (m, 1H), 0.82 (d, J = 6.88Hz, 3H).

[0560] Example 28 Preparation of (14Z)-23-[(4-chlorophenyl)methyl]-8-(2,2-difluoro-3-hydroxypropyl)-2,17-dioxa-4,8,10,23-tetraazatetracyclo[16.3.1.13,6.05,10]triacontac-1(22),3(4),5(6),14,18(19),20-hexaene-7,9-dione JD-3501028

[0561]

[0562] The intermediate 8-chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-350106 and the intermediate trifluoromethanesulfonic acid-6,6-difluoro-2,2-dimethyl-3,3-diphenyl-4-oxa-3-silaheptan-7-yl ester JD-3501028C were prepared by the method of Example 24 to obtain (14E)-23-[(4- JD-3501028 (3.28 mg, 5.72 μmol, yield 20.9%, purity 97.8%) was a black colloid.

[0563] LC-MS [M+H] + =559.1.

[0564] 1H NMR(EC12352-166-P1B)(400MHz,DMSO-d6)δppm 1.69-1.76(m,2H)2.03-2.10(m,2H)3.60-3.66(m,2H)3.92-3.99(m,2H)4.39(br d,J=14.38Hz,2H)4.70(br d,J=5.38Hz,2H)5.42(s,2H)5.51(t,J=6.44Hz,1H)5.60-5.74(m,1H)5.92-6.05 (m,1H)6.81(brt,J=8.25Hz,2H)7.28(t,J=8.25Hz,1H)7.44(s,4H)7.82(s,1H).

[0565] Example 29 Preparation of 20-[(4-chlorophenyl)methyl]-17-(2,3-dihydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501029

[0566]

[0567] (10E)-20-[(4-chlorophenyl)methyl]-17-(2,3-dihydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontria-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501025 (0.106 g, 196.67 μmol, 1 eq) was dissolved in ethyl acetate (3 mL) and added to a mixture of Lindlar reagent (0.1 g, 18.62 μmol, 5% purity, 0.1 eq) dissolved in ethyl acetate (40.0 mL). The suspension was subjected to H 2 Degassing and purging 3 times, the mixture was heated at 25 °C in H 2 The reaction was carried out under the protection of atmosphere (15 psi) for 0.5 hours. LC-MS showed that the starting material was completely consumed, and a main peak with the required mass was detected (LC-MS [MH] + =539.4). The mixture was filtered and the filtrate was concentrated to obtain a residue. The residue was purified by high performance liquid chromatography (chromatographic column: Welch xestimate C18 150*25mm*5um; mobile phase: [water (TFA)-ACN]; B%: 42%--72%, 10 minutes) to obtain 20-[(4-chlorophenyl)methyl]-17-(2,3-dihydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]twenty-three-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501029 (3.51 mg, 6.49 μmol, yield 3.30%) as a white solid.

[0568] LC-MS[MH] + =539.4.

[0569] 1 H NMR:EC12149-33-p1m1(400MHz,DMSO-d 6 )δppm 1.43(br s,4H)1.65-1.87(m,4H)3.76-3.86(m,2H)3.87-3.96(m,2H)3.97-4.06(m,1H)4.12-4.23(m,2H)4.40-4.74(m,2H)5.45(s, 2H)6.76(dd,J=8.32,1.56Hz,1H)6.85(dd,J=8.13,1.50Hz,1H)7.29(t,J=8.25Hz,1H)7.45(s,4H)7.95(t,J=2.25Hz,1H).

[0570] Referring to the preparation method of Example 29, the following Example 30 was prepared

[0571] Example 30 Preparation of 20-[(4-chlorophenyl)methyl]-17-(3-hydroxybutyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501030

[0572]

[0573] Example 28 The method of Example 5 was used to obtain 20-[(4-chlorophenyl)methyl]-17-(3-hydroxybutyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontria-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501030

[0574] (0.008 g, 14.84 μmol, yield 15.94%, purity 100%) as a white solid.

[0575] LC-MS [M+H] + =540.1.

[0576] 1 H NMR (400 MHz, DMSO-d 6 )δppm 1.08(d,J=6.13Hz,3H)1.37-1.49(m,4H)1.52-1.63(m,2H)1.67-1.74(m,2H)1.75-1.84(m,2H)3.59-3.71(m,1H)3.79-3.95(m,3H)3.96- 4.06(m,1H)4.12-4.21(m,2H)5.44(s,2H)6.73-6.78(m,1H)6.81-6.86(m,1H)7.28(t,J=8.19Hz,1H)7.45(s,4H)7.93(t,J=2.06Hz,1H).

[0577] Example 31 Preparation of 20-[(4-chlorophenyl)methyl]-17-(3-hydroxy-2-methylpropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501031

[0578]

[0579] The compound JD-3501031 in Example 31 was prepared by the method of compound JD-3501005 in Example 5 to obtain 20-[(4-chlorophenyl)methyl]-17-(3-hydroxy-2-methylpropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]twenty-three-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501031 (5.00 mg, 8.98 μmol, yield 9.64%, purity 96.8%) as a white solid.

[0580] LC-MS [M] = 539.4.

[0581] 1 H NMR:EC12163-215-P1B(400MHz,DMSO-d 6 )δ=7.94(t,J=2.25Hz,1H),7.45(s,4H),7.26-7.31(m,1H),6.83-6.87(m,1H),6.76(dd,J=8.25,1.63Hz,1H),5.44(s,2H),4.40- 4.44(m,1H),4.13-4.19(m,2H),3.88-3.95(m,2H),3.75-3.86(m,2H),3.19-3.31(m,2H),2.01(dq,J=12.91,6.62Hz,1H),1.79(br s,2H),1.66-1.73(m,2H),1.43(br s, 4H), 0.81 (d, J = 6.88Hz, 3H).

[0582] Example 32 Preparation of 23-[(4-chlorophenyl)methyl]-8-(2,2-difluoro-3-hydroxypropyl)-2,17-dioxa-4,8,10,23-tetraazatetracyclo[16.3.1.13,6.05,10]triacontac-1(22),3(4),5(6),18(19),20-pentaene-7,9-dione JD-3501032

[0583]

[0584] Compound JD-3501032 in Example 32 was prepared by the method of compound JD-3501005 in Example 5 to obtain 23-[(4-chlorophenyl)methyl]-8-(2,2-difluoro-3-hydroxypropyl)-2,17-dioxa-4,8,10,23-tetraazatetracyclo[16.3.1.13,6.05,10]twenty-three-1(22),3(4),5(6),18(19),20-pentaene-7,9-dione JD-3501032 (2.44 mg, 4.35 μmol, yield 17.3%, purity 100%) as a white solid.

[0585] LC-MS [M+H] + =561.3.

[0586] 1 H NMR:EC12352-198-P1A1(400MHz,DMSO-d 6 )δppm 1.43(br s,4H)1.68-1.81(m,4H)3.65(td,J=13.98,5.82Hz,2H)3.88-3.96(m,2H)4.12-4.21(m,2H)4.42(br t,J=14.38Hz,2H)5.43(s,2H)5.52(br t,J=6.00Hz,1H)6.74-6.79(m,1H)6.85(br d,J=7.50Hz,1H)7.29(t,J=8.19Hz,1H)7.44(s,4H)7.93(br s,1H).

[0587] Example 33 Preparation of 3-{20-[(4-chlorophenyl)methyl]-6-fluoro-16,18-dioxy-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontidine-1(21),3(23),4,6,19(22)-pentaen-17-yl}propanal JD-3501033

[0588]

[0589] 20-[(4-chlorophenyl)methyl]-6-fluoro-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontria-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501022 (100 mg, 184 μmol, 1.00 eq) was dissolved in dichloromethane (4.00 mL), DMP (117 mg, 276.25 μmol, 85.59 μL, 1.50 eq) was added, and the mixture was reacted at 25°C for 4 hours. LC-MS showed that the starting material was completely consumed, and a main peak with the required mass was detected (LC-MS [M+H] + =541.3). The reaction mixture was quenched by adding water (4.00 mL) at 25°C, and then extracted with dichloromethane (4.00 mL, 2.00 mL*2). The organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 58%-88% B over 15 min) to give 3-{20-[(4-chlorophenyl)methyl]-6-fluoro-16,18-dioxy-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]twenty-three-1(21),3(23),4,6,19(22)-pentaen-17-yl}propanal JD-3501033 (24.1 mg, 43.2 μmol, yield 23.5%, purity 97.2%) as a brown solid.

[0590] LC-MS [M+H] + =541.3.

[0591] 1 H NMR:EC12352-119-P1A(400MHz,DMSO-d 6 )δppm 1.42(br s,4H)1.65-1.73(m,2H)1.75-1.83(m,2H)2.68(td,J=6.75,1.75Hz,2H)3.86-3.93(m,2H)4.13-4.29(m,4H)5.4 3(s,2H)6.83-6.91(m,1H)7.26(dd,J=11.07,8.94Hz,1H)7.45(s,4H)8.04-8.11(m,1H)9.67(t,J=1.88Hz,1H).

[0592] Example 37 Preparation of (13E)-23-[(4-chlorophenyl)methyl]-8-(3-hydroxypropyl)-17-oxa-3,4,8,10-tetraazatetracyclo[16.3.1.13,6.05,10]triacontac-1(21),4,6(23),13,18(22),19-hexaene-7,9-dione JD-3501037

[0593]

[0594] Step 1 Preparation of 3-amino-5-bromo-1H-pyrazole-4-carboxylic acid ethyl ester JD-3501037-2

[0595]

[0596] 3-Amino-1H-pyrazole-4-carboxylic acid ethyl ester JD-3501037-1 (30.0 g, 1900 mmol, 1.00 eq) was dissolved in tetrahydrofuran (200 mL), and NBS (51.6 g, 290 mmol, 1.50 eq) dissolved in THF (500 mL) was added at 0°C, and the mixture was reacted at 0-25°C for 2 hours. The reaction mixture was quenched by adding water (1000 mL), and then extracted with ethyl acetate (1500 mL, 500 mL*3), and the organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give 3-amino-5-bromo-1H-pyrazole-4-carboxylic acid ethyl ester JD-3501037-2 (10.0 g, 38.0 mmol, yield 19.7%, purity 88.9%) as an orange solid.

[0597] LC-MS[MH] - =233.8.

[0598] Step 2 Preparation of 3-amino-5-bromo-1-[(3-methoxyphenyl)methyl]pyrazole-4-carboxylic acid ethyl ester JD-3501037-3

[0599]

[0600] 3-Amino-5-bromo-1H-pyrazole-4-carboxylic acid ethyl ester JD-3501037-2 (10.0 g, 42.7 mmol, 1.00 eq) was dissolved in DMF (100 mL), and NaH (2.56 g, 64.1 mmol, purity 60.0%, 1.50 eq) was added at 0°C, and the mixture was reacted at 0-25°C for 0.5 hours, and then 1-(chloromethyl)-3-methoxybenzene JD-3501037A (10.0 g, 10.0 g, 64.1 mmol, 8.70 mL, 1.50.0 eq) was added at 0°C, and the mixture was stirred at 0-25°C for 1 hour. The reaction mixture was quenched with ammonium chloride (200 mL) at 0°C, and then extracted with ethyl acetate (150 mL, 50 mL*3), and the organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (TFA conditions; column: Welch Xtixdel C18 150*25mm*5um; mobile phase: [water (TFA)-ACN]; gradient: 32%-62% B over 10 min) to give 3-amino-5-bromo-1-[(3-methoxyphenyl)methyl]pyrazole-4-carboxylic acid ethyl ester JD-3501037-3 (2.00 g, 5.63 mmol, yield 13.2%, purity 99.8%) as a white solid.

[0601] LC-MS [M+H] + =353.9.

[0602] Step 3 Preparation of 5-bromo-3-[(2,2-dimethyl-9-oxydeoxy-3,3-diphenyl-8-aza-4-oxa-3-silanonan-9-yl)amino]-1-[(3-methoxyphenyl)methyl]pyrazole-4-carboxylic acid ethyl ester JD-3501037-4

[0603]

[0604] 3-Amino-5-bromo-1-[(3-methoxyphenyl)methyl]pyrazole-4-carboxylic acid ethyl ester JD-3501037-3 (30.0 mL) (2.50 g, 7.06 mmol, 1.00 eq) was dissolved in tetrahydrofuran (30.0 mL), DIEA (4.56 g, 35.6 g, 5.53 mmol, 6.15 mL, 5.00 eq) and triphosgene (1.05 g, 3.53 mmol, 0.50 mmol) were added at 0° C., and the mixture was reacted at 0° C. for 1 hour. Then, 3-{[(2-methylpropan-2-yl)diphenylsilyl]oxy}propan-1-amine JD-3501037B (2.66 g, 8.47 mmol, 1.20 eq) was added to the mixture at 0° C., and the mixture was reacted at 25° C. for 3 hours. The reaction mixture was quenched by adding water (50 mL) at 0°C, then extracted with ethyl acetate (90 mL, 30 mL*3), and the organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (TFA conditions; column: Phenomenex luna C18 (250*70 mm, 10 um); mobile phase: [water (TFA)-ACN]; gradient: 65%-100% B over 33 min) to obtain 5-bromo-3-[(2,2-dimethyl-9-oxyylidene-3,3-diphenyl-8-aza-4-oxa-3-silanonan-9-yl)amino]-1-[(3-methoxyphenyl)methyl]pyrazole-4-carboxylic acid ethyl ester JD-3501037-4 (1.70 g, 2.43 mmol, yield 34.4%, purity 99.0%) as a yellow oil.

