Tricyclic compound as well as intermediate, preparation method and application thereof

Abstract

The invention discloses a tricyclic compound as well as an intermediate, a preparation method and application thereof. The invention provides a compound shown as a formula A or a pharmaceutically acceptable salt thereof, and an application of the compound or the pharmaceutically acceptable salt in preparation of a positron tomography agent. The compound disclosed by the invention has relatively good binding capacity with beta-amyloid protein, short half-life period and good developing effect; the compound provided by the invention can be used for early diagnosis of Alzheimer's disease and tracking of drug curative effect. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to tricyclic compounds, intermediates thereof, preparation methods and applications. Background Art

[0002] Alzheimer's disease (AD) is the most common cause of dementia, characterized by a progressive loss of cognitive function and a progressive increase in behavioral disorders. This progressive and irreversible brain dysfunction affects the lives of millions of people and imposes a devastating health burden worldwide. In the past two decades, significant progress has been made in deciphering the pathogenesis and developing new treatment methods. The pathological features of AD include neuritic plaques of β-amyloid protein and neurofibrillary tangles of hyperphosphorylated tau protein. The recent trend in the development of AD drugs is to control the production, aggregation, and deposition of amyloid in the brain, as well as to accelerate the metabolism of amyloid from the brain.

[0003] Non-invasive detection of amyloid deposition in the brain has been used to develop anti-amyloid treatment regimens. Direct imaging of amyloid in AD patients is useful for the early diagnosis, formulation, and evaluation of treatment regimens for AD. To this end, compounds suitable for imaging amyloid deposition in the human brain in vivo have been extensively researched and developed. Among these compounds are monoclonal antibodies against Aβ, but these are not taken up by the brain. A conjugate of an Aβ polypeptide-putrescine-gadolinium injected into transgenic mice overexpressing Aβ amyloid has been observed to have amyloid in the mouse brain on MRI. Amyloid deposition can also be imaged and quantified non-invasively using small molecules that easily enter the brain.

[0004] Imaging amyloid with small molecules is the most successful method to date. Some of the most promising compounds for imaging amyloid are derivatives of congo red, thioflavin, stilbene, and FDDNP. Derivatives of congo red and thioflavin have been used for staining brain tissue sections from AD patients and transgenic mice. Two compounds labeled with F18 that are currently undergoing human clinical trials are Florbetapir from Eli Lilly and Flutemetamol from GE. Neither of these imaging agents has the kinetic range shown by PIB labeled with carbon-11.

[0005] CN102532119A discloses a bicyclic compound of benzothiazole-aromatic ring or heteroaromatic ring-diamine, which has the following general formula structure and can be used as a positron emission tomography agent,

[0006]

[0007] An effective management method for AD is to diagnose, monitor, treat, and prevent this disease. Summary of the Invention

[0008] The technical problem to be solved by the present invention is that there are few types of compounds for amyloid imaging. Therefore, the present invention provides a tricyclic compound, its intermediate, preparation method and application. The compound of the present invention has good binding ability to amyloid, short half-life and good imaging effect. And the compound of the present invention can be used to prepare a positron emission tomography agent, and can be used for the early diagnosis of Alzheimer's disease and the tracking of drug efficacy.

[0009] The present invention provides a compound of formula A or a pharmaceutically acceptable salt thereof,

[0010]

[0011] wherein,

[0012] X 1 is O or S;

[0013] X 2 is -CH or N;

[0014] T 1 is -CR 1 or N;

[0015] T 2 is -CH or N;

[0016] R 1 is hydrogen, C substituted by hydroxyl 1 -C 6 alkyl, C substituted by hydroxyl 1 -C 6 alkoxy or

[0017] R 2 is F or 18 F;

[0018] Each R 3 is independently hydrogen or C 1 -C 6 alkyl.

[0019] In one embodiment, the compound of formula A or a pharmaceutically acceptable salt thereof; the definitions of certain groups can be described as follows, and the definitions of other groups can be as described in any of the above embodiments (hereinafter referred to as "in one embodiment"): R 1 Among them, the C 1 -C 6 alkyl can be C 1 -C 4 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl.

[0020] In one embodiment, R 1 in which the C 1 -C 6 alkoxy group can be a C 1 -C 4 alkoxy group, preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, such as ethoxy.

[0021] In one embodiment, R 3 in which the C 1 -C 6 alkyl group can be a C 1 -C 4 , preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0022] In one embodiment, R 1 is

[0023] In one embodiment, each R 3 is independently hydrogen.

[0024] In one embodiment, the compound of formula A or a pharmaceutically acceptable salt thereof can be a compound represented by formula A-1, A-2 or A-3 as follows:

[0025]

[0026] wherein the definitions of T 1 , T 2 and R 2 are as defined above.

[0027] In one embodiment, the compound of formula A or a pharmaceutically acceptable salt thereof can be a compound represented by formula A-4 or A-5 as follows:

[0028]

[0029] wherein the definitions of X 1 , X 2 , R 1 and R 2 are as defined above.

[0030] In one embodiment, the compound of formula A or a pharmaceutically acceptable salt thereof can be any of the following compounds:

[0031]

[0032] The present invention also provides a compound represented by formula P, formula L or formula M,

[0033]

[0034] Among them,

[0035] The T 1 and T 2 and X 1 and X 2 and R 1 and R 2 are defined as described above;

[0036] R 4 is C 1 -C 6 alkyl.

[0037] In one embodiment, the compound represented by Formula P, Formula L or Formula M is any of the following compounds,

[0038]

[0039] The present invention also provides a method for preparing a compound represented by Formula A, which is any of the following embodiments:

[0040] Embodiment 1: It includes the following steps: reacting a substrate with CsF, that's all. The substrate is a compound represented by Formula P or a compound represented by Formula L;

[0041]

[0042] Among them, R 4 is C 1 -C 6 alkyl; the T 1 and T 2 and X 1 and X 2 and R 2 are defined as described above;

[0043] When T 1 is CR 1 and R 1 is C 1 -C 6 alkyl substituted by a hydroxyl group, a compound represented by Formula L is used as a raw material to prepare a compound represented by Formula A;

[0044] Embodiment 2: It includes the following steps: reacting the compound represented by Formula M with the compound represented by Formula D in the presence of an acid, that's all;

[0045]

[0046] Among them, the T 1 and T 2 and X 1, X 2 and R 2 are defined as described above.

[0047] The reaction conditions and operations of the preparation methods in the aforementioned Scheme 1 and Scheme 2 can be the conventional reaction conditions and operations in this type of preparation method in the art; in the present application, preferably:

[0048] In Scheme 1:

[0049] The reaction can be carried out in a solvent, and the solvent can be a strongly polar aprotic solvent. The strongly polar aprotic solvent is preferably dichloromethane or DMF, such as DMF;

[0050] The temperature of the reaction can be 120 - 150 °C, such as 120 °C;

[0051] The molar ratio of the substrate to the CsF can be 1:(3 - 5), such as 1:3;

[0052] The mass - volume ratio of the substrate to the solvent can be 0.1 - 0.5 g / mL, such as 0.5 g / mL;

[0053] In Scheme 2:

[0054] The acid can be an organic acid, such as acetic acid;

[0055] The temperature of the reaction can be 100 - 120 °C, such as 100 °C;

[0056] The molar ratio of the compound represented by formula M to the compound represented by formula D can be 1:(3 - 5), such as 1:3;

[0057] The molar ratio of the compound represented by formula M to the acid can be 1:(2 - 4), such as 1:2.

[0058] The present invention also provides a positron emission tomography agent, which comprises the compound represented by formula A as described above or a pharmaceutically acceptable salt thereof.

[0059] The present invention also provides an application of the compound represented by formula A as described above or a pharmaceutically acceptable salt thereof in the preparation of a positron emission tomography agent.

[0060] Unless otherwise specified, the terms used in the present invention have the following meanings:

[0061] The term "alkyl" refers to a straight - chain or branched - chain, saturated monovalent hydrocarbon group having a specified number of carbon atoms (for example, C 1 -C 4 or C 1 -C 6 ). Alkyl includes but is not limited to: methyl, ethyl, n - propyl, isopropyl, n - butyl, isobutyl, sec - butyl, tert - butyl, etc.

