A tricyclic compound, its intermediate, preparation method and application

Abstract

The present invention provides a tricyclic compound, an intermediate thereof, a preparation method and an application thereof. Specifically, a compound as shown in Formula I or a pharmaceutically acceptable salt thereof is provided; wherein M is O or NH, R 1 、R 2 、R 3 and R 4 One of the '#imgabs0#'s is H, and the other three are H. n is 0, 1, or 2. This compound can bind well to human AD brain tissue, image amyloid proteins, and serve as a positron emission tomography agent for early diagnosis of Alzheimer's disease and tracking drug efficacy. #imgabs1#

Description

Technical Field

[0001] The present invention relates to a tricyclic compound, an intermediate thereof, a preparation method and application. Background Art

[0002] Alzheimer's disease (AD) is the most common cause of dementia, characterized by progressive cognitive loss and increasing behavioral impairment. This progressive, irreversible brain disorder affects millions of people and imposes a devastating health burden worldwide. Over the past two decades, significant progress has been made in deciphering the pathogenesis and developing new treatments. The pathological hallmarks of AD include neuritic plaques of amyloid-β and neurofibrillary tangles of hyperphosphorylated tau. Recent drug development for AD is directed at controlling the production, aggregation, and deposition of amyloid in the brain, as well as accelerating its removal from the brain.

[0003] Non-invasive detection of amyloid deposits in the brain has been used to develop anti-amyloid therapeutics. Direct in vivo imaging of amyloid in AD patients is useful for early diagnosis and the development and evaluation of treatment options. To this end, extensive research and development has been conducted on compounds suitable for in vivo imaging of amyloid deposits in the human brain. Among these compounds are monoclonal antibodies targeting Aβ, but these are not absorbed by the brain. Injection of a conjugate containing an Aβ peptide, putrescine, and gadolinium into transgenic mice overexpressing Aβ amyloid has enabled the visualization of amyloid in the mouse brain on MRI. Amyloid deposits can also be non-invasively imaged and quantified using small molecules that readily enter the brain.

[0004] Imaging amyloid using small molecules is the most successful approach to date. Some of the most promising compounds for amyloid imaging are derivatives of Congo red, thioflavin, stilbene, and FDDNP. Congo red and thioflavin derivatives have been used to stain brain tissue sections from AD patients and transgenic mice. Two compounds currently in human clinical trials as F18 are Florbetapir from Eli Lilly and Company and Flutemetamol from General Electric. Neither of these imaging agents exhibits the dynamic range exhibited by carbon-11-labeled PIB.

[0005] Effective management of AD involves diagnosis, monitoring, treatment and prevention of the disease. Summary of the Invention

[0006] The technical problem to be solved by the present invention is that there are relatively few types of existing imaging agents for amyloid protein imaging. To this end, the present invention provides a tricyclic compound, its intermediate, preparation method and application. The compound can image amyloid protein and can be used as a positron emission tomography agent for early diagnosis of Alzheimer's disease and tracking of drug efficacy.

[0007] The present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof;

[0008]

[0009] Wherein, M is O or NH, R 1 、R 2 、R 3 and R 4 One of the The remaining three are H, and n is 0, 1, or 2.

[0010] In one embodiment, in the compound of Formula I or a pharmaceutically acceptable salt thereof, the compound of Formula I is a compound of Formula Ia or a compound of Formula Ib:

[0011]

[0012] In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof, for

[0013] In one embodiment, in the compound of formula I or a pharmaceutically acceptable salt thereof, the compound of formula I is:

[0014]

[0015] In one embodiment, in the compound of formula I or a pharmaceutically acceptable salt thereof, the compound of formula I is:

[0016]

[0017] The present invention also provides a method for preparing the compound of Formula I or a pharmaceutically acceptable salt thereof, comprising the following steps: reacting the compound of Formula II with CsF in a solvent to obtain the compound of Formula I or a pharmaceutically acceptable salt thereof;

[0018]

[0019] R 5 、R 6 、R7 and R 8 One of the The remaining three are H; S is Ts or does not exist.

[0020] The substitution reaction may be a conventional method and conditions for such a reaction in the art. Preferably, the solvent is a highly polar aprotic solvent, such as dichloromethane or DMF.