[0605] LC-MS [M] = 693.0.

[0606] Step 4 Preparation of 3-bromo-5-(2,2-dimethyl-3,3-diphenyl-4-oxa-3-silaheptan-7-yl)-2-[(3-methoxyphenyl)methyl]-4,5,6,7-tetrahydropyrazolo[3,4-d]pyrimidine-4,6-dione JD-3501037-5

[0607]

[0608] 5-Bromo-3-[(2,2-dimethyl-9-oxyylidene-3,3-diphenyl-8-aza-4-oxa-3-silanonan-9-yl)amino]-1-[(3-methoxyphenyl)methyl]pyrazole-4-carboxylic acid ethyl ester JD-3501037-4 (850 mg, 1.23 mmol, 1.00 eq) was dissolved in methanol (9.00 mL), MeONa (99.3 mg, 1.84 mmol, 1.50 eq) was added, and the mixture was reacted at 60 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure to give 3-bromo-5-(2,2-dimethyl-3,3-diphenyl-4-oxa-3-silaheptan-7-yl)-2-[(3-methoxyphenyl)methyl]-4,5,6,7-tetrahydropyrazolo[3,4-d]pyrimidine-4,6-dione JD-3501037-5 (800 mg, crude) as a yellow oil.

[0609] LC-MS [M+H] + =648.9.

[0610] Step 5 Preparation of 3-bromo-2-[(3-hydroxyphenyl)methyl]-5-(3-hydroxypropyl)-4,5,6,7-tetrahydropyrazolo[3,4-d]pyrimidine-4,6-dione JD-3501037-6

[0611]

[0612] 3-Bromo-5-(2,2-dimethyl-3,3-diphenyl-4-oxa-3-silaheptan-7-yl)-2-[(3-methoxyphenyl)methyl]-4,5,6,7-tetrahydropyrazolo[3,4-d]pyrimidine-4,6-dione JD-3501037-5 (750 mg, 1.16 mmol, 1.00 eq, 1.00 eq) was dissolved in DCM (10.0 mL) and BBr was added. 3(1.45 g, 1.45 g, 5.79 mmol, 558 μL, 5.00 eq), the mixture was reacted at 0°C for 1 hour. Then, MeOH (20.0 mL) was added to the reaction mixture at 0°C, the reaction mixture was quenched with water (20 mL) at 0°C, and then extracted with ethyl acetate (30 mL, 20 mL*3), the organic phase was collected and concentrated under reduced pressure to obtain a residue. 0C quenched, and then concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (TFA conditions; column: phenol C18 250*50mm*10mmum; mobile phase: [water (TFA)-ACN]; gradient: 10%-40% B over 5 min) to give 3-bromo-2-[(3-hydroxyphenyl)methyl]-5-(3-hydroxypropyl)-4,5,6,7-tetrahydropyrazolo[3,4-d]pyrimidine-4,6-dione JD-3501037-6 (200 mg, 476 μmol, yield 41.1%, purity 94.1%) as a white solid.

[0613] LC-MS [M] = 395.0.

[0614] Step 6 Preparation of 3-bromo-7-(but-3-enyl)-2-{[3-(but-3-enyloxy)phenyl]methyl}-5-(3-hydroxypropyl)-4,5,6,7-tetrahydropyrazolo[3,4-d]pyrimidine-4,6-dione JD-3501037-7

[0615]

[0616] 3-Bromo-2-[(3-hydroxyphenyl)methyl]-5-(3-hydroxypropyl)-4,5,6,7-tetrahydropyrazolo[3,4-d]pyrimidine-4,6-dione JD-3501037-6 (400 mg, 1.01 mmol, 1.00 eq) was dissolved in DMF (4.00 mL) and Cs 2 CO 3(989 mg, 3.04 mmol, 3.00 eq) and 4-bromobut-1-ene JD-3501002A (1.37 g, 10.1 mmol, 1.03 mmol, 10.0 eq). The reaction mixture was quenched with water (5 mL), then extracted with ethyl acetate (9 mL, 3 mL*3), and the organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (TFA conditions; column: LunaC18 200*40mm*40mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 50%-80% B over 10 min) to give 3-bromo-7-(but-3-enyl)-2-{[3-(but-3-enyloxy)phenyl]methyl}-5-(3-hydroxypropyl)-4,5,6,7-tetrahydropyrazolo[3,4-d]pyrimidine-4,6-dione JD-3501037-7 (340 mg, 675 μmol, 66.7% yield) as a white solid.

[0617] LC-MS [M] = 503.2.

[0618] Step 7 Preparation of (11E)-20-bromo-17-(3-hydroxypropyl)-8-oxa-1,15,17,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-3(4),5,7(23),11,19(20),21-hexaene-16,18-dione JD-3501037-8

[0619]

[0620] 3-Bromo-7-(but-3-enyl)-2-{[3-(but-3-enyloxy)phenyl]methyl}-5-(3-hydroxypropyl)-4,5,6,7-tetrahydropyrazolo[3,4-d]pyrimidine-4,6-dione JD-3501037-7 (440 mg, 874 μmol, 1.00 eq) was dissolved in DCM (44.0 mL), HG-II (164 mg, 262 μmol, 0.30 eq) was added, and the mixture was reacted at 25° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative thin layer chromatography (silica, petroleum ether: ethyl acetate = 1:2) to give (11E)-20-bromo-17-(3-hydroxypropyl)-8-oxa-1,15,17,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-3(4),5,7(23),11,19(20),21-hexaene-16,18-dione JD-3501037-8 (200 mg, 353 μmol, yield 40.4%, purity 84.0%) as an off-white solid.

[0621] LC-MS [M] = 475.9.

[0622] Step 8 Preparation of (13E)-23-[(4-chlorophenyl)methyl]-8-(3-hydroxypropyl)-17-oxa-3,4,8,10-tetraazatetracyclo[16.3.1.13,6.05,10]triacontac-1(21),4,6(23),13,18(22),19-hexaene-7,9-dione JD-3501037

[0623]

[0624] (11E)-20-bromo-17-(3-hydroxypropyl)-8-oxa-1,15,17,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-3(4),5,7(23),11,19(20),21-hexaene-16,18-dione JD-3501037-8 (100 mg, 210 μmol, 1.00 mL) was dissolved in dioxane and Cs 2 CO 3 (137 mg, 421 μmol, 2.00 eq), 2-[(4-chlorophenyl)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane JD-3501037C (213 mg, 842 μmol, 4.00 eq), water (1.00 mL) and Pd 2 (dba) 3(38.5 mg, 42.1 μmol, 0.20 eq), the mixture was reacted at 100 ° C for 16 hours. The reaction mixture was quenched with water (3 mL), then extracted with ethyl acetate (6 mL, 2 mL * 3), and the organic phase was collected and concentrated under reduced pressure to obtain a residue. Preparative thin layer chromatography (silica, petroleum ether: ethyl acetate = 1: 2) was used to purify (13E)-23-[(4-chlorophenyl)methyl]-8-(3-hydroxypropyl)-17-oxa-3,4,8,10-tetraazatetracyclo[16.3.1.13,6.05,10]twenty-three-1(21),4,6(23),13,18(22),19-hexaene-7,9-dione JD-3501037 (60.0 mg, 108 μmol, yield 51.5%, purity 94.0%) was obtained as a white solid. Then, JD-3501037 was further purified by prep-HPLC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: [CO2-MeOH (0.1% ammonia. H2O)]; B%: 35%, isomorphous elution mode) and SFC (column: Laba AD-3 50x4.6mmID, 3um mobile phase: A phase carbon dioxide, B phase methanol (0.05% DEA); gradient elution: BA from 5% to 40% flow rate: 3mL / min; detector: PDA; column temperature: 35C; back pressure: 100Bar") to obtain JD-3501037 (15.0mg, 28.8μmol, yield 25.0%, purity 96.0%) as a white solid.

[0625] LC-MS [M+H] + =522.9.

[0626] 1 H NMR:EC12163-291-P1(400MHz,DMSO-d 6 )δ=7.04-7.17(m,5H)6.84(d,J=7.38Hz,1H)6.68(dd,J=8.19,1.94Hz,1H)6.07(s,1H)5.48-5.59(m,1H)5.36(s,2H)5.18-5.33( m,1H)4.44(t,J=5.19Hz,1H)4.28(s,2H)4.04-4.08(m,2H)3.90-3.95(m,2H)3.85(brt,J=7.19Hz,2H)3.39-3.48(m,2H)2.42(br s,2H)2.03-2.12(m,2H)1.70(quin,J=6.85Hz,2H).

[0627] Example 44 Preparation of 23-[(4-chlorophenyl)methyl]-8-(3-hydroxypropyl)-17-oxa-3,4,8,10-tetraazatetracyclo[16.3.1.13,6.05,10]triaconic-1(21),4,6(23),18(22),19-pentaene-7,9-dione JD-3501044

[0628]

[0629] Compound JD-3501044 in Example 44 was prepared by the method of compound JD-3501005 in Example 5 to obtain 23-[(4-chlorophenyl)methyl]-8-(3-hydroxypropyl)-17-oxa-3,4,8,10-tetraazatetracyclo[16.3.1.13,6.05,10]triacontac-1(21),4,6(23),18(22),19-pentaene-7,9-dione JD-350104 (10.0 mg, 18.7 μmol, yield 16.2%, purity 97.5%) as a white solid.

[0630] LC-MS[MH] - =521.2.

[0631] 1 H NMR:EC12163-241-P1A1(400MHz,DMSO-d 6 )δ=7.27-7.33(m,4H),7.10(t,J=7.88Hz,1H),7.03(s,1H),6.71-6.78( m,2H),5.22-5.28(m,2H),4.36-4.49(m,3H),4.04-4.11(m,2H),3.97(br t,J=7.25Hz,2H),3.89(br t,J=7.13Hz,2H),3.39-3.44(m,2H),1.62-1.71(m,4H),1.48-1.57(m,2H),1.33-1.44(m,4H).

[0632] Examples 34-44

[0633]

[0634]

[0635]

[0636] The compounds in the following Examples 45-47 and Example 49 were prepared with reference to the compound JD-3501048 in Example 48, and the compounds in Examples 50-52 and Example 54 were prepared with reference to the compound JD-3501053 in Example 53:

[0637]

[0638]

[0639] Example 48 Preparation of (10E)-20-[(4-fluorophenyl)methyl]-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501048

[0640]

[0641] Step 1 Preparation of 3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-1-(3-hydroxypropyl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione JD-3501049-1

[0642]

[0643] 7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione (7.00 g, 12.1 mmol, 1 eq) was dissolved in methanol (140 mL), Pd / C (12.9 g, 12.1 mmol, purity 10%, 1.00 eq) was added, and the mixture was heated at 25 °C under H 2 (30psi) for 16 hours. LC-MS detected a main peak of expected mass (LC-MS [M+Na] = 363.2). The reaction mixture was filtered and concentrated under reduced pressure to obtain 3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-1-(3-hydroxypropyl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione JD-3501049-1 (3.60 g, crude product) as a yellow solid.

[0644] LC-MS [M+Na] = 363.2.

[0645] Step 2 Preparation of 3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501049-3

[0646]

[0647] 3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1-(3-hydroxypropyl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione JD-3501049-1 (1.50 g, 4.41 mmol, 1.00 eq), 1-(chloromethyl)-4-fluorobenzene JD-3501049-2 (764 mg, 5.29 mmol, 630 μL, 1.20 eq), K 2 CO 3 (1.22 g, 2.00 eq) was dissolved in DMF (7.50 mL) and the mixture was washed with N 2 After degassing for 3 times, the mixture was reacted at 25°C for 16 hours. LC-MS detected a main peak of expected mass (LC-MS [M+H] + =449.0). The reaction mixture was quenched by adding water (20.00 mL) at 25°C, then extracted with ethyl acetate (20.00 mL), and the organic phase was collected and concentrated under reduced pressure to obtain the residue 3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501049-3 (1.93 g, crude product) as a white oil.

[0648] LC-MS [M+H] + =449.0.

[0649] Step 3 Preparation of 8-chloro-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501049-4

[0650]

[0651] 3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501049-3 (1.83 g, 4.08 mmol, 1.00 eq) was dissolved in tetrahydrofuran (18.0 mL), NCS (817 mg, 6.12 mmol, 1.50 eq) was added, and the mixture was reacted at 25° C. for 2 hours. LC-MS detected a main peak of the expected mass (LC-MS [M+Na] = 505.0). The reaction mixture was quenched by adding water (20.00 mL) at 25°C, and then extracted with ethyl acetate (20.00 mL). The organic phase was collected and concentrated under reduced pressure to give the residue 8-chloro-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501049-4 (2.20 g, crude product) as a white solid.

[0652] LC-MS [M+Na] = 505.0.