[0062] The term "alkoxy" refers to the group -O-C 1 -C 6 alkyl, wherein the alkyl is as defined above.

[0063] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use in patients) acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, etc. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride salts, sulfate salts, methanesulfonate salts, etc. See specifically Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002).

[0064] On the basis of not violating the common knowledge in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain various preferred examples of the present invention.

[0065] Unless otherwise specified, the reagents and raw materials used in the present invention are all commercially available.

[0066] The positive and progressive effects of the present invention are as follows: The Ki values of the compounds of the present invention are all below 7.8 nM, and they have good binding ability to β-amyloid protein; their clogD 7.4 are all below 3.2, and they have a short half-life, which is beneficial to eliminating the influence of the background during the imaging process and has a good imaging effect. Moreover, the compounds of the present invention can be used to prepare positron emission tomography agents, and can be used for the early diagnosis of Alzheimer's disease and the tracking of drug efficacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0067] Figure 1 It is an autoradiogram of a brain tissue section of a human AD patient. DETAILED DESCRIPTION OF THE INVENTION

[0068] The present invention will be further illustrated below by way of examples, but the present invention is not limited to the scope of the described examples.

[0069] The experimental methods not specified in the following examples are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0070]

[0071] Preparation of Compound A3 in Example 1

[0072]

[0073] General synthesis procedure: 1.0 mmol 1.2 equivalents of NIS, using acetonitrile as the solvent, the reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine. The organic solvent phase was dried over magnesium sulfate. The solvent was evaporated, and the crude product was separated by silica gel column chromatography.

[0074] Compound A3, yield 86%, 1 H NMR (400 MHz; CDCl 3 ), δ 5.10 (s, 2H, CH 2 ), 5.50 (brs, 1H, OH), 6.49 (s, 1H, Ar-H), 8.72 (s, 1H, Ar-H), 11.6 (brs, 1H, Ar-OH).

[0075] Preparation of Compound A5 in Example 2

[0076]

[0077] General synthesis procedure: 1.0 mmol 1.2 equivalents 0.2 equivalent of CuI, 0.2 equivalent of (Ph 3 P) 2 PdCl 2 , using acetonitrile as the solvent, the reaction mixture was heated to 100 °C and stirred until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine. The organic solvent phase was dried over magnesium sulfate. The solvent was evaporated, and the crude product was separated by silica gel column chromatography.

[0078] Compound A5, yield 81%, 1 H NMR (400 MHz; CDCl 3 ), δ 5.82 (s, 2H, NH 2 ), 7.71 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 7.74 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 0.08 (s, 9H).

[0079] Preparation of Compound A6 in Example 3

[0080]

[0081] General synthesis procedure: 1.0 mmol 5 equivalents of KOH (5M aqueous solution), using ethanol as the solvent, the reaction mixture was stirred until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine. The organic solvent phase was dried over magnesium sulfate. The solvent was evaporated, and the crude product was separated by silica gel column chromatography.

[0082] Compound A6, yield 95%, 1 H NMR (400 MHz; CDCl 3 ), δ 4.10 (s, 1H, CH), 5.80 (s, 2H, NH 2 ), 7.70 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 7.76 (d, 3 J HH = 7.5 Hz, 1H, Ar-H).

[0083] Preparation of Compound M1 in Example 4

[0084]

[0085] General synthesis procedure for Compound M1: 1.0 mmol of substrate A6, 1.2 equivalents of 3-iodopyridin-4-ol, 3.0 equivalents of triethylamine, 0.5 equivalent of (Ph 3 P) 2 PdCl 2 , added to the reaction solution in solid form, reacted in acetonitrile at 60 °C for 3 hours, and the color of the solution changed from light yellow to dark red. LC-MS detection showed that A6 completely disappeared. After filtration, the reaction mixture was directly separated by HPLC, phase A was 0.025% aqueous TFA solution, phase B was 0.02% TA acetonitrile solution, 10 - 30% B, 0 - 30 min, and the solvent was evaporated.

[0086] Compound M1, yield 23%, 1 H NMR (400 MHz; CDCl 3 ), δ 5.80 (s, 2H, NH 2 ), 6.54 (s, 1H, Ar-H), 7.85 (d, 3 J HH = 8.6 Hz, 1H, Ar-H), 7.94 (d, 3 J HH = 8.6 Hz, 1H, Ar-H), 8.74 - 8.78 (m, 2H, Ar-H), 9.52 (s, 1H, Ar-H).

[0087] Preparation of Compound M2 in Example 5

[0088]

[0089] General synthesis procedure of compound M2: 1.0 mmol of substrate A6, 1.2 equivalents of 2-(hydroxymethyl)-5-iodopyridin-4-ol, 3.0 equivalents of triethylamine, 0.5 equivalent of (Ph 3 P) 2 PdCl 2 , added to the reaction solution in solid form, reacted in acetonitrile at 60 °C for 3 hours, and the solution color changed from light yellow to dark red. LC-MS detection showed that A6 completely disappeared. After filtration, the reaction mixture was directly separated by HPLC. Phase A was an aqueous solution of 0.025% TFA, and phase B was an acetonitrile solution of 0.025% TFA, 10 - 30% B, 0 - 30 min, and the solvent was dried.

[0090] Compound M2, yield 43%, 1 1H NMR (400 MHz; CDCl 3 ), δ 5.12 (s, 2H, CH 2 ), 5.50 (s, 1H, OH), 5.80 (brs, 2H, NH 2 ), 6.54 (s, 1H, Ar-H), 7.75 (s, 1H, Ar-H), 7.95 (d, 3 J HH = 8.6 Hz, 1H, Ar-H), 8.65 (s, 1H, Ar-H), 8.76 (d, 3 J HH = 8.6 Hz, 1H, Ar-H).

[0091] Preparation of compound P1 in Example 6

[0092]

[0093] General synthesis procedure of compound P1: 1.0 mmol 3.0 equivalents of 2,5-dimethoxytetrahydrofuran, 2.0 mL of HOAc, the reaction mixture was heated to 100 °C and stirred until the reaction was complete. After filtration, the reaction mixture was directly separated by HPLC. Phase A was an aqueous solution of 0.025% TFA, and phase B was an acetonitrile solution of 0.025% TFA, 10 - 30% B, 0 - 30 min, and the solvent was dried.

[0094] Compound P1, yield 89%, 1 1H NMR (400 MHz; CDCl 3 ), δ 6.35 (m, 2H, Ar-H), 6.53 (s, 1H, Ar-H), 7.25 (m, 2H, Ar-H), 7.85 (d,3 J HH = 8.6 Hz, 1H, Ar-H), 8.74 (d, 3 J HH = 8.6 Hz, 1H, Ar-H), 8.88 (d, 3 J HH = 8.6 Hz, 1H, Ar-H), 9.02 (d, 3 J HH = 8.6 Hz, 1H, Ar-H), 9.50 (s, 1H, Ar-H).

[0095] Preparation of Compound P2 in Example 7

[0096]

[0097] General synthetic procedure for Compound P2: 1.0 mmol 3.0 equivalents of 2,5-dimethoxytetrahydrofuran, 2.0 mL of HOAc, the reaction mixture was heated to 100 °C and stirred until the reaction was complete. After filtration of the reaction mixture, it was directly separated by HPLC. Phase A was 0.025% aqueous TFA solution, Phase B was 0.025% TFA acetonitrile solution, 10 - 30% B, 0 - 30 min, and the solvent was dried by suction.

[0098] Compound P2, yield 91%, 1 H NMR (400 MHz; CDCl 3 ), δ 5.12 (s, 2H, CH 2 ), 5.60 (s, 1H, OH), 6.33 (m, 2H, Ar-H), 6.54 (s, 1H, Ar-H), 7.25 (m, 2H, Ar-H), 7.75 (s, 1H, Ar-H), 8.65 (s, 1H, Ar-H), 8.88 (d, 3 J HH = 8.6 Hz, 1H, Ar-H), 9.01 (d, 3 J HH = 8.6 Hz, 1H, Ar-H).