[0021] In the present invention, the preparation method of the compound represented by Formula I can be carried out by any of the following reaction routes:

[0022]

[0023] or,

[0024]

[0025] The present invention also provides a compound or a pharmaceutically acceptable salt thereof:

[0026]

[0027] Wherein, the definitions of each group are the same as described above.

[0028] The present invention also provides a use of the compound shown in formula I in preparing a fluorescent color developing agent for in vitro tissue or in a drug for treating a disease caused by hyperphosphorylated amyloid protein aggregation.

[0029] The present invention also provides a use of the compound shown in formula I as a positron emission tomography agent.

[0030] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0031] Unless otherwise specified, all reagents and raw materials used in the present invention are commercially available.

[0032] The positive progress of the present invention is that the compound of the present invention can better bind to human AD brain tissue, image amyloid protein, and can be used as a positron emission tomography agent for early diagnosis of Alzheimer's disease and tracking the efficacy of drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1The first row shows autoradiography of AD patient brain tissue sections using radioactive LL8 staining. The upper left panel also shows autoradiography of AD patient brain tissue sections in the presence of 1 μM non-radioactive 6-OH-BTA-1 (PIB) using pre-positioning agents, using non-radioactive LL8 staining. The lower left panel shows autoradiography of brain tissue sections from a non-AD patient and the lower right panel shows autoradiography of brain tissue sections from an AD patient using radioactive LL8 staining and without pre-positioning agents, using non-radioactive 6-OH-BTA-1. DETAILED DESCRIPTION

[0034] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0035] Example 1 Preparation of Compounds X1-X3

[0036]

[0037] General synthesis steps: 1.0 mmol 1.2 equivalents of NaH, use The reaction mixture was heated to 120°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 then drained and the crude product was separated using a silica gel column.

[0038] Compound X1, 1 H NMR(400MHz; CDCl3), δ7.67(s,1H,Ar-H),7.54(d, 3 J HH =8.6Hz,1H,Ar-H),6.88(d, 3 J HH =8.6Hz, 4 J HH =2.6Hz,1H,Ar-H),4.33(t, 3 J HH =6.0Hz,2H),3.69(t, 3 J HH =6.0 Hz, 2H).

[0039] Compound X2, 1 H NMR (400MHz; CDCl3), δ7.75 (s, 1H, Ar-H), 7.56 (d, 3 J HH =8.6Hz,1H,Ar-H),6.94(d, 3 J HH =8.6Hz,4 J HH =2.6Hz,1H,Ar-H),4.31(t, 3 J HH =6.0Hz,2H),3.77(t, 3 J HH =6.0Hz,2H),3.54(t, 3 J HH =6.0Hz,2H),3.70(t, 3 J HH =6.0 Hz, 2H).

[0040] Compound X3, 1 H NMR(400MHz; CDCl3), δ7.78(s,1H,Ar-H),7.59(d, 3 J HH =8.6Hz,1H,Ar-H),6.97(d, 3 J HH =8.6Hz, 4 J HH =2.6Hz,1H,Ar-H),4.31(t, 3 J HH =6.0Hz,2H),3.77(t, 3 J HH =6.0Hz,2H),3.70(t, 3 J HH =6.0Hz,2H),3.50-3.60(m,6H).

[0041] Example 2 Preparation of Compounds Y1-Y3 Series

[0042]

[0043] General synthetic procedures for compounds Y1-Y3: 1.0 mmol of substrates X1-X3, 1.2 equivalents of pinacol diboronate, 1.5 equivalents of base (KOAc), 0.2 equivalents of 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride, and 5.0 ml of acetonitrile. The reaction mixture was heated to 80°C and stirred until the reaction was complete. The reaction mixture was then separated between ethyl acetate and saturated brine. The organic solvent phase was dried over magnesium sulfate, the solvent was removed by evacuation, and the crude product was separated on a silica gel column.

[0044] Compound Y1, 1 H NMR (400MHz; CDCl3), δ7.65(d, 3 J HH =8.6Hz,1H,Ar-H),7.46(s,1H,Ar-H),6.54(d,3 J HH = 8.6 Hz, 4 J HH = 2.6 Hz, 1H, Ar - H), 4.33 (t, 3 J HH = 6.0 Hz, 2H), 3.69 (t, 3 J HH = 6.0 Hz, 2H), 1.20 (s, 12H).