[0653] Step 4 Preparation of 3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501049-5

[0654]

[0655] 8-Chloro-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501049-4 (2.20 g, 4.55 mmol, 1.00 eq) and 3-(prop-2-enyloxy)phenol JD-350109C (820 mg, 5.47 mmol, 1.20 eq) were dissolved in DMF (22.0 mL) and K 2 CO 3 (944 mg, 6.83 mmol, 1.50 eq), the mixture was reacted at 80°C for 16 hours. LC-MS detected a main peak of the expected mass (LC-MS [M+H] +=597.2). The reaction mixture was quenched by adding water (20.00 mL) at 25°C, then extracted with ethyl acetate (20.00 mL), and the organic phase was collected and concentrated under reduced pressure to give the residue 3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501049-5 (2.64 g, crude product) as a brown oil.

[0656] (LC-MS [M+H] + =597.2).

[0657] Step 5 Preparation of 7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501049-6

[0658] 3-(5,5-dimethyl-2-oxa-5-silan-1-yl)-7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501049-5 (2.64 g, 4.42 mmol, 1.00 eq) was dissolved in ethanol (26.0 mL), hydrochloric acid (12.0 M, 6.14 mL, 16.6 eq) was added, and the mixture was reacted at 80° C. for 16 hours. LC-MS detected a main peak of the expected mass (LC-MS [M+H] + =467.0). The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (silica, petroleum ether / ethyl acetate=0 / 1) to obtain 7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501049-6 (1.50 g, 3.22 mmol, yield 72.6%) as a brown oil.

[0659] (LC-MS [M+H] + =467.0).

[0660] Step 6 Preparation of 7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-3-(pent-4-enyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501049-7

[0661]

[0662] 7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501049-6 (0.3 g, 643.14 μmol, 1 eq) was dissolved in DMF (3 mL) and Cs 2 CO 3 (419.09 mg, 1.29 mmol, 2 eq) and 5-bromopent-1-ene JD-3501003A (143.77 mg, 964.71 μmol, 1.5 eq), the mixture was reacted at 80°C for 2 hours. LC-MS detected a main peak of the expected mass (LC-MS [M+H] + =535.2). The reaction mixture was quenched by adding water (4.00 mL) at 25°C, then extracted with ethyl acetate (4.00 mL), and the organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was subjected to preparative thin layer chromatography (silica, petroleum ether: ethyl acetate = 1:1, product R f =0.43) was purified to give 7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-3-(pent-4-enyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501049-7 (200 mg, 355.42 μmol, yield 55.26%, purity 95%) as a yellow oil.

[0663] (LC-MS [M+H] + =535.2).

[0664] 1H NMR:EC13118-87-P1A1_NMR(400MHz,CHLOROFORM-d)δppm 1.79(quin,J=7.38Hz,2H)1.91(dt,J=11.16,5.74Hz,2H)2.06-2.11(m,2H)3.54(t,J=5 .50Hz,2H)3.93-4.06(m,2H)4.17-4.24(m,2H)4.50-4.58(m,2H)4.89-5.05(m,2H)5.29- 5.48(m,4H)5.77(ddt,J=17.03,10.37,6.44,6.44Hz,1H)6.05(ddt,J=17.23,10.54,5. 25,5.25Hz,1H)6.81-6.89(m,3H)7.00-7.08(m,2H)7.28-7.34(m,1H)7.46-7.53(m,2H).

[0665] Step 7 Preparation of (10E)-20-[(4-fluorophenyl)methyl]-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501049

[0666]

[0667] 7-[(4-Fluorophenyl)methyl]-1-(3-hydroxypropyl)-3-(pent-4-enyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501049-7 (0.2 g, 374.13 μmol, 1 eq) was dissolved in dichloromethane (20 mL), HG-II (70.33 mg, 112.24 μmol, 0.3 eq) was added, and the mixture was heated at 25 °C under N 2 The reaction was carried out under atmosphere protection for 16 hours. LC-MS showed that the starting material was completely consumed, and a main peak with the required mass was detected ((LC-MS [M+H] +=507.2). The reaction mixture was quenched with water (100 mL), extracted with dichloromethane (60 mL, 30 mL*2), and the organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-thin layer chromatography (silica, petroleum ether: ethyl acetate = 1:1, product Rf = 0.3) to obtain the desired crude product as a white solid. The crude product was purified by preparative high performance liquid chromatography (chromatographic column: Welchxestimate C18 150*25mm*5um; mobile phase: [water (TFA)-ACN]; B%: 50%-70%, 10min) to obtain (10E)-20-[(4-fluorophenyl)methyl]-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]twenty-three-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501049 (150 mg, 287.25 μmol, yield 76.78%, purity 97%) as a white solid.

[0668] LC-MS [M+H] + =507.2.

[0669] 1 H NMR:JD-wx-202_NMR(400MHz,DMSO-d6)δppm 1.61-1.82(m,4H)2.07(br d,J=4.88Hz,2H)3.43(t,J=6.38Hz,2H)3.81-4.05(m,4H)4.34-4.55(m,1H)4.70(br d,J=5.38Hz,2H)5.41(s,2H)5.66(dt,J=15.67,5.55Hz,1H)5.92-6.05(m,1H)6.81(ddd,J=10 .72,8.41,1.88Hz,2H)7.15-7.33(m,3H)7.49(dd,J=8.63,5.50Hz,2H)7.83(t,J=2.25Hz,1H).

[0670] Example 49 Preparation of (10E)-20-[(3-chlorophenyl)methyl]-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501049

[0671]

[0672] The intermediate 3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-1-(3-hydroxypropyl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione JD-3501049-1 and 3-chloro-1-(chloromethyl)benzene were prepared by the method of Example 48 to give (10E)-20-[(3-chlorophenyl)methyl]-17-(3-hydroxypropyl)- 2,8-Dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triac-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501049 (0.20 g, 382 μmol, yield 9.24%, purity 100%) was obtained as an off-white solid.

[0673] LC-MS [M+H] + =523.3.

[0674] 1 H NMR:EC12352-180-P1A(400MHz,DMSO-d 6 )δ=1.65-1.76(m,4H),2.02-2.10(m,2H),3.41-3.45(m,2H),3.89-3.98(m,4H),4.66-4.73(m,2H),5.41-5.46(m,2H),5.60-5 .72(m,1H),5.95-6.05(m,1H),6.76-6.84(m,2H),7.24-7.30(m,1H),7.33-7.42(m,3H),7.49-7.52(m,1H),7.82-7.85(m,1H).

[0675] Example 53 Preparation of 20-[(4-fluorophenyl)methyl]-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501053

[0676]

[0677] The compound JD-3501053 in Example 53 was prepared by the method of compound JD-3501005 in Example 5, 20-[(4-fluorophenyl)methyl]-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]twenty-three-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501053 (26 mg, 50.62 μmol, yield 25.64%, purity 99%) was a white solid.

[0678] 1 H NMR: JD-wx-203_NMR (400MHz, DMSO-d6) δppm 1.42 (br d, J=1.25Hz, 4H) 1.63-1.86 (m, 6H) 3.44 (br t,J=6.38Hz,2H)3.84-3.98(m,4H)4.10-4.21(m,2H)5.43(s,2H)6.75(dd,J=8.25,1.75Hz,1H)6.8 5(dd,J=8.07,1.56Hz,1H)7.17-7.32(m,3H)7.49(dd,J=8.63,5.50Hz,2H)7.93(t,J=2.19Hz,1H).

[0679] Example 54 Preparation of 20-[(3-chlorophenyl)methyl]-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501054

[0680]

[0681] Compound JD-3501054 in Example 54 was prepared by the method of compound JD-3501005 in Example 5 to obtain 20-[(3-chlorophenyl)methyl]-17-(3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontria-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501054 (17.1 mg, 32.5 μmol, yield 9.45%, purity 99.8%) as a white solid.

[0682] LC-MS [M+H] + =525.3.

[0683] 1 H NMR:EC12352-186-P1A(400MHz,DMSO-d 6 )δ=1.43(br d, J=2.13Hz,4H),1.65-1.82(m,6H),3.41-3.47(m,2H),3.89-3.96(m,4H),4.12-4.19(m,2H),4.43-4.49(m,1H),5.45(s,2H),6.73-6.79(m,1H),6.81-6.90(m,1H),7.25-7.32(m,1H),7.34-7.44(m,3H),7.50-7.55(m,1H),7.94(t,J=2.25Hz,1H). Preparation of Intermediate 4-Methylbenzenesulfonic Acid-2-Fluoro-3-Hydroxypropyl Ester JD-3501055C

[0684]

[0685] Step 1 Preparation of 2-fluoropropane-1,3-diol JD-3501055B

[0686]

[0687] Methyl 2-fluoro-3-methoxy-3-oxopropanoate JD-3501055A (10.0 g, 66.6 mmol, 1.00 eq) was dissolved in a mixed solution of tetrahydrofuran (50.0 mL) and ethanol (50.0 mL). The mixture was then cooled to 0°C, and sodium borohydride (5.11 g, 135 mmol, 2.00 eq) was slowly added, and the reaction was heated to 25°C for 10 hours. TLC (petroleum ether: ethyl acetate = 0: 1, Rf = 0.39) showed that the starting material was completely consumed. The reaction was then cooled to -10°C, and hydrochloric acid (100 mL, 2 M) was slowly added. The reaction solution was filtered, washed with ethyl acetate (90 mL, 3*30.0 mL), and the organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 50 / 1 to 2 / 1) to give 2-fluoropropane-1,3-diol JD-3501055B (3.00 g, 31.8 mmol, yield 47.8%) as a yellow oil.

[0688] 1 H NMR: EC12352-244-P1A (400MHz, DMSO-d6) δ = 3.26-3.63 (m, 4H), 4.31-4.53 (m, 1H), 4.82 (br s, 2H).

[0689] Step 2 Preparation of 4-methylbenzenesulfonic acid 2-fluoro-3-hydroxypropyl ester JD-3501055C

[0690]

[0691] 2-Fluoropropane-1,3-diol JD-3501055B (1.00 g, 10.6 mmol, 1.00 eq) was dissolved in THF (10.0 mL), triethylamine (1.08 g, 10.6 mmol, 1.48 mL, 1.00 eq), TosCl (2.03 g, 10.6 mmol, 1.00 eq) and DMAP (259 mg, 2.13 mmol, 0.20 eq) were added, and the mixture was reacted at 25 °C for 16 hours. TLC (petroleum ether: ethyl acetate = 2: 1, Rf = 0.36) showed that the starting material was completely consumed. Water (10.0 mL) was added to quench the reaction mixture, and then extracted with ethyl acetate (20.0 mL, 10.0 mL*2). The organic phase was collected and washed with a saturated sodium chloride solution (2.00 mL, aq), and the collected organic phase was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 50 / 1 to 2 / 1) to give 4-methylbenzenesulfonic acid 2-fluoro-3-hydroxypropyl ester JD-3501055C (700 mg, 2.82 mmol, yield 26.5%) as a yellow oil.

[0692] 1 H NMR:EC12352-254-P1A(400MHz,DMSO-d 6 )δ=2.43(s,3H),3.42-3.69(m,2H),4.12-4.31(m,2H),4.53-4.77(m,1H),7.49(br dd,J=8.13,2.75Hz,2H),7.71-7.85(m,2H).

[0693] Example 55 Preparation of (14Z)-23-[(4-chlorophenyl)methyl]-8-(2-fluoro-3-hydroxypropyl)-2,17-dioxa-4,8,10,23-tetraazatetracyclo[16.3.1.13,6.05,10]triacontac-1(22),3(4),5(6),14,18(19),20-hexaene-7,9-dione JD-3501055

[0694]

[0695] The intermediate 8-chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-350106 and 4-methylbenzenesulfonic acid-2-fluoro-3-hydroxypropyl ester JD-3501055C were prepared by the method of Example 24 to obtain (14Z)-23-[(4-chlorophenyl)methyl]-8 -(2-Fluoro-3-hydroxypropyl)-2,17-dioxa-4,8,10,23-tetraazatetracyclo[16.3.1.13,6.05,10]tricosan-1(22),3(4),5(6),14,18(19),20-hexaene-7,9-dione JD-3501055 (10.8 mg, 20.0 μmol, 11.4% yield) was obtained as a gray solid.

[0696] LC-MS [M+H] + =541.3.

[0697] 1 H NMR:EC12352-284-P1A(400MHz,DMSO-d 6 )δ=1.74(br d,J=7.13Hz,2H),2.07(s,2H),3.46-3.71(m,2H),3.84(td,J=14.38,3.63Hz,3H),4.33-4.46(m,1H),4.61-4.80(m,3H),4 .98-5.06(m,1H),5.42(s,2H),5.62-5.72(m,1H),5.95-6.05(m,1H),6.81(s,2H),7.28(s,1H),7.44(s,4H),7.83(s,1H).

[0698] Example 56 Preparation of 23-[(4-chlorophenyl)methyl]-8-(2-fluoro-3-hydroxypropyl)-2,17-dioxa-4,8,10,23-tetraazatetracyclo[16.3.1.13,6.05,10]triaconic-1(22),3(4),5(6),18(19),20-pentaene-7,9-dione JD-3501056

[0699]

[0700] Compound JD-3501056 in Example 56 was prepared by the method of compound JD-3501005 in Example 5 to obtain 23-[(4-chlorophenyl)methyl]-8-(2-fluoro-3-hydroxypropyl)-2,17-dioxa-4,8,10,23-tetraazatetracyclo[16.3.1.13,6.05,10]twenty-three-1(22),3(4),5(6),18(19),20-pentaene-7,9-dione JD-3501056 (10.8 mg, 20.0 μmol, yield 11.4%) as a white solid.