[0099] Preparation of Compound P21 in Example 8

[0100]

[0101] General synthetic procedure for Compound P21: 1.0 mmol 3.0 equivalents of 3,4-dihydropyran and 0.1 equivalent of TsOH. The reaction mixture was heated to 100 °C and stirred until the reaction was complete. After filtration, the reaction mixture was directly separated by HPLC. Phase A was an aqueous solution of 0.025% TFA, and phase B was an acetonitrile solution of 0.025% TFA. 10 - 30% B, 0 - 30 min, and the solvent was dried by suction.

[0102] Compound P21, yield 76%, 1 H NMR (400 MHz; CDCl 3 ), δ 1.54 - 1.78 (m, 6H, CH 2 ), 3.64 - 3.74 (m, 2H, CH 2 O), 4.58 (t, 3 J HH = 7.0 Hz, 1H, CHO 2 ), 4.92 (s, 2H, CH 2 ), 6.31 (m, 2H, Ar - H), 6.54 (s, 1H, Ar - H), 7.20 (m, 2H, Ar - H), 7.75 (s, 1H, Ar - H), 8.65 (s, 1H, Ar - H), 8.88 (d, 3 J HH = 8.6 Hz, 1H, Ar - H), 9.01 (d, 3 J HH = 8.6 Hz, 1H, Ar - H).

[0103] Preparation of Compound L21 in Example 9

[0104]

[0105] General synthetic procedure for Compound L21: 1.0 mmol 3.0 equivalents of CsF, 2 mL of DMF. The reaction mixture was heated to 120 °C and stirred until the reaction was complete. After filtration, the reaction mixture was directly separated by HPLC. Phase A was an aqueous solution of 0.025% TFA, and phase B was an acetonitrile solution of 0.02% TFA. 10 - 30% B, 0 - 30 min. The solvent was dried by suction.

[0106] Compound L21, yield 53%, 1 H NMR (400 MHz; CDCl 3 ), δ 1.52 - 1.80 (m, 6H, CH 2 ), 3.64 - 3.74 (m, 2H, CH 2 O), 4.58 (t, 3 J HH = 7.0 Hz, 1H, CHO 2), 4.90 (s, 2H, CH 2 ), 6.30 (m, 2H, Ar-H), 6.50 (s, 1H, Ar-H), 7.27 (m, 2H, Ar-H), 7.75 (s, 1H, Ar-H), 8.28 (d, 3 J HH = 8.6 Hz, 1H, Ar-H), 8.65 (s, 1H, Ar-H), 8.74 (d, 3 J HH = 8.6 Hz, 1H, Ar-H).

[0107] Preparation of Compound I in Example 10

[0108]

[0109] General synthetic procedure for Compound I: 1.0 mmol 3.0 equivalents of CsF, 2 mL of DMF, the reaction mixture was heated to 120 °C and stirred until the reaction was complete. After filtration, the reaction mixture was directly separated by HPLC. Phase A was 0.025% aqueous TFA solution, Phase B was 0.025% TFA acetonitrile solution, 10 - 30% B, 0 - 30 min, and the solvent was dried up.

[0110] Compound I, yield 33%, 1 H NMR (400 MHz; CDCl 3 ), δ 6.30 (m, 2H, Ar-H), 6.52 (s, 1H, Ar-H), 7.19 (m, 2H, Ar-H), 7.80 (d, 3 J HH = 8.6 Hz, 1H, Ar-H), 8.21 (d, 3 J HH = 8.6 Hz, 1H, Ar-H), 8.70 (m, 2H, Ar-H), 9.05 (s, 1H, Ar-H).

[0111] Preparation of Compound II in Example 11

[0112]

[0113] General synthetic procedure for Compound II: 1.0 mmol 3.0 equivalents of CsF, 2 mL of DMF, the reaction mixture was heated to 120 °C and stirred until the reaction was complete. After filtration, the reaction mixture was directly separated by HPLC. Phase A was 0.025% aqueous TFA solution, Phase B was 0.025% TFA acetonitrile solution, 10 - 30% B, 0 - 30 min, and the solvent was dried up.

[0114] Compound II, yield 53% 1 H NMR (400 MHz; CDCl 3 ), δ 5.15 (s, 2H, CH 2 ), 5.70 (s, 1H, OH), 6.37 (m, 2H, Ar-H), 6.52 (s, 1H, Ar-H), 7.23 (m, 2H, Ar-H), 7.75 (s, 1H, Ar-H), 8.24 (s, 1H, Ar-H), 8.61 (s, 1H, Ar-H), 8.75 (dd, 3 J HH = 4 J HF = 8.6 Hz, 1H, Ar-H).

[0115] Preparation of Compound B2 in Example 12

[0116]

[0117] General synthetic procedure for Compound B2: 1.0 mmol 3.0 equivalents of Boc 2 O, 0.2 equivalent of DMAP, 2 mL of ACN, the reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine. The organic solvent phase was dried over magnesium sulfate. The solvent was evaporated, and the crude product was separated by silica gel column chromatography.

[0118] Compound B2, yield 86% 1 H NMR (400 MHz; CDCl 3 ), δ 1.49 (s, 9H, CH 3 ), 7.39 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 7.64 (dd, 3 J HH = 7.5 Hz, 4JHF = 5.0 Hz, 1H, Ar-H), 9.80 (brs, 1H, NH).

[0119] Preparation of Compound B4 in Example 13

[0120]

[0121] General synthetic procedure for Compound B4: 1.0 mmol 3.0 equivalents of Boc 2 O, 0.2 equivalent of DMAP, 2 mL of ACN, the reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine. The organic solvent phase was dried over magnesium sulfate. The solvent was evaporated, and the crude product was separated by silica gel column chromatography.

[0122] Compound B4, yield 93% 1 H NMR (400 MHz; CDCl 3 ), δ 1.49 (s, 9H, CH 3 ), 7.39 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 7.64 (dd, 3 J HH = 7.5 Hz, 4 J HF = 5.0 Hz, 1H, Ar-H), 9.80 (brs, 1H, NH).

[0123] Preparation of the compounds of the R3 series in Example 14

[0124]

[0125] General synthetic procedure for compound R3: (1) 1.0 mmol 1.0 mL SOCl 2 , the reaction mixture was stirred at room temperature for 1 h and at 65 °C for 1 h. 1 mL of CHCl 3 was added, and the solvent was removed using a rotary evaporator. In the solvent collection flask, NaHCO 3 was added to absorb the acid gas, and a pale yellow solid was obtained. (2) K 2 CO 3 was dissolved in water to obtain a 7.25 M solution. 4 equivalents, 0.2 mL, were taken. PEG400 was dissolved in water (1:9), and 2 mL was taken. 4 equivalents of NaBH 4 solid was suspended in 2 mL of CH 2 Cl 2 , 0.2 mL of K 2 CO 3 and 2 mL of PEG400 were added, and the mixture was stirred to obtain a mixed solution. (3) The acyl chloride (pale yellow solid) synthesized in step (1) above was dissolved in 5 mL of CH 2 Cl 2 , and it was added dropwise to the mixed solution prepared in step (2). The reaction was stirred at room temperature for 1 h or until the reaction was complete. (4) The reaction mixture was separated between ethyl acetate and saturated brine. The organic solvent phase was dried over magnesium sulfate. The solvent was evaporated to dryness, and the crude product was separated by silica gel column chromatography.

[0126] Compound R3, yield 66% 1 H NMR (400 MHz; CDCl 3 ), δ 4.62 (s, 2H, CH 2 O), 5.60 (brs, 1H, OH), 7.21 (d,3 J HH = 7.5 Hz, 1H, Ar-H), 7.32 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 7.53 (s, 1H, Ar-H), 7.95 (s, 1H, Ar-H).

[0127] Preparation of Compound R5 in Example 15

[0128]

[0129] General synthetic procedure for Compound R5: 1.0 mmol 1.0 mL SOCl 2 , the reaction mixture was stirred at room temperature for 1 h, stirred at 65 °C for 1 h, 1 mL of CHCl 3 was added, the solvent was removed with a rotary evaporator, in the solvent collection flask, NaHCO 3 was added to absorb the acid gas, and a pale yellow solid was obtained. 5 mL of concentrated ammonia water (28%) was added. The reaction was stirred at room temperature for 1 h or until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine. The organic solvent phase was dried over magnesium sulfate. The solvent was evaporated to dryness, and the crude product was separated by silica gel column chromatography.