[0045] Compound Y2, 1 H NMR (400 MHz; CDCl3), δ 7.67 (d, 3 J HH = 8.6 Hz, 1H, Ar - H), 7.43 (s, 1H, Ar - H), 6.58 (d, 3 J HH = 8.6 Hz, 4 J HH = 2.6 Hz, 1H, Ar - H), 4.31 (t, 3 J HH = 6.0 Hz, 2H), 3.77 (t, 3 J HH = 6.0 Hz, 2H), 3.70 (t, 3 J HH = 6.0 Hz, 2H), 3.54 (t, 3 J HH = 6.0 Hz, 2H), 1.20 (s, 12H).

[0046] Compound Y3, 1 H NMR (400 MHz; CDCl3), δ 7.68 (d, 3 J HH = 8.6 Hz, 1H, Ar - H), 7.45 (s, 1H, Ar - H), 6.59 (d, 3 J HH = 8.6 Hz, 4 J HH = 2.6 Hz, 1H, Ar - H), 4.31 (t, 3 J HH = 6.0 Hz, 2H), 3.78 (t, 3 J HH = 6.0 Hz, 2H), 3.70 (t, 3 J HH = 6.0 Hz, 2H), 3.50 - 3.60 (m, 6H), 1.20 (s, 12H).

[0047] Example 3 Preparation of Compounds A4-A6 Series

[0048]

[0049] General synthetic steps of compounds A4-A6: 1.0 mmol 1.2 equivalents of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-ol, 0.2 equivalents of Pd(PPh3)4, 1.2 equivalents of NaOH, and 5.0 ml of THF / H2O were heated to reflux and stirred until the reaction was complete. The reaction mixture was poured into ice water and the pH was adjusted to neutral with acetic acid. Ethyl acetate and saturated brine were added to the reaction mixture and separated. The organic solvent phase was dried over magnesium sulfate, the solvent was drained, and the crude product was used directly.

[0050] Compound A4, 1 H NMR (400MHz; CDCl3), δ9.10 (s, 1H, Ar-H), 8.10 (d, 3 J HH =9.0Hz,1H,Ar-H),7.40-7.70(m,4H,Ar-H),6.77(d, 3 J HH =9.0 Hz, 1H, Ar-H).

[0051] Compound A5, 1 H NMR (400MHz; CDCl3), δ9.11 (s, 1H, Ar-H), 8.12 (d, 3 J HH =9.0Hz,1H,Ar-H),7.67(d, 3 J HH =9.0Hz,1H,Ar-H),7.40-7.50(m,3H,Ar-H),6.79(d, 3 J HH =9.0 Hz, 1H, Ar-H).

[0052] Compound A6, 1 H NMR (400MHz; CDCl3), δ9.14 (s, 1H, Ar-H), 8.11 (d, 3 J HH =9.0Hz,1H,Ar-H),7.50-7.60(m,4H,Ar-H),6.73(d, 3 J HH =9.0 Hz, 1H, Ar-H).

[0053] Example 4 Preparation of Compounds B4-B7 Series

[0054]

[0055] General synthetic procedures for compounds B4-B7: 1.0 mmol of substrate A4-A6, 3 equivalents of PhCO₃tBu, 0.2 equivalents of Pd(OAc)₂, and 5.0 ml of C₆F₆ / 1,3-dimethyl-2-imidazolidinone. The reaction mixture was stirred at room temperature overnight until the reaction was complete. The reaction mixture was partitioned between ethyl acetate and saturated brine. The organic solvent phase was dried over magnesium sulfate, the solvent was removed by evaporation, and the crude product was separated using a silica gel column.

[0056] Compound B4, 1 H NMR(400MHz; CDCl3), δ9.52(s,1H,py-H),8.74(d, 3 J HH =9.0Hz,1H,py-H),7.86(d, 3 J HH =9.0Hz,1H,py-H),7.53(d, 3 J HH =9.0Hz,1H,Ar-H),7.20-7.30(m,2H,Ar-H).