[0701] LC-MS [M+H] + =543.0.

[0702] 1 H NMR EC12352-257-P1A (400MHz, DMSO-d 6 )δ=1.42(br s,4H),1.65-1.82(m,4H),3.60(br d,J=5.88Hz,2H),3.78-3.97(m,3H),4.11-4.20(m,2H),4.40(br d,J=8.50Hz,1H),4.61-4.82(m,1H),5.05(t,J=5.69Hz,1H),5.43(s,2H),6.70-6.90(m,2H),7.28(s,1H),7.44(s,4H),7.94(s,1H).

[0703] Example 57 Preparation of 19-fluoro-23-[(4-fluorophenyl)methyl]-8-(3-hydroxypropyl)-2,17-dioxa-4,8,10,23-tetraazatetracyclo[16.3.1.13,6.05,10]triacontac-1(22),3(4),5(6),18(19),20-pentaene-7,9-dione JD-3501057

[0704]

[0705] The compound JD-3501057 in Example 57 was prepared by referring to the method of Example 22 compound JD-3501022 and compound 4-fluoro-1-(chloromethyl) to obtain 19-fluoro-23-[(4-fluorophenyl)methyl]-8-(3-hydroxypropyl)-2,17-dioxa-4,8,10,23-tetraazatetracyclo[16.3.1.13,6.05,10]twenty-three-1(22),3(4),5(6),18(19),20-pentaene-7,9-dione JD-3501057 (17.1 mg, 32.5 μmol, yield 9.45%, purity 99.8%) which was off-white.

[0706] LC-MS [M+H] + =527.3.

[0707] 1 H NMR:EC12149-187-P1M1(400MHz,DMSO-d 6 )δ=8.07(dd,J=2.6,7.4Hz,1H),7.49(dd,J=5.6,8.3Hz,2H),7.29-7.15(m,3H),6.87(td,J=3.0,8.8Hz,1H),5.41(s,2H),4.47(br t,J=4.3Hz,1H),4.28-4.18(m,2H),3.98-3.83(m,4H),3.47-3.40(m,2H),1.78(br s,2H),1.73-1.62(m,4H),1.40(br s,4H).

[0708] The compounds in Examples 58-65 below were prepared with reference to the compound JD-3501060 in Example 60.

[0709]

[0710]

[0711]

[0712] Example 60 Preparation of (13E)-24-[(4-fluorophenyl)methyl]-7-(3-hydroxypropyl)-18-oxa-3,7,9,24-tetraazatetracyclo[17.3.1.12,5.04,9]twenty-tetra-1(22),2(3),4(5),13,19(23),20-hexaene-6,8-dione JD-3501060

[0713]

[0714] Step 1 Preparation of 8-chloro-7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501060-1

[0715]

[0716] 8-Chloro-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501049-4 (3 g, 6.21 mmol, 1 eq) was dissolved in ethanol (30 mL), hydrochloric acid (3 mL, 12 M) was added, and the mixture was reacted at 80° C. for 16 hours. LC-MS analysis showed that the starting material was completely consumed, and a main peak of the required mass was detected (LC-MS [M] = 352.7). The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1 to 100 / 1) to give 8-chloro-7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501060-1 (0.9 g, 12.09 mmol, yield 33.68%, purity 82%) as a white solid.

[0717] LC-MS [M] = 352.7.

[0718] Step 2 Preparation of 8-chloro-7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-3-(pent-4-enyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501060-2

[0719]

[0720] Compound 8-chloro-7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501060-1 (2.00 g, 5.67 mmol, 1.00 eq) was dissolved in DMF (14.0 mL) and Cs 2 CO 3 (3.69 g, 11.3 mmol, 2.00 eq) and 5-bromopent-1-ene JD-3501003A (1.27 g, 8.50 mmol, 1.50 eq), the mixture was reacted at 80°C for 1 hour. Water (15.0 mL) was added to quench the reaction mixture, and then extracted with ethyl acetate (30.0 mL, 15.0 mL*2), the organic phase was collected and washed with saturated sodium chloride (3 mL) solution, and the organic phase was concentrated under reduced pressure to obtain 8-chloro-7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-3-(pent-4-enyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501060-2 (2.80 g, crude product) as a yellow oil.

[0721] LC-MS [M] = 420.8.

[0722] Step 3 Preparation of 7-[(4-fluorophenyl)methyl]-8-(3-hydroxyphenyl)-1-(3-hydroxypropyl)-3-(pent-4-enyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501060-3

[0723]

[0724] Compound 8-chloro-7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-3-(pent-4-enyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501060-2 (2.00 g, 1.00 eq) was dissolved in a mixed solution of dioxane (15.0 mL) and water (3.00 mL), and K 2 CO 3 (1.31 g, 9.50 mmol, 2.00 eq) and (3-hydroxyphenyl)boranediol JD-3501060A (983 mg, 7.13 mmol, 1.50 eq), then in N 2 Pd(Ph 3 ) 4 (1.10 g, 950 μmol, 0.20 eq), the mixture was reacted at 90 ° C for 1 hour. Water (15.0 mL) was added to quench, then extracted with ethyl acetate (30.0 mL, 15.0 mL * 2), and the organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 50 / 1 to 2 / 1) to obtain 7-[(4-fluorophenyl)methyl]-8-(3-hydroxyphenyl)-1-(3-hydroxypropyl)-3-(pent-4-enyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501060-3 (2 g, 4.18 mmol, yield 87.95%) as a yellow solid.

[0725] LC-MS [M+H] + =479.2.

[0726] Step 4 Preparation of 7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-3-(pent-4-enyl)-8-[3-(pent-4-enyloxy)phenyl]-1,2,3,6-tetrahydropurine-2,6-dione JD-3501060-4

[0727]

[0728] Compound 7-[(4-fluorophenyl)methyl]-8-(3-hydroxyphenyl)-1-(3-hydroxypropyl)-3-(pent-4-enyl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501060-3 (400 mg, 835 μmol, 1.00 eq) was dissolved in DMF (2.40 mL) and K 2 CO 3 (231 mg, 1.67 mmol, 2.00 eq) and 5-bromopent-1-ene JD-3501003A (249 mg, 1.67 mmol, 2.00 eq), the mixture was reacted at 80°C for 16 hours, water (2.0 mL) was added to quench, and then extracted with ethyl acetate (4.0 mL, 2.0 mL*2), and the organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative thin layer chromatography (silica, petroleum ether: ethyl acetate = 1: 1) to obtain 7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-3-(pent-4-enyl)-8-[3-(pent-4-enyloxy)phenyl]-1,2,3,6-tetrahydropurine-2,6-dione JD-3501060-4 (200 mg, 365 μmol, yield 43.7%) as a yellow oil.

[0729] LC-MS [M+H] + =547.6.

[0730] Step 5 Preparation of (13E)-24-[(4-fluorophenyl)methyl]-7-(3-hydroxypropyl)-18-oxa-3,7,9,24-tetraazatetracyclo[17.3.1.12,5.04,9]twenty-tetra-1(22),2(3),4(5),13,19(23),20-hexaene-6,8-dione JD-3501060

[0731]

[0732] Compound 7-[(4-fluorophenyl)methyl]-1-(3-hydroxypropyl)-3-(pent-4-enyl)-8-[3-(pent-4-enyloxy)phenyl]-1,2,3,6-tetrahydropurine-2,6-dione JD-3501060-4 (180 mg, 329 μmol, 1.00 eq) was dissolved in DCE (54.0 mL), HG-II (61.9 mg, 98.7 μmol, 0.30 eq) was added, and the mixture was reacted at 50° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. Purification by prep-HPLC (column: Welch UlC18 150*25mm*5um; mobile phase: [water (TFA)-ACN]; gradient: 50%-80% B over 2 min) gave (13E)-24-[(4-fluorophenyl)methyl]-7-(3-hydroxypropyl)-18-oxa-3,7,9,24-tetraazatetracyclo[17.3.1.12,5.04,9]twenty-tetra-1(22),2(3),4(5),13,19(23),20-hexaene-6,8-dione JD-3501060 (12.3 mg, 23.8 μmol, yield: 7.24%) as an off-white solid.

[0733] LC-MS [M+H] + =519.3.

[0734] 1 H NMR:EC12352-363-P1A1(400MHz,DMSO-d 6 )δ=1.65-1.74(m,2H)1.88(br s,4H)2.10(br d,J=5.00Hz,4H)3.43(q,J=6.17Hz,2H)3.93(br t,J=7.25Hz,2H)4.08-4.25(m,4H)4.46(t,J=5.25Hz,1H)5.72-5.90(m,3H)6.06(br s,1H)6.95-7.01(m,1H)7.07(brd,J=7.50Hz,1H)7.18(d,J=7.13Hz,4H)7.28-7.34(m,1H)7.67(br s,1H).

[0735] Example 61 Preparation of 24-[(4-fluorophenyl)methyl]-7-(3-hydroxypropyl)-18-oxa-3,7,9,24-tetraazatetracyclo[17.3.1.12,5.04,9]twenty-tetra-1(22),2(3),4(5),19(23),20-pentaene-6,8-dione JD-3501061

[0736]

[0737] Wet palladium on carbon (2.05 mg, 1.93 μmol, 10% purity, 0.10 eq) was dissolved in ethyl acetate (1.00 mL) and added to a mixed solution of (13E)-24-[(4-fluorophenyl)methyl]-7-(3-hydroxypropyl)-18-oxa-3,7,9,24-tetraazatetracyclo[17.3.1.12,5.04,9]twenty-tetra-1(22),2(3),4(5),13,19(23),20-hexaene-6,8-dione JD-3501060 (10 mg, 19.28 μmol, 1.00 eq) dissolved in ethyl acetate (5.00 mL). The suspension was heated with H 2 Degassing was performed three times, and the mixture was heated at 25 °C in H 2 (15Psi) for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: WelchUlC18 150*25mm*5um; mobile phase: [water (TFA)-ACN]; gradient: 55%-85% B over 2min). Compound JD-3501061 (1.91mg, 3.67μmol, yield 19.0%) was a white solid.

[0738] LC-MS [M+H] + =521.2.

[0739] 1 H NMR: EC12352-381-P1A (400MHz, DMSO-d6) δ = 1.33 (br d, J = 6.00Hz, 2H) 1.46 (br s, 4H)

[0740] 1.66-1.73(m,4H)1.81(br s,4H)3.42(s,2H)3.89-3.95(m,2H)4.05-4.19(m,4H)5.70(s,2H)6.95-7.04(m,2H)7.13-7.21(m,4H)7.32(t,J=7.94Hz,1H)7.41(br s,1H).

[0741] Example 62 Preparation of 22-[(4-fluorophenyl)methyl]-3-(3-hydroxypropyl)-12-oxa-3,5,20,22-tetraazatetracyclo[17.2.1.05,21.013,18]triacontac-1(21),13(14),15,17,19(20)-pentaene-2,4-dione JD-3501062

[0742]

[0743] The intermediate (8E)-22-[(4-fluorophenyl)methyl]-3-(3-hydroxypropyl)-12-oxa-3,5,20,22-tetraazatetracyclo[17.2.1.05,21.013,18]twenty-two-1(21),8,13(14),15,17,19(20)-hexaene-2,4-dione JD-3501062-1 (200 mg, 407 μmol, 1.00 eq.) was prepared by the method of Example 60 JD-3501060. ), and then the method of Example 5 JD-3501005 was used to prepare 22-[(4-fluorophenyl)methyl]-3-(3-hydroxypropyl)-12-oxa-3,5,20,22-tetraazatetracyclo[17.2.1.05,21.013,18]twenty-1(21),13(14),15,17,19(20)-pentaene-2,4-dione JD-3501062 (83.2 mg, 169 μmol, yield 41.4%) as an off-white solid.

[0744] LC-MS[MH] - =493.2.

[0745] 1H NMR:EC12149-346-P1M(400MHz,DMSO-d6)δppm 1.17(br s,2H)1.54(br s,2H)1.69(br s,6H)3.42(br s,2H)3.82-3.96(m,4H)4.12(br s,2H)5.47(br s,2H)6.96-7.20(m,6H)7.36(br d,J=6.88Hz,1H)7.49(br t,J=6.69Hz,1H).

[0746] Example 63 Preparation of (8Z)-23-[(4-fluorophenyl)methyl]-3-(3-hydroxypropyl)-13-oxa-3,5,21,23-tetraazatetracyclo[18.2.1.05,22.014,19]triacontac-1(22),8,14(15),16,18,20(21)-hexaene-2,4-dione JD-3501063

[0747]

[0748] The method of Example 60 JD-3501060 was used to prepare (8Z)-23-[(4-fluorophenyl)methyl]-3-(3-hydroxypropyl)-13-oxa-3,5,21,23-tetraazatetracyclo[18.2.1.05,22.014,19]triacontac-1(22),8,14(15),16,18,20(21)-hexaene-2,4-dione JD-3501063 (10.4 mg, 20.7 μmol, yield 11.0%) as a brown solid.