[0130] Compound R5, yield 87%, 1 H NMR (400 MHz; CDCl 3 ), δ 9.10 (s, 1H, Ar-H), 8.81 (s, 1H, Ar-H), 8.41 (s, 1H, Ar-H), 8.16 (brs, 2H, NH 2 ).

[0131] Preparation of Compound R6 Series in Example 16

[0132]

[0133] General synthetic procedure for Compound R6: (1) 1.0 mmol 1.0 mL SOCl 2 , the reaction mixture was stirred at room temperature for 1 h, stirred at 65 °C for 1 h, 1 mL of CHCl 3 was added, the solvent was removed with a rotary evaporator, in the solvent collection flask, NaHCO 3 was added to absorb the acid gas, and a pale yellow solid was obtained. (2) K 2 CO 3 was dissolved in water to obtain a 7.25 M solution, 4 equivalents, 0.2 mL were taken. PEG400 was dissolved in water (1:9), 2 mL were taken. 4 equivalents of NaBH 4 solid was suspended in 2 mL of CH2 Cl 2 , add 0.2 mL of K 2 CO 3 , 2 mL of PEG400, stir to obtain a mixed solution. (3) The acyl chloride (pale yellow solid) synthesized in the above step (1) is dissolved in 5 mL of CH 2 Cl 2 , and added dropwise to the mixed solution prepared in step (2). The reaction is stirred at room temperature for 1 h or until the reaction is complete. (4) The reaction mixture is separated between ethyl acetate and saturated brine. The organic solvent phase is dried over magnesium sulfate. The solvent is evaporated, and the crude product is separated by silica gel column chromatography.

[0134] Compound R6, yield 76%, 1 H NMR (400 MHz; CDCl 3 ), δ 9.09 (s, 1H, Ar-H), 8.60 (s, 1H, Ar-H), 7.75 (s, 1H, Ar-H), 5.35 (brs, 1H, OH), 5.10 (brs, 2H, CH 2 ).

[0135] Preparation of Compound R4 in Example 17

[0136]

[0137] General synthetic procedure for compound R4: 1.0 mmol 2eq IC 2 H 4 OH, 3eq Cs 2 CO 3 , and the reaction mixture is stirred at 65 °C for 12 h. The reaction mixture is separated between ethyl acetate and saturated brine. The organic solvent phase is dried over magnesium sulfate. The solvent is evaporated, and the crude product is separated by silica gel column chromatography.

[0138] Compound R4, yield 66%, 1 H NMR (400 MHz; CDCl 3 ), δ 3.72 (t, 3 J HH = 7.0 Hz, 2H, CH 2 O), 4.31 (t, 3 J HH = 7.0 Hz, 2H, CH 2 O), 4.80 (brs, 1H, OH), 6.86 (s, 1H, Ar-H), 6.94 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 7.55 (d, 3 J HH= 7.5 Hz, 1H, Ar-H), 7.95 (s, 1H, Ar-H).

[0139] Preparation of Compound E3 Series in Example 18

[0140]

[0141] General synthesis procedure of Compound E3: 1.0 mmol 1 eq Pd(OAc) 2 (0.03 eq), Cu(OAc) 2 (0.2 eq), PPh 3 (0.5 eq) and potassium carbonate (2.0 eq) were added to toluene (15 mL). The mixture was evacuated and replaced with nitrogen three times, then heated to 100 °C and reacted overnight. The disappearance of the raw materials was monitored by TLC (PE:EA = 2:1). Heating was stopped and the mixture was cooled to room temperature. Water and EA were added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and the crude product was triturated with a small amount of methanol, filtered to obtain a yellow solid (600 mg). The yellow solid was added to a mixture of methanol (7 mL) and ethyl acetate (9 mL), heated to reflux, dissolved and then cooled for crystallization. After filtration and drying, Compound E3 (350 mg, purity: 90%) was obtained.

[0142] Compound E3, yield 56%, 1 H NMR (400 MHz; CDCl 3 ), δ 1.49 (s, 9H, CH 3 ), 4.56 (s, 2H, CH 2 O), 5.60 (brs, 1H, OH), 7.22 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 7.29 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 7.53 (s, 1H, Ar-H), 8.18 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 7.65 (dd, 3 J HH = 7.5 Hz, 4 J HF = 5.0 Hz, 1H, Ar-H), 9.80 (brs, 1H, NH).

[0143] Preparation of Compound E4 in Example 19

[0144]

[0145] General synthesis procedure of compound E4: 1.0 mmol 1eq Pd(OAc) 2 (0.03eq), Cu(OAc) 2 (0.2eq), PPh 3 (0.5eq) and potassium carbonate (2.0eq) were added to toluene (15 mL). The mixture was evacuated and purged with nitrogen three times, then heated to 100 °C and reacted overnight. The disappearance of the starting materials was monitored by TLC (PE:EA = 2:1). Heating was stopped and the mixture was cooled to room temperature. Water and EA were added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and the crude product was triturated with a small amount of methanol, filtered to obtain a yellow solid (600 mg). The yellow solid was added to a mixture of methanol (7 mL) and ethyl acetate (9 mL), heated to reflux, dissolved, and then cooled to crystallize. The crystals were filtered and dried to obtain compound E4 (350 mg, purity 90%).

[0146] Compound E4, yield 47%, 1 H NMR (400 MHz; CDCl 3 ), δ 1.45 (s, 9H, CH 3 ), 3.67 (t, 3 J HH = 7.5 Hz, 2H, CH 2 ), 4.31 (t, 3 J HH = 7.5 Hz, 2H, CH 2 ), 4.80 (brs, 1H, OH), 6.86 (s, 1H, ArH), 6.95 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 7.59 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 8.17 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 8.60 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 9.72 (brs, 1H, NH).

[0147] Preparation of compound E5 in Example 20

[0148]

[0149] General synthesis procedure of compound E5: 1.0 mmol 1eq Pd(OAc) 2 (0.03eq), Cu(OAc)2 (0.2 eq), PPh 3 (0.5 eq) and potassium carbonate (2.0 eq) were added to toluene (15 mL). The mixture was evacuated and replaced with nitrogen three times, then heated to 100 °C and reacted overnight. The disappearance of the starting materials was monitored by TLC (PE:EA = 2:1). Heating was stopped and the mixture was cooled to room temperature. Water and EA were added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and the crude product was triturated with a small amount of methanol and filtered to obtain a yellow solid (600 mg). The yellow solid was added to a mixture of methanol (7 mL) and ethyl acetate (9 mL), heated to reflux, dissolved, and then cooled to crystallize. The crystals were filtered and dried to obtain compound E5 (350 mg, purity 90%).

[0150] Compound E5, yield 56%, 1 H NMR (400 MHz; CDCl 3 ), δ 1.44 (s, 9H, CH 3 ), 8.15 (m, 3H, NH 2 + ArH), 8.37 (s, 1H, Ar-H), 8.66 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 8.87 (s, 1H, Ar-H), 9.80 (brs, 1H, NH).

[0151] Preparation of Compound E6 in Example 21

[0152]

[0153] General synthetic procedure for compound E6: 1.0 mmol 1 eq Pd(OAc) 2 (0.03 eq), Cu(OAc) 2 (0.2 eq), PPh 3 (0.5 eq) and potassium carbonate (2.0 eq) were added to toluene (15 mL). The mixture was evacuated and replaced with nitrogen three times, then heated to 100 °C and reacted overnight. The disappearance of the starting materials was monitored by TLC (PE:EA = 2:1). Heating was stopped and the mixture was cooled to room temperature. Water and EA were added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and the crude product was triturated with a small amount of methanol and filtered to obtain a yellow solid (600 mg). The yellow solid was added to a mixture of methanol (7 mL) and ethyl acetate (9 mL), heated to reflux, dissolved, and then cooled to crystallize. The crystals were filtered and dried to obtain compound E6 (350 mg, purity 90%).

[0154] Compound E6, yield 56%, 1 H NMR (400 MHz; CDCl 3), δ 1.43 (s, 9H, CH 3 ), 5.17 (s, 2H, CH 2 O), 5.40 (brs, 1H, OH), 7.73 (s, 1H, Ar-H), 8.14 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 8.69 (m, 2H, Ar-H), 9.70 (brs, 1H, NH).