[0057] Compound B5, 1 H NMR (400MHz; CDCl3), δ9.50 (s, 1H, py-H), 8.75 (d, 3 J HH =9.0Hz,1H,py-H),8.06(s,1H,Ar-H),7.82(d, 3 J HH =9.0Hz,1H,py-H),7.50(d, 3 J HH =9.0Hz,1H,Ar-H),7.38(d, 3 J HH =9.0 Hz, 1H, Ar-H).

[0058] Compound B6, 1 H NMR(400MHz; CDCl3), δ9.51(s,1H,py-H),8.74(d, 3 J HH =9.0Hz,1H,py-H),8.26(s,1H,Ar-H),7.82(d, 3 J HH =9.0Hz,1H,py-H),7.71(d, 3 JHH =9.0Hz,1H,Ar-H),7.30(d, 3 J HH =9.0 Hz, 1H, Ar-H).

[0059] Compound B7, 1 H NMR(400MHz; CDCl3), δ9.49(s,1H,py-H),8.74(d, 3 J HH =9.0Hz,1H,py-H),7.92(d, 3 J HH =9.0Hz,1H,Ar-H),7.84(d, 3 J HH =9.0Hz,1H,py-H),7.36(d, 3 J HH =9.0Hz,1H,Ar-H),7.21(t, 3 J HH =8.8 Hz, 1H, Ar-H).

[0060] Example 5 Preparation of Compounds C4-E7 Series

[0061]

[0062] General synthesis procedures for compound C4-E7: 1.0 mmol of substrates B4-B7, 1.2 equivalents of Y1-Y3, 0.2 equivalents of Pd(PPh3)4, and 5.0 ml of THF / H2O. The reaction mixture was stirred overnight at 120°C 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 then drained, and the crude product was separated using a silica gel column.

[0063] Compound C4, 1 H NMR (400MHz; CDCl3), δ9.50 (s, 1H, py-H), 8.75 (d, 3 J HH =9.0Hz,1H,py-H),8.10(d, 3 J HH =9.0Hz,1H,py-H),8.06(d, 3 J HH =9.0Hz,1H,Ar-H),8.03(s,1H,Ar-H),7.82(d, 3 J HH =9.0Hz,1H,Ar-H),7.70(d, 3 J HH= 9.0 Hz, 1H, Ar-H), 7.60 (t, 3 J HH = 9.0 Hz, 1H, Ar-H), 6.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.33 (t, 3 J HH = 6.0 Hz, 2H), 3.69 (t, 3 J HH = 6.0 Hz, 2H).

[0064] Compound C5, 1 H NMR (400 MHz; CDCl3), δ 9.55 (s, 1H, py-H), 8.71 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.10 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.03 (s, 1H, Ar-H), 7.80 - 7.90 (m, 4H, 3Ar-H + py-H), 6.73 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.32 (t, 3 J HH = 6.0 Hz, 2H), 3.71 (t, 3 J HH = 6.0 Hz, 2H).

[0065] Compound C6, 1 H NMR (400 MHz; CDCl3), δ 9.51 (s, 1H, py-H), 8.70 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.00 - 8.10 (m, 3H, Ar-H + 2py-H), 7.70 - 7.90 (m, 3H, 2Ar-H + 1py-H), 6.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.31 (t, 3 J HH = 6.0 Hz, 2H), 3.70 (t, 3 J HH = 6.0 Hz, 2H).

[0066] Compound C7, 1 H NMR (400 MHz; CDCl3), δ 9.48 (s, 1H, py-H), 8.72 (d, 3 JHH = 9.0 Hz, 1H, py-H), 8.00 - 8.10 (m, 4H, 2Ar-H + 2py-H), 7.86 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 7.50 (t, 3 J HH = 9.0 Hz, 1H, Ar-H), 6.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.33 (t, 3 J HH = 6.0 Hz, 2H), 3.72 (t, 3 J HH = 6.0 Hz, 2H).

[0067] Compound D4, 1 H NMR (400 MHz; CDCl3), δ 9.50 (s, 1H, py-H), 8.75 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.10 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.06 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.03 (s, 1H, Ar-H), 7.80 - 7.90 (m, 2H, Ar-H + py-H), 7.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 7.57 (t, 3 J HH = 9.0 Hz, 1H, Ar-H), 6.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.33 (t, 3 J HH = 6.0 Hz, 2H), 3.70 - 3.80 (m, 4H), 3.54 (t, 3 J HH = 6.0 Hz, 2H).