[0749] LC-MS [M+H] + =505.2.

[0750] 1 H NMR:EC12149-347-P1(400MHz,DMSO-d 6 )δppm 1.58-1.75(m,4H)1.96(br d,J=4.13Hz,2H)2.37(br s,2H)3.43(t,J=6.44Hz,2H)3.83(br s,2H)3.94(br t,J=7.25Hz,2H)4.11-4.20(m,2H)5.24-5.33(m,1H)5.36(s,2H)5.45-5.54(m,1H)6.91(dd,J=8.5 7,5.57Hz,2H)7.01-7.08(m,2H)7.12-7.22(m,2H)7.40(dd,J=7.50,1.38Hz,1H)7.50-7.56(m,1H).

[0751] Example 64 Preparation of 23-[(4-fluorophenyl)methyl]-3-(3-hydroxypropyl)-13-oxa-3,5,21,23-tetraazatetra[18.2.1.05,22.014,19]triaconic-1(22),14(15),16,18,20(21)-pentaene-2,4-dione JD-3501064

[0752]

[0753] By adopting the method of Example 5 JD-3501005 and using Example 60 as raw material, 23-[(4-fluorophenyl)methyl]-3-(3-hydroxypropyl)-13-oxa-3,5,21,23-tetraazatetra[18.2.1.05,22.014,19]twenty-three-1(22),14(15),16,18,20(21)-pentaene-2,4-dione JD-3501064 (11.5 mg, 22.7 μmol, yield 76.3%) was prepared as a white solid.

[0754] LC-MS [M+H] + =507.0.

[0755] 1H NMR:EC12149-359-P1M(400MHz,DMSO-d6)δppm 1.03-1.14(m,2H)1.26-1.38(m,2H)1.55-1.72(m,6H)1.73-1.83(m,2H)3.40(br s,2H)3.90-4.01(m,4H)4.12(br t,J=5.38Hz,2H)

[0756] 5.41 (s, 2H) 6.90-6.97 (m, 2H) 7.01-7.11 (m, 3H) 7.23 (d, J = 8.38Hz, 1H) 7.39 (dd, J = 7.50, 1.25Hz, 1H) 7.48-7.54 (m, 1H).

[0757] Example 66 Preparation of 24-[(4-fluorophenyl)methyl]-3-(3-hydroxypropyl)-14-oxa-3,5,22,24-tetraazatetracyclo[19.2.1.05,23.015,20]triaconta-1(23),15(16),17,19,21(22)-pentaene-2,4-dione JD-3501066

[0758]

[0759] The intermediate (10E)-24-[(4-fluorophenyl)methyl]-3-(3-hydroxypropyl)-14-oxa-3,5,22,24-tetraazatetracyclo[19.2.1.05,23.015,20]twenty-tetra-1(23),9,15(16),17,19,21(22)-hexaene-2,4-dione JD-3501066-1 (16.93 mg, 32.6 μmol, yield 17.8%) was prepared by the method of Example 60 JD-3501060. The method of Example 5 JD-3501005 was then used to prepare 24-[(4-fluorophenyl)methyl]-3-(3-hydroxypropyl)-14-oxa-3,5,22,24-tetraazatetracyclo[19.2.1.05,23.015,20]twentetra-1(23),15(16),17,19,21(22)-pentaene-2,4-dione JD-3501066 (33.62 mg, 64.1 μmol, yield 55.4%, purity 99.2%) as a yellow oil.

[0760] LC-MS [M+H] + =521.3.

[0761] 1 H NMR: EC7857-454-P1B (400MHz, DMSO-d6) δ = 7.55-7.48 (m, 1H), 7.32 (dd, J = 1.6, 7.5Hz, 1H),7.13(d,J=8.3Hz,1H),7.09-7.00(m,3H),6.99-6.92(m,2H),5.33(s,2H),4.07(br t,J=6.3Hz,2H),3.98-3.86(m,4H),3.43(t,J=6.5Hz,2H),1.82-1.64(m,4H),1.54-1.40(m,2H),1.35-1.26(m,2H),1.25-1.11(m,6H).

[0762] Example 67 Preparation of (7Z)-16-[(4-fluorophenyl)methyl]-19-(3-hydroxypropyl)-1,19-diaza-14-oxatricyclo[13.5.3.017,21]tricosyl-7,15(16),17(21),22-tetraene-18,20-dione JD-3501067

[0763]

[0764] Step 1 Preparation of 3-(4-fluorophenyl)-4-methoxy-1,3-dihydro-2-benzofuran-1-one JD-3501067-2

[0765]

[0766] 2,2,6,6-Tetramethylpiperidine (92.8 g, 657 mmol, 111 mL, 5.00 eq) was dissolved in tetrahydrofuran (100 mL), and n-BuLi (2.50 M, 262 mL, 5.00 eq) was added dropwise at -78 °C. The reaction mixture was kept at this temperature for 0.5 hours and then gradually heated to 0 °C for reaction. Then 3-methoxybenzoic acid (20.0 g, 131 mmol, 1.00 eq) dissolved in tetrahydrofuran (100 mL) was added dropwise to the reaction mixture. The reaction mixture was kept at 0 °C for reaction for 2 hours. Then 4-fluorobenzene-1-carboxaldehyde (81.6 g, 657 mmol, 69.3 mL, 5.00 eq) dissolved in tetrahydrofuran (40 mL) was added dropwise. The reaction mixture was kept at 0 °C for reaction for 1 hour and then gradually heated to room temperature for reaction for 18 hours. The reaction was then heated at 50 °C for 2 hours. The reaction mixture was quenched with ice water (600 mL) at 0°C, then extracted with ethyl acetate (400 mL, 200 mL*2), the aqueous layer was acidified to pH = 1 with concentrated hydrochloric acid, and then extracted with ethyl acetate (2x200 mL). The collected organic phase was washed with saturated sodium carbonate (50 mL, aq) and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 50 / 1 to 2 / 1) to obtain 3-(4-fluorophenyl)-4-methoxy-1,3-dihydro-2-benzofuran-1-one JD-3501067-2 (9 g, 34.85 mmol, yield 26.51%, purity 100%) as a white solid.

[0767] LC-MS [M+H] + =259.2.

[0768] Step 2 Preparation of 3-(4-fluorophenyl)-4-methoxy-7-nitro-1,3-dihydro-2-benzofuran-1-one JD-3501067-3

[0769]

[0770] 3-(4-Fluorophenyl)-4-methoxy-1,3-dihydro-2-benzofuran-1-one JD-3501067-2 (6.00 g, 23.2 mmol, 1.00 eq) was dissolved in acetic anhydride (180 mL), and then HNO was added to the reaction mixture at -40 °C. 3 (7.32g,116mmol,5.23mL,5.00eq),H 2 SO 4 (4.66 g, 47.5 mmol, 2.53 mL, 2.04 eq) and H 2O (19.5g, 1.08mol, 19.5mL, 46.6eq) mixed solution, the reaction was slowly heated to 0℃ for 1 hour, and then reacted at 25℃ for 18 hours. The reaction mixture was quenched with water (600mL), then extracted with ethyl acetate (300mL, 150mL*2), and the organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm, 10um); mobile phase: [water (TFA)-ACN]; gradient: 35%-65% B over 5min) to obtain 3-(4-fluorophenyl)-4-methoxy-7-nitro-1,3-dihydro-2-benzofuran-1-one JD-3501067-3 (1.80g, 5.05mmol, yield 21.720%, purity 85.0%) as an off-white solid.

[0771] LC-MS [M+H] + =304.1.

[0772] Step 3 Preparation of 6-amino-2-[(4-fluorophenyl)methyl]-3-methoxybenzoic acid JD-3501067-4

[0773]

[0774] At 25 °C, 3-(4-fluorophenyl)-4-methoxy-7-nitro-1,3-dihydro-2-benzofuran-1-one JD-3501067-3 (1.00 g, 3.30 mmol, 1.00 eq) was dissolved in ethanol (150 mL), perchloric acid (3.05 g, 30.3 mmol, 1.84 mL, 9.21 eq) was added, and then Pd / C (384 mg, 361 μmol, 10.0% purity, 0.11 eq) dissolved in ethanol (20 mL) was added. The reaction mixture was heated with H 2 Replace the gas 3 times, then replace the 2 (15Psi) for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 200*40mm*10um; mobile phase: [water (TFA)-ACN]; gradient: 17%-47% B over 10min) to obtain 6-amino-2-[(4-fluorophenyl)methyl]-3-methoxybenzoic acid JD-3501067-4 (0.40 g, 1.45 mmol, yield 44.0%) as an off-white solid.

[0775] LC-MS [M+H] + =276.2.

[0776] Step 4 Preparation of 5-[(4-fluorophenyl)methyl]-6-methoxy-2,4-dihydro-1H-benzo[d][1,3]oxazacyclohexane-2,4-dione JD-3501067-5

[0777]

[0778] At 0°C, 6-amino-2-[(4-fluorophenyl)methyl]-3-methoxybenzoic acid JD-3501067-4 (0.18 g, 653 μmol, 1.00 eq) was dissolved in tetrahydrofuran (40 mL), and triphosgene (0.32 g, 1.08 mmol, 1.65 eq) was added. The reaction was allowed to react at 0°C for 0.5 hours. The reaction mixture was quenched with water (40 mL), and then extracted with ethyl acetate (40 mL, 20 mL*2). The organic phase was collected and concentrated under reduced pressure to obtain 5-[(4-fluorophenyl)methyl]-6-methoxy-2,4-dihydro-1H-benzo[d][1,3]oxazacyclohexane-2,4-dione JD-3501067-5 (0.20 g, crude product) as a white solid.

[0779] LC-MS [M+H] + =302.1.

[0780] Step 5 Preparation of 5-[(4-fluorophenyl)methyl]-3-(3-hydroxypropyl)-6-methoxy-1,2,3,4-tetrahydroquinazoline-2,4-dione JD-3501067-6

[0781]

[0782] 5-[(4-Fluorophenyl)methyl]-6-methoxy-2,4-dihydro-1H-benzo[d][1,3]oxazepine-2,4-dione JD-3501067-5 (0.20 g, 663 μmol, 1.00 eq) was dissolved in tetrahydrofuran (25 mL), 3-aminopropan-1-ol JD-3501067B (125 mg, 1.66 mmol, 128 μL, 2.51 eq) was added, and then TEA (181 mg, 1.80 mmol, 250 μL, 2.71 eq) was added, and the reaction mixture was reacted at 80° C. for 2 hours, and then concentrated hydrochloric acid (12 M, 2.50 mL, 45.1 eq) was added at 80° C., and the reaction mixture was reacted for 1 hour. The reaction mixture was quenched with water (30 mL), then extracted with ethyl acetate (30 mL, 15 mL*2), and the organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative thin layer chromatography (silica, petroleum ether / ethyl acetate = 0:1) to obtain 5-[(4-fluorophenyl)methyl]-3-(3-hydroxypropyl)-6-methoxy-1,2,3,4-tetrahydroquinazoline-2,4-dione JD-3501067-6 (0.15 g, 406 μmol, yield 61.1%, purity 97%) as an off-white solid.

[0783] LC-MS [M+H] + =359.1.

[0784] Step 6 Preparation of 5-[(4-fluorophenyl)methyl]-6-hydroxy-3-(3-hydroxypropyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione JD-3501067-7

[0785]

[0786] 5-[(4-fluorophenyl)methyl]-3-(3-hydroxypropyl)-6-methoxy-1,2,3,4-tetrahydroquinazoline-2,4-dione JD-3501067-6 (2.00 g, 1.09 mmol, 1.00 eq) was dissolved in dichloromethane (250 mL) and BBr was added dropwise at 0 °C. 3 (16.9 g, 67.5 mmol, 6.50 mL, 24.2 eq) was added to the mixed solution, and then the mixture was reacted at 25 ° C for 16 hours. The reaction mixture was quenched with water (100 mL), then extracted with dichloromethane (200 mL, 100 mL*2), and the organic phase was collected and concentrated under reduced pressure to obtain 5-[(4-fluorophenyl)methyl]-6-hydroxy-3-(3-hydroxypropyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione JD-3501067-7 (1.00 g, crude product) as an off-white solid.

[0787] LC-MS [M+H] + =345.1.

[0788] Step 7 Preparation of 5-[(4-fluorophenyl)methyl]-1-(hept-6-enyl)-6-(hept-6-enyloxy)-3-(3-hydroxypropyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione JD-3501067-8

[0789]

[0790] 5-[(4-Fluorophenyl)methyl]-6-hydroxy-3-(3-hydroxypropyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione JD-3501067-7 (0.50 g, 1.45 mmol, 1.00 eq) was dissolved in DMF (3 mL) and Cs 2 CO 3 (946 mg, 2.90 mmol, 2.00 eq) and 7-bromohept-1-ene JD-3501067C (514 mg, 2.90 mmol, 2.00 eq), the mixture was reacted at 80 ° C for 2 hours. The reaction mixture was quenched with water (100 mL), and then extracted with ethyl acetate (6 mL, 3 mL * 2), and the organic phase was collected and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative thin layer chromatography (silica, petroleum ether / ethyl acetate = 1: 1) to obtain 5-[(4-fluorophenyl)methyl]-1-(hept-6-enyl)-6-(hept-6-enyloxy)-3-(3-hydroxypropyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione JD-3501067-8 (0.17 g, 269 μmol, yield 18.5%, purity 85.0%) as an off-white solid.