[0155] Preparation of Compound F3 in Example 22

[0156]

[0157] General synthetic procedure for Compound F3: 1.0 mmol 1 eq Pd(OAc) 2 (0.03 eq), Cu(OAc) 2 (0.2 eq), PPh 3 (0.5 eq) and potassium carbonate (2.0 eq) were added to toluene (15 mL). The mixture was evacuated and replaced with nitrogen three times, then heated to 100 °C and reacted overnight. The disappearance of the starting materials was monitored by TLC (PE:EA = 2:1). Heating was stopped and the mixture was cooled to room temperature. Water and EA were added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was triturated with a small amount of methanol and filtered to obtain a yellow solid (600 mg). The yellow solid was added to a mixture of methanol (7 mL) and ethyl acetate (9 mL), heated to reflux, dissolved, and then cooled for crystallization. Filtration and drying gave Compound F3 (350 mg, purity 90%).

[0158] Compound F3, yield 56%, 1 H NMR (400 MHz; CDCl 3 ), δ 1.45 (s, 9H, CH 3 ), 4.64 (s, 2H, CH 2 O), 5.30 (brs, 1H, OH), 7.22 (m, 2H, Ar-H), 7.54 (s, 1H, Ar-H), 8.76 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 8.94 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 9.70 (brs, 1H, NH).

[0159] Preparation of Compound F4 in Example 23

[0160]

[0161] General synthesis procedure of compound F4: 1.0 mmol 1eq Pd(OAc) 2 (0.03eq), Cu(OAc) 2 (0.2eq), PPh 3 (0.5eq) and potassium carbonate (2.0eq) were added to toluene (15 mL). The mixture was evacuated and purged with nitrogen three times, then heated to 100 °C and reacted overnight. The disappearance of the starting materials was monitored by TLC (PE:EA = 2:1). Heating was stopped and the mixture was cooled to room temperature. Water and EA were added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and the crude product was triturated with a small amount of methanol, filtered to obtain a yellow solid (600 mg). The yellow solid was added to a mixture of methanol (7 mL) and ethyl acetate (9 mL), heated to reflux, dissolved, and then cooled to crystallize. After filtration and drying, compound F4 (350 mg, purity 90%) was obtained.

[0162] Compound F4, yield 56%, 1 H NMR (400 MHz; CDCl 3 ), δ 1.46 (s, 9H, CH 3 ), 3.65 (t, 3 J HH = 7.5 Hz, 2H, CH 2 ), 4.36 (t, 3 J HH = 7.5 Hz, 2H, CH 2 ), 4.90 (brs, 1H, OH), 6.81 (s, 1H, ArH), 6.91 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 7.57 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 8.77 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 8.89 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 9.76 (brs, 1H, NH).

[0163] Preparation of compound F5 in Example 24

[0164]

[0165] General synthesis procedure of compound F5: 1.0 mmol 1eq Pd(OAc) 2(0.03 eq), Cu(OAc) 2 (0.2 eq), PPh 3 (0.5 eq) and potassium carbonate (2.0 eq) were added to toluene (15 mL). The mixture was evacuated and purged with nitrogen three times, then heated to 100 °C and reacted overnight. The disappearance of the starting materials was monitored by TLC (PE:EA = 2:1). Heating was stopped and the mixture was cooled to room temperature. Water and EA were added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was triturated with a small amount of methanol and filtered to obtain a yellow solid (600 mg). The yellow solid was added to a mixture of methanol (7 mL) and ethyl acetate (9 mL), heated to reflux, dissolved, and then cooled to crystallize. The crystals were filtered and dried to obtain Compound F5 (350 mg, purity 90%).

[0166] Compound F5, yield 56%, 1 H NMR (400 MHz; CDCl 3 ), δ 1.47 (s, 9H, CH 3 ), 8.20 (brs, 2H, NH 2 ), 8.44 (s, 1H, Ar-H), 8.76 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 8.88 (s, 1H, Ar-H), 8.96 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 9.70 (brs, 1H, NH).

[0167] Preparation of Compound F6 Series in Example 25

[0168]

[0169] General synthetic procedure for Compound F6: 1.0 mmol 1 eq Pd(OAc) 2 (0.03 eq), Cu(OAc) 2 (0.2 eq), PPh 3 (0.5 eq) and potassium carbonate (2.0 eq) were added to toluene (15 mL). The mixture was evacuated and purged with nitrogen three times, then heated to 100 °C and reacted overnight. The disappearance of the starting materials was monitored by TLC (PE:EA = 2:1). Heating was stopped and the mixture was cooled to room temperature. Water and EA were added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was triturated with a small amount of methanol and filtered to obtain a yellow solid (600 mg). The yellow solid was added to a mixture of methanol (7 mL) and ethyl acetate (9 mL), heated to reflux, dissolved, and then cooled to crystallize. The crystals were filtered and dried to obtain Compound F6 (350 mg, purity 90%).

[0170] Compound F6, yield 56% 1 H NMR (400 MHz; CDCl 3 ), δ 1.47 (s, 9H, CH 3 ), 5.11 (s, 2H, CH 2 O), 5.36 (brs, 1H, OH), 7.78 (s, 1H, Ar-H), 8.68 (s, 1H, Ar-H), 8.74 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 8.96 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 9.80 (brs, 1H, NH).

[0171] Preparation of Compound G3 in Example 26

[0172]

[0173] General synthetic procedure for Compound G3: 1.0 mmol was added to trifluoroacetic acid (5 mL), and the reaction was carried out overnight at room temperature. The disappearance of the starting material was monitored by TLC (PE:EA = 2:1). The solvent was evaporated to dryness, and the yellow solid obtained was Compound G3.

[0174] Compound G3, yield 66% 1 H NMR (400 MHz; CDCl 3 ), δ 4.62 (s, 2H, CH 2 O), 5.23 (brs, 1H, OH), 5.83 (brs, 2H, NH 2 ), 7.22 - 7.26 (m, 2H, Ar-H), 7.58 (s, 1H, Ar-H), 7.96 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 8.74 (d, 3 J HH = 7.5 Hz, 1H, Ar-H).

[0175] Preparation of Compound G4 in Example 27

[0176]

[0177] 1.0 mmol was added to trifluoroacetic acid (5 mL), and the reaction was carried out overnight at room temperature. The disappearance of the starting material was monitored by TLC (PE:EA = 2:1). The solution was evaporated to dryness, and the yellow solid obtained was Compound G4.

[0178] Compound G4, yield 44%1 H NMR (400 MHz; CDCl 3 ), δ 3.67 (t, 3 J HH = 7.5 Hz, 2H, CH 2 ), 4.30 (t, 3 J HH = 7.5 Hz, 2H, CH 2 ), 4.80 (brs, 1H, OH), 5.76 (brs, 2H, NH 2 ), 6.85 (s, 1H, ArH), 6.94 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 7.61 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 7.95 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 8.74 (d, 3 J HH = 7.5 Hz, 1H, Ar-H).

[0179] Preparation of Compound G5 in Example 28

[0180]

[0181] General synthetic procedure for Compound G5: 1.0 mmol was added to trifluoroacetic acid (5 mL), and the reaction was carried out overnight at room temperature. The disappearance of the starting material was monitored by TLC (PE:EA = 2:1). After dissolution and evaporation to dryness, a yellow solid was obtained, which was Compound G5.

[0182] Compound G5, yield 56%, 1 H NMR (400 MHz; CDCl 3 ), δ 5.82 (brs, 2H, NH 2 ), 7.89 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 8.14 (brs, 2H, NH 2 ), 8.41 (s, 1H, Ar-H), 8.74 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 8.85 (s, 1H, Ar-H).

[0183] Preparation of Compound G6 in Example 29

[0184]

[0185] General synthetic procedure for Compound G6: 1.0 mmol It was added to trifluoroacetic acid (5 mL), and the reaction was carried out overnight at room temperature. The disappearance of the starting material was monitored by TLC (PE:EA = 2:1). After dissolution and evaporation to dryness, a yellow solid was obtained, which was Compound G6.