[0068] Compound D5, 1 H NMR (400 MHz; CDCl3), δ 9.52 (s, 1H, py-H), 8.71 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.10 (d, 3 J HH= 9.0 Hz, 1H, py-H), 8.06 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.02 (s, 1H, Ar-H), 7.80 - 7.90 (m, 3H, 2Ar-H + py-H), 6.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.31 (t, 3 J HH = 6.0 Hz, 2H), 3.70 - 3.80 (m, 4H), 3.51 (t, 3 J HH = 6.0 Hz, 2H).

[0069] Compound D6, 1 H NMR (400 MHz; CDCl3), δ 9.53 (s, 1H, py-H), 8.70 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.00 - 8.10 (m, 3H, Ar-H + 2py-H), 7.80 - 7.90 (m, 3H, 2Ar-H + py-H), 6.73 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.32 (t, 3 J HH = 6.0 Hz, 2H), 3.70 - 3.80 (m, 4H), 3.50 (t, 3 J HH = 6.0 Hz, 2H).

[0070] Compound D7, 1 H NMR (400 MHz; CDCl3), δ 9.49 (s, 1H, py-H), 8.73 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.00 - 8.10 (m, 4H, 2Ar-H + 2py-H), 7.86 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 7.51 (t, 3 J HH = 9.0 Hz, 1H, Ar-H), 6.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.35 (t, 3 J HH = 6.0 Hz, 2H), 3.70 - 3.80 (m, 4H), 3.52 (t, 3 JHH = 6.0 Hz, 2H).

[0071] Compound E4, 1 H NMR (400 MHz; CDCl3), δ 9.55 (s, 1H, py-H), 8.75 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.10 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.03 (s, 1H, py-H), 7.80 - 7.90 (m, 2H, Ar-H + py-H), 7.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 7.55 (t, 3 J HH = 9.0 Hz, 1H, Ar-H), 6.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.33 (t, 3 J HH = 6.0 Hz, 2H), 3.70 - 3.80 (m, 4H), 3.50 - 3.60 (m, 6H).

[0072] Compound E5, 1 H NMR (400 MHz; CDCl3), δ 9.50 (s, 1H, py-H), 8.71 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.11 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.00 (s, 1H, py-H), 7.80 - 7.90 (m, 4H, 3Ar-H + py-H), 6.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.35 (t, 3 J HH = 6.0 Hz, 2H), 3.70 - 3.80 (m, 4H), 3.50 - 3.60 (m, 6H).

[0073] Compound E6, 1 H NMR (400 MHz; CDCl3), δ 9.52 (s, 1H, py-H), 8.70 (d, 3 J HH=9.0Hz,1H,py-H),8.00-8.10(m,2H,Ar-H+2py-H),7.80-7.90(m,3H,2Ar-H+py-H),8.11(d, 3 J HH =9.0Hz,1H,Ar-H),8.00(s,1H,py-H),7.80-7.90(m,4H,3Ar-H+py-H),6.71(d, 3 J HH =9.0Hz,1H,Ar-H),4.32(t, 3 J HH =6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H).

[0074] Compound E7, 1 H NMR(400MHz; CDCl3), δ9.49(s,1H,py-H),8.75(d, 3 J HH =9.0Hz,1H,py-H),8.00-8.10(m,4H,2Ar-H+2py-H),7.86(d, 3 J HH =9.0Hz,1H,py-H),7.50(t, 3 J HH =9.0Hz,1H,Ar-H),6.71(d, 3 J HH =9.0Hz,1H,Ar-H),4.36(t, 3 J HH =6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H).

[0075] Example 7 Preparation of Compounds C8-E11 Series

[0076]

[0077] General synthesis procedures for compound C8-E11: 1.0 mmol of substrate B8-B11, 1.2 equivalents of Y1-Y3, 0.2 equivalent of Pd(PPh3)4, and 5.0 ml of THF / H2O. The reaction mixture was stirred overnight at 120°C 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 then drained, and the crude product was separated using a silica gel column.

[0078] Compound C8, 11H NMR (400 MHz; CDCl3), δ 9.34 (s, 1H, py-H), 8.40 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.00 - 8.10 (m, 2H, 2py-H), 7.90 (d, 3 J HH = 9.0 Hz, 1H, py-H), 7.71 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 7.50 - 7.60 (m, 2H, Ar-H + py-H), 6.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.30 (t, 3 J HH = 6.0 Hz, 2H), 3.71 (t, 3 J HH = 6.0 Hz, 2H).