[0791] LC-MS [M+H] + =537.3.

[0792] Step 8 Preparation of (7Z)-16-[(4-fluorophenyl)methyl]-19-(3-hydroxypropyl)-1,19-diaza-14-oxatricyclo[13.5.3.017,21]triacontac-7,15(16),17(21),22-tetraene-18,20-dione JD-3501067

[0793]

[0794] 5-[(4-fluorophenyl)methyl]-1-(hept-6-enyl)-6-(hept-6-enyloxy)-3-(3-hydroxypropyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione JD-3501067-8 (0.08 g, 158 μmol, 1.00 eq) was dissolved in DCE (80 mL), HG-II (29.7 mg, 47.5 μmol, 0.30 eq) was added, and the mixture was reacted at 80° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Welch Xtidel C18 150*25mm*5um; mobile phase: [water (TFA)-ACN]; gradient: 55%-85% B over 2 min) to give (7Z)-16-[(4-fluorophenyl)methyl]-19-(3-hydroxypropyl)-1,19-diaza-14-oxatricyclo[13.5.3.017,21]twenty-three-7,15(16),17(21),22-tetraene-18,20-dione JD-3501067 (0.01 g, 19.66 μmol, yield 12.41%) as a black solid.

[0795] LC-MS [M+H] + =509.2.

[0796] 1 H NMR (400MHz, DMSO-d6) δppm 0.80-0.92 (m, 2H) 1.05 (br t, J=7.00Hz, 6H) 1.17 (br d,J=6.88Hz,2H)1.38-1.47(m,2H)1.62-1.73(m,6H)1.77-1.87(m,2H)3.92-3.97(m,2H)4.17-4.43(m,4H)4.64-4.72(m, 2H)4.94-4.99(m,1H)5.01-5.08(m,1H)6.99(t,J=8.88Hz,2H)7.07-7.13(m,2H)7.53(d,J=9.63Hz,1H)7.58-7.65(m,1H).

[0797] Example 68 Preparation of (10Z)-20-[(4-chlorophenyl)methyl]-17-[3-(deuteroxy)propyl]-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501068

[0798]

[0799] JD-3501003 (30.0 mg, 57.3 μmol, 1.00 eq) was dissolved in CD 3 OD (1.00 mL) and CDCl 3 (0.50 mL) and stirred at 25°C for 5 days. LC-MS (EC12149-454-P1A) detected a main peak from the raw material MS. Water was added and freeze-dried to obtain compound (10Z)-20-[(4-chlorophenyl)methyl]-17-[3-(deuteroxy)propyl]-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]twenty-three-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501068 (17.3 mg, 33.0 μmol, 57.6% yield) as an off-white solid.

[0800] LC-MS [M+H] + =524.1.

[0801] 1 H NMR (EC12149-454-P1M1): (400MHz, METHANOL-d4) δppm 1.78-1.91 (m, 4H) 2.06-2.17 (m, 2H) 3.57 (t, J = 6.13Hz, 2H) 3.99-4.15 (m, 4H) 4.68 (br s,2H)5.41(s,2H)5.70(dt,J=15.67,5.36Hz,1H)5.89-5.98(m,1H)6.73(dd,J=8.00,1.75Hz,1H)6.80(dd,J= 8.19, 2.06Hz, 1H) 7.22 (t, J = 8.19Hz, 1H) 7.31 (d, J = 8.38Hz, 2H) 7.42 (d, J = 8.50Hz, 2H) 7.82 (t, J = 2.25Hz, 1H).

[0802] Example 69 20-[(4-chlorophenyl)methyl]-17-[3-(deuteroxy)propyl]-2,8-dioxa-15,17,20,21-tetraazatetracyclo

[0803] Preparation of [13.5.2.13,7.019,22]twenty-three-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501069

[0804]

[0805] JD-3501007 (100 mg, 190 μmol, 1.00 eq) was dissolved in CD3 OD (1.00 mL) and CDCl 3 (0.50 mL) and stirred at 25°C for 5 days. LC-MS (EC12149-455-P1A) showed a main peak of the raw material MS. Water was added and freeze-dried to obtain compound 20-[(4-chlorophenyl)methyl]-17-[3-(deuteroxy)propyl]-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]twenty-three-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501069 (74.4 mg, 141 μmol, yield 74.3%) as a gray solid.

[0806] LC-MS [M+H] + =526.9.

[0807] 1 H NMR(EC12149-P1M):(400MHz,METHANOL-d4)δppm 1.47-1.58(m,4H)1.76-1.95(m,6H)3.60(t,J=6.38Hz,2H)3.99-4.12(m,4H)4.14-4.22(m,2H)5.48( s,2H)6.71-6.79(m,2H)7.21-7.29(m,1H)7.32-7.39(m,2H)7.42-7.49(m,2H)7.97(t,J=2.25Hz,1H).

[0808] Example 70 Preparation of 20-[(4-chlorophenyl)methyl]-17-(3,3-dideutero-3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501070

[0809]

[0810] Step 1 Preparation of methyl 3-{8-chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-2,6-dioxypurin-1-yl}propanoate JD-3501070-1

[0811]

[0812] 8-Chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silahex-1-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-350106 (5.00 g, 11.33 mmol, 1.00 eq) was dissolved in DMF (40.0 mL) and K 2 CO 3 (3.13 g, 22.7 mmol, 2.00 eq) and methyl 3-bromopropionate JD-3501070A (5.68 g, 33.98 mmol, 3.72 mL, 3.00 eq) were stirred at 80 °C for 16 hours. LC-MS showed that the raw materials were completely consumed and a main peak that met the requirements of MS was detected. The reaction solution was added dropwise with H 2 O 50.0mL dilution, then add EtOAc 60.0mL (20.0mL*3) for washing, the organic phases are combined and concentrated under reduced pressure to obtain a residue. The residue is purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to obtain 3-{8-chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-2,6-dioxypurin-1-yl}propanoic acid methyl ester JD-3501070-1 (3.00 g, 5.69 mmol, yield 50.21%) as a white solid.

[0813] LC-MS [M+Na] = 549.0.

[0814] Step 2 Preparation of 8-chloro-7-[(4-chlorophenyl)methyl]-1-(3,3-dideutero-3-hydroxypropyl)-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501070-2

[0815]

[0816] 3-{8-chloro-7-[(4-chlorophenyl)methyl]-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-2,6-dioxypurin-1-yl}propanoic acid methyl ester JD-3501070-1 (2.20 g, 4.17 mmol, 1.00 eq) was dissolved in THF (22.0 mL) and AlCl 3 (834 mg, 6.26 mmol, 341 μL, 1.50 eq) and LiAlD 4 (316 mg, 8.34 mmol, 430 μL, 2.00 eq) was stirred at 0-30 °C for 3 hours. LC-MS showed that the raw material remained about 30%, and a main peak that met the requirements of MS was detected.2 O (10.0 mL), then ethyl acetate (10.0 mL) was added for extraction, and the organic phase was separated, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain 8-chloro-7-[(4-chlorophenyl)methyl]-1-(3,3-dideutero-3-hydroxypropyl)-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501070-2 (300 mg, 598 μmol, yield 14.3%) as a colorless jelly.

[0817] LC-MS [M+Na] = 523.0.

[0818] Step 3 Preparation of 7-[(4-chlorophenyl)methyl]-1-(3,3-dideutero-3-hydroxypropyl)-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501070-3

[0819]

[0820] K 2 CO 3 (165 mg, 1.20 mmol, 2.00 eq) was added to a DMF (3.00 mL) solution of 8-chloro-7-[(4-chlorophenyl)methyl]-1-(3,3-dideutero-3-hydroxypropyl)-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-1,2,3,6-tetrahydropurine-2,6-dione JD-3501070-2 (300 mg, 598 μmol, 1.00 eq) and 3-(prop-2-enyloxy)phenol JD-350109A (197 mg, 1.32 mmol, 2.20 eq) and stirred at 80 ° C for 16 hours. LC-MS showed that the raw material was completely consumed and a main peak that met the requirements of MS was detected. The reaction solution was added with H 2 O (10.0 mL), then ethyl acetate (10.0 mL) was added, the organic phase was separated and concentrated under reduced pressure to give 7-[(4-chlorophenyl)methyl]-1-(3,3-dideutero-3-hydroxypropyl)-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501070-3 (560 mg, crude) as a brown oil.

[0821] LC-MS [M] = 615.2.

[0822] Step 4 Preparation of 7-[(4-chlorophenyl)methyl]-1-(3,3-dideutero-3-hydroxypropyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501070-4

[0823]

[0824] 7-[(4-chlorophenyl)methyl]-1-(3,3-dideuteryl-3-hydroxypropyl)-3-(5,5-dimethyl-2-oxa-5-silanhex-1-yl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501070-3 (560 mg, 910 μmol, 1.00 eq) was added to an ethyl acetate (5.00 mL) solution, and hydrochloric acid (12.0 M, 2.80 mL, 36.9 eq) was added and stirred at 80°C for 16 hours. LC-MS showed that the starting material was completely consumed, and a main peak that met the requirements of MS was detected. The mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative chromatography (SiO2, DCM:MeOH=10:1) to give 7-[(4-chlorophenyl)methyl]-1-(3,3-dideutero-3-hydroxypropyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501070-4 (130 mg, 268 μmol, yield 29.4%) as a brown oil.

[0825] LC-MS [M+H] + =485.1.

[0826] Step 5 Preparation of 7-[(4-chlorophenyl)methyl]-1-(3,3-dideutero-3-hydroxypropyl)-3-(pent-4-enyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501070-5

[0827]

[0828] 7-[(4-chlorophenyl)methyl]-1-(3,3-dideutero-3-hydroxypropyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501070-4 (130 mg, 268 μmol, 1.00 eq) and 5-bromopent-1-ene JD-3501003A (47.9 mg, 321 μmol, 38.0 μL, 1.20 eq) were added to a DMF (1.00 mL) solution, and Cs2 CO 3 (131 mg, 402 μmol, 1.50 eq) and stirred at 80 °C for 2 h. LC-MS showed that the starting material was completely consumed and a main peak that met the MS requirements was detected. 2 O (10.0 mL), then ethyl acetate (10.0 mL) was added for extraction, the organic phase was separated and concentrated under reduced pressure to give 7-[(4-chlorophenyl)methyl]-1-(3,3-dideutero-3-hydroxypropyl)-3-(pent-4-enyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501070-5 (190 mg, crude) as a brown oil.

[0829] LC-MS [M] = 553.1.

[0830] Step 6 Preparation of (10Z)-20-[(4-chlorophenyl)methyl]-17-(3,3-dideutero-3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501070-6

[0831]

[0832] 7-[(4-chlorophenyl)methyl]-1-(3,3-dideuteryl-3-hydroxypropyl)-3-(pent-4-enyl)-8-{[3-(prop-2-enyloxy)phenyl]oxy}-1,2,3,6-tetrahydropurine-2,6-dione JD-3501070-5 (190 mg, 343 μmol, 1.00 eq) was added to a DCM (20.0 mL) solution of HG-Ⅱ (64.5 mg, 103 μmol, 0.30 eq) (64.5 mg, 103 μmol, 0.30 eq) and stirred at 25 ° C for 16 hours. LC-MS showed that the starting material was completely consumed, and a main peak that met the requirements of MS was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate = 1 / 1) to obtain (10Z)-20-[(4-chlorophenyl)methyl]-17-(3,3-dideutero-3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501070-6 (50.0 mg, 95.2 μmol, yield 27.7%) as a green oil.

[0833] LC-MS [M] = 525.1.

[0834] Step 7 Preparation of 20-[(4-chlorophenyl)methyl]-17-(3,3-dideutero-3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501070

[0835]

[0836] Lindlar (9.52 μmol, 0.10 eq) was added to a solution of (10Z)-20-[(4-chlorophenyl)methyl]-17-(3,3-dideutero-3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontria-1(21),3(23),4,6,10,19(22)-hexaene-16,18-dione JD-3501070-6 (50.0 mg, 95.2 μmol, 1.00 eq) in ethyl acetate (20.0 mL) and stirred at 25°C for 5 hours. LC-MS showed that the starting material was completely consumed and a main peak that met the requirements of MS was detected. The residue was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC to give 20-[(4-chlorophenyl)methyl]-17-(3,3-dideutero-3-hydroxypropyl)-2,8-dioxa-15,17,20,21-tetraazatetracyclo[13.5.2.13,7.019,22]triacontac-1(21),3(23),4,6,19(22)-pentaene-16,18-dione JD-3501070 (26.0 mg, 49.3 μmol, 51.8% yield) as an off-white solid.

[0837] LC-MS [M] = 527.1.

[0838] 1H NMR (EC12149-450-P1M): (400MHz, DMSO-d6) δ = (br d,J=1.50Hz,4H),1.64-1.84(m,6H),3.87-3.98(m,4H),4.12-4.20(m,2H),4.39(s,1H),5.43(s,2H),6.75 (dd,J=8.19,1.81Hz,1H),6.84(dd,J=8.07,1.31Hz,1H),7.28(t,J=8.25Hz,1H),7.45(s,4H),7.93(s,1H).