[0186] Compound G6, yield 71%, 1 H NMR (400 MHz; CDCl 3 ), δ 5.10 (s, 2H, CH 2 O), 5.42 (brs, 1H, OH), 5.80 (brs, 2H, NH 2 ), 7.71 (s, 1H, Ar-H), 7.94 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 8.62 (s, 1H, Ar-H), 8.71 (d, 3 J HH = 7.5 Hz, 1H, Ar-H).

[0187] Preparation of Compound M3 in Example 30

[0188]

[0189] General synthetic procedure for Compound M3: 1.0 mmol It was added to trifluoroacetic acid (5 mL), and the reaction was carried out overnight at room temperature. The disappearance of the starting material was monitored by TLC (PE:EA = 2:1). After dissolution and evaporation to dryness, a yellow solid was obtained, which was Compound M3.

[0190] Compound M3, yield 66%, 1 H NMR (400 MHz; CDCl 3 ), δ 4.60 (s, 2H, CH 2 O), 5.20 (brs, 1H, OH), 5.81 (brs, 2H, NH 2 ), 7.22 - 7.26 (m, 2H, Ar-H), 7.52 (s, 1H, Ar-H), 7.64 (dd, 3 J HH = 7.5 Hz, 3 J HH = 5.0 Hz, 1H, Ar-H), 8.14 (d, 3 J HH = 7.5 Hz, 1H, Ar-H).

[0191] Preparation of Compound M4 in Example 31

[0192]

[0193] 1.0 mmol It was added to trifluoroacetic acid (5 mL), and the reaction was carried out overnight at room temperature. The disappearance of the raw materials was monitored by TLC (PE:EA = 2:1). It was dissolved and dried by evaporation to obtain a yellow solid, which was compound M4.

[0194] Compound M4, yield 44%, 1 H NMR (400 MHz; CDCl 3 ), δ 3.65 (t, 3 J HH = 7.5 Hz, 2H, CH 2 ), 4.32 (t, 3 J HH = 7.5 Hz, 2H, CH 2 ), 4.76 (brs, 1H, OH), 5.86 (brs, 2H, NH 2 ), 6.89 (s, 1H, ArH), 6.97 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 7.60 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 7.66 (dd, 3 J HH = 7.5 Hz, 3 J HH = 5.0 Hz, 1H, Ar-H), 8.10 (d, 3 J HH = 7.5 Hz, 1H, Ar-H).

[0195] Preparation of Compound M5 in Example 32

[0196]

[0197] General synthetic procedure for Compound M5: 1.0 mmol It was added to trifluoroacetic acid (5 mL), and the reaction was carried out overnight at room temperature. The disappearance of the raw materials was monitored by TLC (PE:EA = 2:1). It was dissolved and dried by evaporation to obtain a yellow solid, which was compound M5.

[0198] Compound M5, yield 56%, 1 H NMR (400 MHz; CDCl 3 ), δ 5.75 (brs, 2H, NH 2 ), 7.69 (dd, 3 J HH = 7.5 Hz, 3 J HF= 5.0 Hz, 1H, Ar-H), 8.14 - 8.18 (m, 3H, NH 2 + ArH), 8.44 (s, 1H, Ar-H), 8.82 (s, 1H, Ar-H).

[0199] Preparation of Compound M6 Series in Example 33

[0200]

[0201] General synthetic procedure for Compound M6: 1.0 mmol was added to trifluoroacetic acid (5 mL), and the reaction was carried out overnight at room temperature. The disappearance of the starting material was monitored by TLC (PE:EA = 2:1). After dissolution and evaporation to dryness, a yellow solid was obtained, which was Compound M6.

[0202] Compound M6, yield 71%, 1 H NMR (400 MHz; CDCl 3 ), δ 5.15 (s, 2H, CH 2 O), 5.40 (brs, 1H, OH), 5.85 (brs, 2H, NH 2 ), 7.69 - 7.76 (m, 2H, Ar-H), 8.24 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 8.60 (s, 1H, Ar-H).

[0203] Preparation of Compound P3 in Example 34

[0204]

[0205] General synthetic procedure for Compound P3: 1.0 mmol 3.0 equivalents of 2,5 - dimethoxytetrahydrofuran, 2.0 mL of HOAc, and the reaction mixture was heated to 100 °C and stirred until the reaction was complete. After filtration of the reaction mixture, it was directly separated by HPLC. Phase A was 0.025% aqueous TFA solution, Phase B was 0.025% TFA acetonitrile solution, 10 - 30% B, 0 - 30 min, and the solvent was evaporated to dryness.

[0206] Compound P3, yield 93%, 1 H NMR (400 MHz; CDCl 3 ), δ 4.56 (s, 2H, CH 2 ), 5.25 (brs, 1H.OH), 6.30 (d, 3 J HH= 7.6 Hz, 2H, Ar-H), 7.22 - 7.28 (m, 4H, Ar-H), 7.53 (s, 1H, Ar-H), 8.80 (d, 3 J HH = 7.6 Hz, 1H, Ar-H), 9.07 (d, 3 J HH = 7.6 Hz, 1H, Ar-H).

[0207] Preparation of Compound P4 in Example 35

[0208]

[0209] General synthetic procedure for Compound P4: 1.0 mmol 3.0 equivalents of 2,5 - dimethoxytetrahydrofuran, 2.0 mL of HOAc, the reaction mixture was heated to 100 °C and stirred until the reaction was complete. After filtration, the reaction mixture was directly separated by HPLC. Phase A was 0.025% aqueous TFA solution, Phase B was 0.025% TFA acetonitrile solution, 10 - 30% B, 0 - 30 min, and the solvent was dried by suction.

[0210] Compound P4, yield 93%, 1 H NMR (400 MHz; CDCl 3 ), δ 3.63 (t, 3 J HH = 7.5 Hz, 2H, CH 2 ), 4.37 (t, 3 J HH = 7.5 Hz, 2H, CH 2 ), 4.86 (brs, 1H, OH), 6.36 (m, 2H, Ar-H), 6.95 - 6.86 (m, 2H, ArH), 7.26 (m, 2H, ArH), 7.58 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 8.80 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 9.10 (d, 3 J HH = 7.5 Hz, 1H, Ar-H).

[0211] Preparation of Compound P5 in Example 36

[0212]

[0213] General synthetic procedure for Compound P5: 1.0 mmol 3.0 equivalents of 2,5-dimethoxytetrahydrofuran, 2.0 mL of HOAc, the reaction mixture was heated to 100 °C and stirred until the reaction was complete. After filtration, the reaction mixture was separated directly by HPLC. Phase A was an aqueous solution of 0.025% TFA, and phase B was an acetonitrile solution of 0.025% TFA. 10 - 30% B, 0 - 30 min, and the solvent was dried up.

[0214] Compound P5, yield 93%, 1 H NMR (400 MHz; CDCl 3 ), δ 6.33 (m, 2H, ArH), 7.26 (m, 2H, ArH), 8.25 (brs, 2H, NH 2 ), 8.44 (s, 1H, Ar - H), 8.85 - 8.95 (m, 2H, ArH), 9.14 (d, 3 J HH = 7.5 Hz, 1H, Ar - H).

[0215] Preparation of Compound P6 in Example 37

[0216]

[0217] General synthetic procedure for Compound P6: 1.0 mmol 3.0 equivalents of 2,5-dimethoxytetrahydrofuran, 2.0 mL of HOAc, the reaction mixture was heated to 100 °C and stirred until the reaction was complete. After filtration, the reaction mixture was separated directly by HPLC. Phase A was an aqueous solution of 0.025% TFA, and phase B was an acetonitrile solution of 0.02% TA. 10 - 30% B, 0 - 30 min, and the solvent was dried up.

[0218] Compound P6, yield 93%, 1 H NMR (400 MHz; CDCl 3 ), δ 5.08 (s, 2H, CH 2 ), 5.35 (brs, 1H, OH), 6.33 (m, 2H, ArH), 7.26 (m, 2H, ArH), 7.70 (s, 1H, Ar - H), 8.60 (s, 1H, Ar - H), 8.90 (d, 3 J HH = 7.5 Hz, 1H, Ar - H), 9.14 (d, 3 J HH = 7.5 Hz, 1H, Ar - H).

[0219] Preparation of Compound P31 in Example 38

[0220]

[0221] General synthesis procedure of compound P31: 1.0 mmol 3.0 equivalents of 3,4-dihydropyran, 0.1 equivalent of TsOH, the reaction mixture was heated to 100 °C and stirred until the reaction was complete. After filtration, the reaction mixture was directly separated by HPLC. Phase A was 0.025% aqueous TFA solution, Phase B was 0.02% TA acetonitrile solution, 10 - 30% B, 0 - 30 min, and the solvent was dried up.

[0222] Compound P31, yield 76%, 1 H NMR (400 MHz; CDCl 3 ), δ 1.50 - 1.80 (m, 6H, CH 2 ), 3.61 - 3.75 (m, 2H, CH 2 O), 4.58 - 4.64 (m, 3H, CHO), 6.30 (m, 2H, Ar - H), 7.20 - 7.31 (m, 4H, Ar - H), 7.52 (s, 1H, Ar - H), 8.85 (d, 3 J HH = 8.6 Hz, 1H, Ar - H), 9.06 (d, 3 J HH = 8.6 Hz, 1H, Ar - H).

[0223] Preparation of compound P41 in Example 39

[0224]

[0225] General synthesis procedure of compound P41: 1.0 mmol 3.0 equivalents of 3,4-dihydropyran, 0.1 equivalent of TsOH, the reaction mixture was heated to 100 °C and stirred until the reaction was complete. After filtration, the reaction mixture was directly separated by HPLC. Phase A was 0.025% aqueous TFA solution, Phase B was 0.02% TA acetonitrile solution, 10 - 30% B, 0 - 30 min, and the solvent was dried up.

[0226] Compound P41, yield 76%, 1 H NMR (400 MHz; CDCl 3 ), δ 1.55 - 1.84 (m, 6H, CH 2 ), 3.62 - 3.80 (m, 2H, CH 2 O), 4.10 (t, 3 J HH = 7.0 Hz, 2H, CH 2 O), 4.58 (t, 3 J HH= 7.0 Hz, 1H, CHO 2 ), 6.31 (m, 2H, Ar-H), 6.85 (s, 1H, Ar-H), 6.94 (d, 3 J HH = 8.6 Hz, 1H, Ar-H), 7.24 (m, 2H, Ar-H), 7.57 (d, 3 J HH = 8.6 Hz, 1H, Ar-H), 8.82 (d, 3 J HH = 8.6 Hz, 1H, Ar-H), 9.05 (d, 3 J HH = 8.6 Hz, 1H, Ar-H).

[0227] Preparation of Compound P61 in Example 40

[0228]

[0229] General synthetic procedure for Compound P61: 1.0 mmol 3.0 equivalents of 3,4-dihydropyran, 0.1 equivalent of TsOH, the reaction mixture was heated to 100 °C and stirred until the reaction was complete. After filtration, the reaction mixture was directly separated by HPLC. Phase A was an aqueous solution of 0.025% TFA, and Phase B was an acetonitrile solution of 0.02% TA. 10 - 30% B, 0 - 30 min, and the solvent was dried by suction.

[0230] Compound P61, yield 76%, 1 H NMR (400 MHz; CDCl 3 ), δ 1.51 - 1.82 (m, 6H, CH 2 ), 3.63 - 3.75 (m, 2H, CH 2 O), 4.57 (t, 3 J HH = 7.0 Hz, 1H, CHO 2 ), 4.93 (s, 2H, CH 2 O), 6.30 (m, 2H, Ar-H), 7.24 (m, 2H, Ar-H), 7.71 (s, 1H, Ar-H), 8.61 (s, 1H, Ar-H), 8.87 (d, 3 J HH = 8.6 Hz, 1H, Ar-H), 9.09 (d, 3 J HH = 8.6 Hz, 1H, Ar-H).

[0231] Preparation of Compound III in Example 41

[0232]

[0233] General synthetic procedure for Compound III: 1.0 mmol 3.0 equivalents of 2,5 - dimethoxytetrahydrofuran, 2.0 mL of HOAc, the reaction mixture was heated to 100 °C and stirred until the reaction was complete. After filtration, the reaction mixture was directly separated by HPLC. Phase A was 0.025% aqueous TFA solution, Phase B was 0.025% TFA acetonitrile solution, 10 - 30% B, 0 - 30 min, and the solvent was dried up.

[0234] Compound III, yield 93%, 1 H NMR (400 MHz; CDCl 3 ), δ 4.60 (s, 2H, CH 2 ), 5.35 (brs, 1H.OH), 6.32 (m, 2H, Ar - H), 7.22 - 7.28 (m, 4H, Ar - H), 7.55 (s, 1H, Ar - H), 8.28 (d, 3 J HH = 7.6 Hz, 1H, Ar - H), 8.70 (d, 3 J HH = 7.6 Hz, 1H, Ar - H).

[0235] Preparation of Compound IV series in Example 42

[0236]

[0237] General synthetic procedure for Compound IV: 1.0 mmol 3.0 equivalents of 2,5 - dimethoxytetrahydrofuran, 2.0 mL of HOAc, the reaction mixture was heated to 100 °C and stirred until the reaction was complete. After filtration, the reaction mixture was directly separated by HPLC. Phase A was 0.025% aqueous TFA solution, Phase B was 0.025% TFA acetonitrile solution, 10 - 30% B, 0 - 30 min, and the solvent was dried up.

[0238] Compound IV, yield 93%, 1 H NMR (400 MHz; CDCl 3 ), δ 3.68 (t, 3 J HH = 7.5 Hz, 2H, CH 2 ), 4.39 (t, 3 J HH = 7.5 Hz, 2H, CH 2), 4.76 (brs, 1H, OH), 6.35 (m, 2H, Ar-H), 6.97 - 6.88 (m, 2H, ArH), 7.24 (m, 2H, ArH), 7.52 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 8.24 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 8.70 (dd, 3 J HH = 7.5 Hz, 4 J HF = 5.0 Hz, 1H, Ar-H).

[0239] Preparation of Compound V in Example 43

[0240]

[0241] General synthetic procedure for Compound V: 1.0 mmol 3.0 equivalents of 2,5 - dimethoxytetrahydrofuran, 2.0 mL of HOAc, the reaction mixture was heated to 10 °C and stirred until the reaction was complete. After filtration, the reaction mixture was directly separated by HPLC. Phase A was 0.025% aqueous TFA solution, Phase B was 0.02% TA acetonitrile solution, 10 - 30% B, 0 - 30 min, and the solvent was dried up.

[0242] Compound V, yield 93%, 1 H NMR (400 MHz; CDCl 3 ), δ 6.31 (m, 2H, ArH), 7.29 (m, 2H, ArH), 8.18 - 8.25 (m, 3H, NH 2 + ArH), 8.40 (s, 1H, Ar-H), 8.75 (m, 1H, ArH), 8.94 (s, 1H, Ar-H).

[0243] Preparation of Compound VI in Example 44

[0244]

[0245] General synthetic procedure for Compound VI: 1.0 mmol 3.0 equivalents of 2,5 - dimethoxytetrahydrofuran, 2.0 mL of HOAc, the reaction mixture was heated to 100 °C and stirred until the reaction was complete. After filtration, the reaction mixture was directly separated by HPLC. Phase A was 0.025% aqueous TFA solution, Phase B was 0.02% TA acetonitrile solution, 10 - 30% B, 0 - 30 min, and the solvent was dried up.

[0246] Compound VI, yield 93% 1 H NMR (400 MHz; CDCl 3 ), δ 5.06 (s, 2H, CH 2 ), 5.38 (brs, 1H, OH), 6.36 (m, 2H, ArH), 7.28 (m, 2H, ArH), 7.79 (s, 1H, Ar-H), 8.23 (d, 3 J HH = 7.5 Hz, 1H, Ar-H), 8.69 (s, 1H, Ar-H), 8.78 (d, 3 J HH = 7.5 Hz, 1H, Ar-H).