[0839] Effect Example

[0840] 1. Calcium Flux Assay

[0841] This test uses Calcium 5Assay Kit screens small molecules. The TRPC5 stable cell line constructed by HEK293 cells is plated in a black light-proof 96-well plate treated with L-polylysine and allowed to adhere overnight. The small molecule is prepared as a 10mM stock solution with DMSO and then diluted to the required concentration with the preparation solvent (30% DMSO + 70% HBS). The stain in the kit and the cells are incubated at 37°C and 5% CO 2 The cells were incubated under the same conditions for 50 minutes, and then equal volumes of small molecule solutions of different concentrations, positive inhibitors, and negative control solvents were added to the 96-well plate and incubated for another 10 minutes. Cell fluorescence was excited at 488nM, and fluorescence emission was detected at 535nM. The 96-well plate was placed on the FlexStation 3 instrument to test the fluorescence intensity. The test time for each well was 90s, and the data acquisition interval was 1.52s. After recording for 25s, the positive agonist EA was added by the instrument's liquid addition arm, and the remaining data points were collected. The fluorescence signal is expressed as (F-F0) / F0, where F represents the fluorescence intensity collected at a specific time point, and F0 represents the average fluorescence recorded at the first 25 time points. IC 50 The values ​​were plotted using a nonlinear equation, inhibition (Y-axis) and logarithmic values ​​of compound concentration (X-axis). All graphs were generated using GraphPad Prism version 8.0.

[0842] The experimental results are shown in the following table, where IC 50 Activity data "A":IC 50 ≤10nΜ; "B":10nΜ <IC 50 ≤100nΜ; "C": 100nM <IC 50 ≤1000nΜ.

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852]

[0853]

[0854] As can be seen from the above table, the compounds of the present invention exhibit good inhibitory activity against TRPC5 in the TRPC5 stably transfected cell line constructed by HEK293 cells.

[0855] 2. Electrophysiological Test

[0856] The whole-cell patch clamp technique can be used to record the TRPC5 channel current in cell lines. Take HEK293T cells transfected with channel proteins for about 24 hours, discard the culture medium, add extracellular solution, and continuously perfuse the recording bath with 22°C extracellular solution. Use a peristaltic pump perfusion system to control the flow rate of the perfusion solution, and control the flow rate to 2mL / min. Find the appropriate target cell under the microscope. Usually, a single full cell with clear edges and no depression is selected. Fill the glass microelectrode with a pre-drawn liquid impedance of 2-2.5MΩ into the electrode liquid. Move the glass electrode through micromanipulation, and control the air pressure in the glass electrode with a syringe to establish a high-resistance (GΩ) seal between the glass electrode opening and the cell membrane. Continue to give negative pressure to the glass electrode to rupture the cell membrane so that the cell is connected to the glass electrode. The intracellular fluid and the glass electrode fluid can be exchanged. The amplifier connected to the glass electrode (HEKA EPC10 amplifier, supporting patchmaster recording software) can control the intracellular voltage and set different voltages to record the channel current of the whole cell. The extracellular solution used for TRPC5 recording was formulated as follows: 140 mM NaCl, 5 mM KCl, 1 mM MgCl 2 , 2 mM CaCl 2, 10mM HEPES, 10mM D-glucose, dissolved in deionized water, pH adjusted to 7.4 with NaOH, measured osmotic pressure was about 319mOsm; electrode solution formula is as follows: 130mM CsCl, 1mMMgCl 2 , 10 mM CaCl 2 , 10 mM EGTA, 10 mM HEPES, dissolved in deionized water, pH adjusted to 7.4 using CsOH, osmotic pressure to 313 mOsm.

[0857] While keeping the cell voltage at 0mV, give the cell a voltage ramp stimulus of -100mV to +100mV. The stimulation duration is 1s, and the stimulation is performed every 10s. The channel current is continuously recorded. The recording sampling frequency is 50KHz, and a low-pass filter of 2KHz is used to filter out high-frequency interference noise. When detecting the effects of drugs targeting TRPC5 on the TRPC5 channel current, different drug concentration gradients are set, and the drug is dissolved in extracellular fluid. If there are water-insoluble drugs, after using DMSO to assist in dissolution, the proportion of DMSO in the final drug concentration should not exceed 0.1% to avoid DMSO causing damage to the recorded cells. While recording the current, different concentrations of drugs are continuously administered through the drug delivery device to observe the effects of different concentrations on the cell current, calculate the current amplitude of the channel current at a stimulation voltage of 100mV, and make a scatter plot of amplitude versus time. In order to calculate the half-inhibitory concentration (IC) of the drug on TRPC5 50 ), usually set 5-6 concentration gradients, calculate the inhibition rate of different concentrations on the current, fit the concentration inhibition curve with Hill equation in the software graphpad, and calculate the half-inhibitory concentration. Before formally testing the compound, it is usually necessary to use the positive inhibitor HC070 of TRPC5 to do an overall test on the system to ensure that there is no problem with the patch clamp recording system. The half-inhibitory concentration (IC50) of HC070 obtained in the current testing phase is 43.05nM.

[0858] The experimental results show that the compounds of the present invention have good inhibitory activity on TRPC5.

Claims

1. A compound as represented by formula (I), a pharmaceutically acceptable salt thereof or an isotope compound thereof, in, It is a benzene ring or a 5-membered heteroaromatic ring containing two N atoms; n 1 is 0 or 1; n 2 is 0; L 1 -(CH2) n -, n is 1, 2 or 3, -(CH2) n -1, 2 or 3 -CH2- in - are optionally replaced by one or more selected from the following groups: -NL 1-1 -, -O- or -S-, L 1-1 is H or C1-C6 alkyl; R 1 C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, 1, 2 or 3 R 1-1 Substituted C6-C 10 Aryl or 1, 2 or 3 R 1-2 substituted 5-10 membered heteroaryl, substituted by 1, 2 or 3 R 1-3 Substituted C3-C8 cycloalkyl or 1, 2 or 3 R 1-4 Substituted 3-8 membered heterocycloalkyl, wherein in each "5-10 membered heteroaryl" and each "3-8 membered heterocycloalkyl", the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R 1-1 , R 1-2 , R 1-3 and R 1-4 are independently halogen, -CN, -OH, -NR 1-1-1 R 1-1-2 , -C(=O)H, -C(=O)NR 1-1-1 R 1 -1-2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1, 2 or 3 halogens, or C1-C6 alkoxy substituted by 1, 2 or 3 halogens; R 1-1-1 and R 1-1-2 are independently H or C1-C6 alkyl; L 3 is the connection key; or L 3 for Among them, X 1 For connecting bonds, -CH2-, -NR X-1 -, -O- or -S-; R X-1 is H or C1-C6 alkyl; Phenyl or "a 5-6 membered heteroaromatic ring in which the heteroatom is N and the number of heteroatoms is 1 or 2"; n 3 is 0, 1, 2, or 3; R 2 are independently halogen, -CN, -OH, -NR 2-1 R 2-2 , -C(=O)H, -C(=O)NR 2-1 R 2-2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1, 2 or 3 halogens, or C1-C6 alkoxy substituted by 1, 2 or 3 halogens; R 2-1 and R 2-2 are independently H or C1-C6 alkyl; R 3 is C1-C6 alkyl, 1, 2 or 3 R 3-1 Substituted C1-C6 alkyl, 1, 2 or 3 R 3-2 Substituted C2-C6 alkenyl or 1, 2 or 3 R 3-3 Substituted C2-C6 alkynyl; R 3-1 , R 3-2 and R 3-3 are independently deuterium, halogen, -OH, -OD, -NR 3-1-1 R 3-1-2 or -C(=O)H; R 3-1-1 and R 3-12 are independently H or C1-C6 alkyl; L 2 -(CH2) m -, m is 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, -(CH2) m -1, 2 or 3 -CH2- in - are optionally selected from -NR L-1 -, -O-, -S- and -CH=CH-; R L-1 are independently H or C1-C6 alkyl.

2. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt or its isotope compound, characterized in that: It meets one or both of the following conditions: (1)L 2 for The a side and connected; and (2)R 3 for 3. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt or its isotope compound, which is any one of the following schemes: Scenario 1: It is a benzene ring or a 5-membered heteroaromatic ring containing two N atoms; n 1 is 0 or 1; n 2 is 0; L 1 -(CH2) n -, n is 1, 2 or 3 R 1 C6-C 10 Aryl, 5-10 membered heteroaryl, 1, 2 or 3 R 1-1 Substituted C6-C 10 Aryl or 1, 2 or 3 R 1-2 A substituted 5-10 membered heteroaryl group, wherein In each "5-10 membered heteroaryl", the heteroatom is selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2 or 3; R 1-1 and R 1-2 are independently halogen, -CN, -OH, -NR 1-1-1 R 1-1-2 , -C(=O)H, -C(=O)NR 1-1-1 R 1-1-2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1, 2 or 3 halogens, or C1-C6 alkoxy substituted by 1, 2 or 3 halogens; R 1-1-1 and R 1-1-2 are independently H or C1-C6 alkyl; L 3 is the connection key; or L 3 for Among them, X 1 and Connected, With L 2 connected; X 1 For connecting bonds, -CH2-, -NR X-1 -, -O- or -S-; R X-1 is H or C1-C6 alkyl; Phenyl or "a 5-6 membered heteroaromatic ring in which the heteroatom is N and the number of heteroatoms is 1 or 2"; n 3 is 0, 1, 2, or 3; R 2 are independently halogen, -CN, -OH, -NR 2-1 R 2-2 , -C(=O)H, -C(=O)NR 2-1 R 2-2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1, 2 or 3 halogens, or C1-C6 alkoxy substituted by 1, 2 or 3 halogens; R 2-1 and R 2-2 are independently H or C1-C6 alkyl; R 3 is C1-C6 alkyl, 1, 2 or 3 R 3-1 Substituted C1-C6 alkyl, 1, 2 or 3 R 3-2 Substituted C2-C6 alkenyl or 1, 2 or 3 R 3-3 Substituted C2-C6 alkynyl; R 3-1 , R 3-2 and R 3-3 are independently deuterium, halogen, -OH, -OD, -NR 3-1-1 R 3-1-2 or -C(=O)H; R 3-1-1 and R 3-1-2 are independently H or C1-C6 alkyl; L 2 -(CH2) m -, m is 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, -(CH2) m -1, 2 or 3 -CH2- in - are optionally selected from -NR L-1 -, -O-, -S- and -CH=CH-; R L-1 are independently H or C1-C6 alkyl; Scenario 2: for L 1 is -CH2-; R 1 For 1 R 1-1 Substituted phenyl, R 1-1 is a halogen, and R 1-1 Located in L 1 The para or meta position of; L 3 for X 1 is a connecting bond, -CH2- or O, is a benzene ring or a 5-6 membered heteroaromatic ring in which the heteroatom is N and the number of heteroatoms is 1 or 2, n3 is 0 or 1, R 2 is halogen or C1-C6 alkyl substituted by 1, 2 or 3 halogens; L 2 Any of the following options: I:L 2 -(CH2) m-1 -O- a 、-(CH2) m-2 -O-CH2- a or -(CH2) m-2 -NR L-1 -CH2- a , m is 6, 7 or 8, -(CH2) m-1 -or-(CH2) m-2 -1 -CH2- in - is optionally replaced by NR L-1 or O replacement, where the a side is connected; II:L 2 -CH2-(CH2) m-2 -O- a , m is 5, 6 or 7, -(CH2) m-2 -, at least one -CH2- is replaced by -CH=CH-, and the a side connected; R 3 For 1, 2 or 3 R 3-1 Substituted C1-C6 alkyl, 1, 2 or 3 R 3-2 Substituted C2-C6 alkenyl or 1, 2 or 3 R 3-3 Substituted C2-C6 alkynyl; R 3-1 , R 3-2 and R 3-3 Each independently deuterium, halogen, -OH, -OD, -NR 3-1-1 R 3-1-2 or -C(=O)H; R 3-1-1 and R 3-1-2 are independently C1-C6 alkyl; Scenario 3: for L 1 is -CH2-; R 1 For 1 R 1-1 Substituted phenyl, R 1-1 is a halogen, and R 1-1 Located in L 1 The para or meta position of; L 3 for X 1 is a connecting bond or -CH2-, is a benzene ring or a 5-6 membered heteroaromatic ring in which the heteroatom is N and the number of heteroatoms is 1 or 2, n3 is 0 or 1, R 2 is halogen or C1-C6 alkyl substituted by 1, 2 or 3 halogens; L 2 Any of the following options: I:L 2 -(CH2) m-1 -O- a 、-(CH2) m-2 -O-CH2- a or -(CH2) m-2 -NR L-1 -CH2- a , m is 6, 7 or 8, -(CH2) m-1 -or-(CH2) m-2 -1 -CH2- in - is optionally replaced by NR L-1 or O replacement, where the a side is connected; II:L 2 -CH2-(CH2) m-2 -O- a , m is 5, 6 or 7, -(CH2) m-2 -, at least one -CH2- is replaced by -CH=CH-, and the a side connected; R 3 For 1, 2 or 3 R 3-1 Substituted C1-C6 alkyl, 1, 2 or 3 R 3-2 Substituted C2-C6 alkenyl or 1, 2 or 3 R 3-3 Substituted C2-C6 alkynyl; R 3-1 , R 3-2 and R 3-3 Each is independently deuterium, halogen, -OH or -OD.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, in, It is a benzene ring or a 5-membered heteroaromatic ring containing two N atoms; n 1 is 0 or 1; n 2 is 0; L 1 -(CH2) n -, n is 1, 2 or 3, -(CH2) n -1, 2 or 3 -CH2- in - are optionally replaced by one or more selected from the following groups: -NL 1-1 -, -O- or -S-, L 1-1 is H or C1-C6 alkyl; R 1 C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, 1, 2 or 3 R 1-1 Substituted C6-C 10 Aryl or 1, 2 or 3 R 1-2 substituted 5-10 membered heteroaryl, substituted by 1, 2 or 3 R 1-3 Substituted C3-C8 cycloalkyl or 1, 2 or 3 R 1-4 Substituted 3-8 membered heterocycloalkyl, wherein in each "5-10 membered heteroaryl" and each "3-8 membered heterocycloalkyl", the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R 1-1 , R 1-2 , R 1-3 and R 1-4 are independently halogen, -CN, -OH, -NR 1-1-1 R 1-1-2 , -C(=O)H, -C(=O)NR 1-1-1 R 1 -1-2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1, 2 or 3 halogens, or C1-C6 alkoxy substituted by 1, 2 or 3 halogens; R 1-1-1 and R 1-1-2 are independently H or C1-C6 alkyl; L 3 is the connection key; or L 3 for Among them, X 1 -CH2-, -NR X-1 -, -O- or -S-; R X-1 is H or C1-C6 alkyl; Phenyl or "a 5-6 membered heteroaromatic ring in which the heteroatom is N and the number of heteroatoms is 1 or 2"; n 3 is 0, 1, 2, or 3; R 2 are independently halogen, -CN, -OH, -NR 2-1 R 2-2 , -C(=O)H, -C(=O)NR 2-1 R 2-2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1, 2 or 3 halogens, or C1-C6 alkoxy substituted by 1, 2 or 3 halogens; R 2-1 and R 2-2 are independently H or C1-C6 alkyl; R 3 is C1-C6 alkyl or is substituted by 1, 2 or 3 R 3-1 Substituted C1-C6 alkyl; R 3-1 are independently halogen, -OH, -NR 3-1-1 R 3-1-2 or -C(=O)H; R 3-1-1 and R 3-1-2 are independently H or C1-C6 alkyl; L 2 -(CH2) m -, m is 4, 5, 6, 7, 8, 9 or 10, -(CH2) m -1, 2 or 3 -CH2- in - are optionally selected from -NR L -1 -, -O-, -S- and -CH=CH-; R L-1 are independently H or C1-C6 alkyl.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4, characterized in that: It meets one or more of the following conditions: (1) Each "5-6 membered heteroaromatic ring" is independently a pyrrole ring, a pyrazole ring, an imidazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring; (2) Each "C6-C 10 "Aryl" is independently phenyl or naphthyl; (3) Each "5-10 membered heteroaryl" is independently a 5-6 membered heteroaryl having one or more heteroatoms selected from N, O and S, and having 1 or 2 heteroatoms; (4) each "halogen" is independently F, Cl, Br or I; (5) each "C1-C6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (6) each "C1-C6 alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy; (7) each "C3-C8 cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (8) Each "3- to 8-membered heterocycloalkyl" is independently a 4- to 6-membered heterocycloalkyl group having one or two heteroatoms selected from N and O, and having one or two heteroatoms.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4, characterized in that: It meets one or more of the following conditions: (1) each "5-10 membered heteroaryl" is independently pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; (2) each "halogen" is independently F or Cl; (3) Each "3- to 8-membered heterocycloalkyl" is independently azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydropyranyl, piperidinyl, morpholinyl or piperazinyl.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4, characterized in that: Each "5-10 membered heteroaryl" is independently 8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4 or 5, characterized in that: It meets one or more of the following conditions: (1) is a 5-membered heteroaromatic ring containing two N atoms; (2) for (3)L 1 exist The connection site on L 3 exist The connection sites on the 1 exist The connection site on The atoms marked with "b" are adjacent; (4)L 1 is -CH2-; (5)R 1 is a 5-10 membered heteroaryl or is substituted by 1, 2 or 3 R 1-1 Substituted C6-C 10 Aryl, R 1-1 is a halogen; (6) When L 3 for hour, X 1 is -O- or -CH2-; n3 is 0 or 1; R 2 is halogen or C1-C6 alkyl substituted by 1, 2 or 3 halogens; for (7)L 2 Any of the following options: I:L 2 -(CH2) m -, m is 6, 7 or 8, -(CH2) m One or two -CH2- in - are independently replaced by NR L-1 or O, R L-1 are independently H or C1-C6 alkyl; II:L 2 -(CH2) m -, m is 5, 6, 7, 8 or 9, -(CH2) m -, at least one -CH2- is replaced by -CH=CH-; (8) When L 2 When -CH=CH- is contained in the group, the configuration of -CH=CH- is Z configuration or E configuration.