[0247] Example 45 Radiochemical Labeling Experiment

[0248] General synthesis procedure: 2.0 mg of precursors P1, P21, P31, P41, P5, P61, > 3 eq K 2 CO 3 + K222 reagent (the molar amount of potassium carbonate is less than half of K222), 0.5 mL of DMF, phosphazene organic base (Phosphazene base P1-t-Bu-tris, phosphazene ligand P1-tert-butyl tris(methylene)), 1 - 30 μL), the reaction mixture is heated to 90 - 150 °C and reacted for 10 - 30 min. Separated by HPLC and used after making into a radioactive reagent. Radiochemical yield RCY: 10 - 60%.

[0249] The purity and specific activity of the radioactive reagent are determined by the ultraviolet spectrum of conventional radioactive HPLC in the art. The specific activity is determined by measuring the radioactive amount injected into the HPLC reagent, and the molar amount of the reagent is determined by the standard curve established from the absorption peak of the non-radioactive standard reagent. The specific activity is calculated by the ratio of the radioactive amount to the molar amount of the reagent. The range of the specific activity is 1 - 3 Ci / μmol.

[0250] Effect Example 1

[0251] In Vitro Binding Experiment

[0252] Human AD brain tissue homogenate in 1:500 PBS, 800 μL is used in each test tube. The concentration of [3H]BTA-1 (deuterium-labeled BTA-1) is diluted from the stock solution of 1 mCi / mL to 1 μCi / 100 μL with ethanol. Further diluted to 2.7×10 -2 μCi / 100 μL, and 100 μL is used in each tube. "Cold" 6-OH-BTA-1 or other compounds to be tested (such as the compound shown in Formula A of the present invention) are dissolved in dimethyl sulfoxide to obtain 1×10 -3M solution, prepared with dimethyl sulfoxide at a concentration of 1×10 -4 to 1×10 -10 M solution, and 10 μL of each solution was used per tube. After assembling the above three solutions, vortex the test tubes and react at 37 °C for 2 hours. Separate using a cell collector and wash the filter paper with PBS containing 10% ethanol. Place the filter paper into a 4 mL plastic bottle and add 2 mL of scintillation fluid. Count the samples. Analyze the data using GraphPad to obtain the binding constant.

[0253] For the in vitro binding experiment, tritium-labeled 6-OH-BTA-1 was used as the labeling reagent, and competitive binding assays were performed using non-radioactive 6-OH-BTA-1 and the compound shown in Formula A of the present invention, respectively, to determine the binding constant Ki.

[0254] The binding constants Ki of Compounds I-VI of the present invention are listed in Table 1:

[0255] Table 1. Binding constant Ki

[0256]

[0257]

[0258] C logD 7.4 value is obtained by taking the logarithm of the solubility value of the compound in n-butanol / the solubility value of the compound in water, which represents the hydrophilic-lipophilic property of the compound and further reflects the half-life of the compound. In the developer, the smaller the clogD 7.4 value, the shorter the half-life, the more beneficial it is to eliminate the influence of the background during development, and the better the development effect. From the results in Table 1, it can be seen that the clogD of the compounds in this application 7.4 are all below 3.2, significantly better than the comparative compound [3H]BTA-1, with a better development effect, and thus are more suitable for preparing positron emission tomography agents. From the binding constant Ki values of the compounds in Table 1, it can be seen that the Ki values of the compounds in this application are all below 7.8 nM, significantly better than the comparative compound [3H]BTA-1.

[0259] Effect Example 2

[0260] Autoradiography study results of brain tissue sections at different positions of human AD patients, and the results are shown in Figure 1。In the figure, the first row shows the tissue sections of AD patients stained with the compound shown by radioactive formula A. The upper left figure shows autoradiography of the tissue sections of AD patients' brains in the presence of 1 μM non-radioactive 6-OH-BTA-1 (PIB) with the non-radioactive 6-OH-BTA-1 pre-occupying the position simultaneously. In the second row, the lower left figure shows a non-AD patient and the lower right figure shows an AD patient, both stained with the compound shown by radioactive formula A without using non-radioactive 6-OH-BTA-1 to occupy the position, showing autoradiography of the tissue sections without an occupying agent.

[0261]

[0262]

[0263] It can be seen from Figure 1 above that the compound shown by the radioactive labeled molecular formula A clearly shows the spots of amyloid deposition in the cerebral cortex. After pretreatment with 6-OH-BTA-1, the developed spots no longer show up. Therefore, the compound shown by the radioactive labeled formula A has characteristic imaging for amyloid deposition.

[0264] Conclusion

[0265] The present invention describes the synthesis and radioactive labeling of a new class of radioactive labeled compounds. These radioactive labeled compounds show characteristic absorption on the brain sections of AD patients and are good imaging agents, promising to provide sensitive molecular probes for the early diagnosis of Alzheimer's disease.

Claims

1. A compound of formula A or a pharmaceutically acceptable salt thereof, wherein, X 1 is O or S; X 2 is -CH or N; T 1 is -CR 1 or N; T 2 is -CH or N; R 1 is hydrogen, C substituted by hydroxyl 1 -C 6 alkyl, C substituted by hydroxyl 1 -C 6 alkoxy or R 2 is F or 18 F; Each R 3 is independently hydrogen or C 1 -C 6 alkyl group.

2. The compound of formula A or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, the compound of formula A or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (1)R 1 Among them, the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl; (2)R 1 Among them, the C 1 -C 6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, such as ethoxy; and (3)R 3 In, the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

3. The compound of formula A or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R 1 For And / or, each R 3 is independently hydrogen.

4. The compound of formula A or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, the compound of formula A or a pharmaceutically acceptable salt thereof is a compound represented by the following formula A-1, A-2, A-3, A-4 or A-5: Among them, the definition of the said T 1 , T 2 , X 1 , X 2 , R 1 and R 2 is as defined in any one of claims 1-3.

5. The compound of formula A or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, characterized in that, the compound of formula A or a pharmaceutically acceptable salt thereof is any of the following compounds:

6. A compound represented by formula P, formula L or formula M, wherein, The said T 1 and T 2 and X 1 and X 2 and R 1 and R 2 are defined as described in any one of claims 1 - 3; R 4 is C 1 -C 6 alkyl; preferably, the compound represented by formula P, formula L or formula M is any of the following compounds, 7. A method for preparing a compound of formula A, characterized in that, it is any of the following schemes: Scheme 1: It includes the following steps: reacting a substrate with CsF, that's all, the substrate is a compound represented by formula P or a compound represented by formula L; Among them, R 4 is C 1 -C 6 alkyl; the T 1 , T 2 , X 1 , X 2 and R 2 are defined as described in any one of claims 1-3; When T 1 is CR 1 , R 1 is a C 1 -C 6 alkyl substituted by a hydroxyl group, a compound represented by formula L is used as a raw material to prepare a compound represented by formula A; Scheme 2: It includes the following steps: reacting the compound represented by formula M with the compound represented by formula D in the presence of an acid, that's all; Among them, the definition of the said T 1 , T 2 , X 1 , X 2 and R 2 is as defined in any one of claims 1-3.

8. The method for preparing a compound of formula A according to claim 7, characterized in that, the method for preparing the compound of formula A satisfies one or more of the following conditions: (1) In Scheme 1, the reaction is carried out in a solvent, the solvent is a strongly polar aprotic solvent, and the strongly polar aprotic solvent is preferably dichloromethane or DMF, such as DMF; (2) In Scheme 1, the temperature of the reaction is 120-150 °C, such as 120 °C; (3) In Scheme 1, the molar ratio of the substrate to the CsF is 1:(3-5), such as 1:3; (4) In Scheme 1, the mass-volume ratio of the substrate to the solvent is 0.1-0.5 g / mL, such as 0.5 g / mL; (5) In Scheme 2, the acid is an organic acid, such as acetic acid; (6) In Scheme 2, the temperature of the reaction is 100-120 °C, such as 100 °C; (7) In Scheme 2, the molar ratio of the compound represented by formula M to the compound represented by formula D is 1:(3-5), such as 1:3; and (8) In Scheme 2, the molar ratio of the compound represented by formula M to the acid is 1:(2-4), such as 1:

2.

9. A positron emission tomography agent, characterized in that, it comprises the compound of formula A or a pharmaceutically acceptable salt thereof according to any one of claims 1-5.

10. Use of the compound of formula A or a pharmaceutically acceptable salt thereof according to any one of claims 1-5 for preparing a positron emission tomography agent.

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