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4 or 5, characterized in that: It meets one or more of the following conditions: (1)R 1 "a 5-6 membered heteroaryl group having one or two heteroatoms selected from N, O and S" or 1 R 1-1 Substituted phenyl, R 1-1 is a halogen, and R 1-1 Located in L 1 The para or meta position of; (2) When L 3 for hour, X 1 for -O-; n3 is 0 or 1; R 2 is Cl, F or CF3; for X 1 exist The connection site on L 2 exist The attachment sites on are separated by one ring atom; (3)L 2 Any of the following options: I:L 2 -(CH2) m-1 -O-, -(CH2) m-2 -O-CH2- or -(CH2) m-2 -NR L-1 -CH2-, -(CH2) m-1 -or-(CH2) m-2 -1 -CH2- in - is optionally replaced by NR L-1 or O replacement; II:L 2 -(CH2) m-1 -O-, -(CH2) m-1 -, at least one -CH2- is replaced by -CH=CH-; (4) When L 2 When -CH=CH- is contained in the group, the configuration of -CH=CH- is E configuration.

10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4 or 5, characterized in that: It meets one or more of the following conditions: (1)R 1 For 1 R 1-1 Substituted phenyl, R 1-1 is a halogen, and R 1-1 Located in L 1 The para or meta position of; (2)L 2 Any of the following options: I:L 2 -(CH2) m-1 -O- a 、-(CH2) m-2 -O-CH2- a or -(CH2) m-2 -NR L-1 -CH2- a , -(CH2) m-1 -or-(CH2) m-2 -1 -CH2- in - is optionally replaced by NR L-1 or O replacement, where the a side is connected; II:L 2 -CH2-(CH2) m-2 -O-, -(CH2) m-2 -, at least one -CH2- is replaced by -CH=CH-.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4 or 5, characterized in that: L 2 Any of the following options: I:L 2 -(CH2) m-1 -O- a 、-(CH2) m-2 -O-CH2- a or -(CH2) m-2 -NR L-1 -CH2- a , -(CH2) m-1 -or-(CH2) m-2 -1 -CH2- in - is optionally replaced by NR L-1 or O replacement, where the a side is connected; II:L 2 -CH2-(CH2) m-2 -O- a , -(CH2) m-2 -, at least one -CH2- is replaced by -CH=CH-, and the a side connected.

12. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4 or 5, characterized in that: It meets one or more of the following conditions: (1) for (2) for (3)R 1 for (4) When L 3 for hour, for (5)L 2 -(CH2)4-CH=CH-CH2-O-, -(CH2)2-CH=CH-CH2-O-, -(CH2)3-CH=CH-CH2-O-, -(CH2)2-CH=CH-CH2-O-CH2-, -(CH2)7-O-, -(CH2)5-O-, -(CH2)6-O-, -(CH2)5-O-CH2-, -(CH2)2-O-(CH2)2-O-CH2-, -(CH2)5-NH-CH2-, -(CH2)5-N(CH3)-CH2-, -(CH2)3-NH-(CH2)2-O-, -(CH2)2-CH=CH-(CH2)2-O-, -CH2-CH=CH-(CH2)3-O-, -(CH2)3-CH=CH-(CH2)4-O- or -(CH2)3-CH=CH-(CH2)3-O-; (6)R 3 for 13. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4 or 5, characterized in that: It meets one or more of the following conditions: (1) for (2) for (3)R 1 for (4) When L 3 for hour, for (5)L 2 for 14. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4 or 5, characterized in that: It meets one or more of the following conditions: (1) for (2) When L 3 for hour, for (3)L 2 for The a side and connected.

15. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4 or 5, characterized in that: L 2 for The a side and connected.

16. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4 or 5, which is any one of the following schemes: Scenario 1: It is a benzene ring or a 5-membered heteroaromatic ring containing two N atoms; n 1 is 0 or 1; n 2 is 0; L 1 -(CH2) n -, n is 1, 2 or 3 R 1 C6-C 10 Aryl, 5-10 membered heteroaryl, 1, 2 or 3 R 1-1 Substituted C6-C 10 Aryl or 1, 2 or 3 R 1-2 A substituted 5-10 membered heteroaryl group, wherein In each "5-10 membered heteroaryl", the heteroatom is selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2 or 3; R 1-1 and R 1-2 are independently halogen, -CN, -OH, -NR 1-1-1 R 1-1-2 , -C(=O)H, -C(=O)NR 1-1-1 R 1-1-2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1, 2 or 3 halogens, or C1-C6 alkoxy substituted by 1, 2 or 3 halogens; R 1-1-1 and R 1-1-2 are independently H or C1-C6 alkyl; L 3 is the connection key; or L 3 for Among them, X 1 and Connected, With L 2 connected; X 1 -CH2-, -NR X-1 -, -O- or -S-; R X-1 is H or C1-C6 alkyl; Phenyl or "a 5-6 membered heteroaromatic ring in which the heteroatom is N and the number of heteroatoms is 1 or 2"; n 3 is 0, 1, 2, or 3; R 2 are independently halogen, -CN, -OH, -NR 2-1 R 2-2 , -C(=O)H, -C(=O)NR 2-1 R 2-2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted by 1, 2 or 3 halogens, or C1-C6 alkoxy substituted by 1, 2 or 3 halogens; R 2-1 and R 2-2 are independently H or C1-C6 alkyl; R 3 is C1-C6 alkyl or is substituted by 1, 2 or 3 R 3-1 Substituted C1-C6 alkyl; R 3-1 are independently halogen, -OH, -NR 3-1-1 R 3-1-2 or -C(=O)H; R 3-1-1 and R 3-1-2 are independently H or C1-C6 alkyl; L 2 -(CH2) m -, m is 4, 5, 6, 7, 8, 9 or 10, -(CH2) m -1, 2 or 3 -CH2- in - are optionally selected from -NR L -1 -, -O-, -S- and -CH=CH-; R L-1 are independently H or C1-C6 alkyl; Scenario 2: for L 1 is -CH2-; R 1 For 1 R 1-1 Substituted phenyl, R 1-1 is a halogen, and R 1-1 Located in L 1 The para or meta position of; L 3 for X 1 For O, is a benzene ring or a 5-6 membered heteroaromatic ring in which the heteroatom is N and the number of heteroatoms is 1 or 2, n3 is 0 or 1, R 2 is halogen or C1-C6 alkyl substituted by 1, 2 or 3 halogens; L 2 Any of the following options: I:L 2 -(CH2) m-1 -O- a 、-(CH2) m-2 -O-CH2- a or -(CH2) m-2 -NR L-1 -CH2- a , m is 6, 7 or 8, -(CH2) m-1 -or-(CH2) m-2 -1 -CH2- in - is optionally replaced by NR L-1 or O replacement, where the a side is connected; II:L 2 -CH2-(CH2) m-2 -O- a , m is 5, 6 or 7, -(CH2) m-2 -, at least one -CH2- is replaced by -CH=CH-, and the a side connected; R 3 For 1, 2 or 3 R 3-1 Substituted C1-C6 alkyl; R 3-1 are independently halogen, -OH, -NR 3-1-1 R 3-1-2 or -C(=O)H; R 3-1-1 and R 3-1-2 are independently C1-C6 alkyl.

17. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4 or 5, characterized in that: The compound represented by formula (I) is any one of the following compounds:

18. A pharmaceutical composition comprising a substance X and a pharmaceutically acceptable excipient, wherein the substance X is a compound of formula (I) according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

19. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 in the preparation of a TRPC5 inhibitor.

20. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 in the preparation of a medicament for a disease associated with TRPC5.

21. The use according to claim 20, characterized in that The TRPC5-related disease is a nervous system disease.

22. The use according to claim 20, characterized in that The TRPC5-related diseases are depression, anxiety disorder, traumatic stress disorder or chronic kidney disease.

23. The use according to claim 22, characterized in that The chronic kidney disease is diabetic nephropathy or focal segmental glomerulosclerosis.

24. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 17 in the preparation of a medicament for treating and / or preventing a nervous system disease.

25. The use according to claim 24, characterized in that The nervous system disease is depression, anxiety disorder, traumatic stress disorder or chronic kidney disease.

26. The use according to claim 25, characterized in that The chronic kidney disease is diabetic nephropathy or focal segmental glomerulosclerosis.

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