[0079] Compound C9, 1 1H NMR (400 MHz; CDCl3), δ 9.35 (s, 1H, py-H), 8.42 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.00 - 8.10 (m, 3H, 2py-H + Ar-H), 7.90 (s, 1H, py-H), 7.77 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 7.45 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 6.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.30 (t, 3 J HH = 6.0 Hz, 2H), 3.73 (t, 3 J HH = 6.0 Hz, 2H).

[0080] Compound C10, 1 1H NMR (400 MHz; CDCl3), δ 9.31 (s, 1H, py-H), 8.40 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.31 (d, 3 J HH= 9.0 Hz, 1H, py-H), 8.00 - 8.10 (m, 2H, py-H + Ar-H), 7.91 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 7.74 (s, 1H, Ar-H), 7.45 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 6.68 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.31 (t, 3 J HH = 6.0 Hz, 2H), 3.68 (t, 3 J HH = 6.0 Hz, 2H).

[0081] Compound C11, 1 H NMR (400 MHz; CDCl3), δ 9.30 (s, 1H, py-H), 8.37 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.29 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.00 - 8.10 (m, 3H, 2py-H + Ar-H), 7.40 - 7.50 (m, 2H, Ar-H + py-H), 6.69 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.30 (t, 3 J HH = 6.0 Hz, 2H), 3.65 (t, 3 J HH = 6.0 Hz, 2H).

[0082] Compound D8, 1 H NMR (400 MHz; CDCl3), δ 9.30 (s, 1H, py-H), 8.41 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.00 - 8.10 (m, 2H, 2py-H), 7.90 (d, 3 J HH = 9.0 Hz, 1H, py-H), 7.71 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 7.50 - 7.60 (m, 2H, Ar-H + py-H), 6.70 (d, 3 J HH= 9.0 Hz, 1H, Ar-H), 4.29 (t, 3 J HH = 6.0 Hz, 2H), 3.67 (t, 3 J HH = 6.0 Hz, 2H).

[0083] Compound D9, 1 1H NMR (400 MHz; CDCl3), δ 9.35 (s, 1H, py-H), 8.43 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.00−8.10 (m, 3H, 2py-H + Ar-H), 7.90 (s, 1H, py-H), 7.77 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 7.50−7.60 (m, 2H, Ar-H + py-H), 7.46 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 6.71 (d, 3 J ' HH = 9.0 Hz, 1H, Ar-H), 4.31 (t, 3 J HH = 6.0 Hz, 2H), 3.70−3.80 (m, 4H), 3.52 (t, 3 J<~ HH = 6.0 Hz, 2H).

[0084] Compound D10, 1 1H NMR (400 MHz; CDCl3), δ 9.30 (s, 1H, py-H), 8.41 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.31 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.00−8.10 (m, 2H, 2py-H), 7.90 (d, 3 J HH = 9.0 Hz, 1H, py-H), 7.74 (s, 1H, Ar-H), 7.45 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 6.70 (d, 3 J HH [[ID=~~62]]= 9.0 Hz, 1H, Ar-H), 4.30 (t, 3 J HH It should be noted that there seems to be a small error in the original text where "J HH " is written as "J<~` HH " in the translation. Also, "J HH " at the end of the original text has an extra "~`" in the provided original which might be a typo. The translation has been done as accurately as possible based on the given text.= 6.0 Hz, 2H), 3.70 - 3.80 (m, 4H), 3.50 (t, 3 J HH = 6.0 Hz, 2H).

[0085] Compound D11, 1 1H NMR (400 MHz; CDCl3), δ 9.28 (s, 1H, py - H), 8.39 (d, 3 J HH = 9.0 Hz, 1H, py - H), 8.28 (d, 3 J HH = 9.0 Hz, 1H, Ar - H), 8.00 - 8.10 (m, 3H, 2py - H + Ar - H), 7.40 - 7.50 (m, 2H, py - H + Ar - H), 6.70 (d, 3 J HH = 9.0 Hz, 1H, Ar - H), 4.33 (t, 3 J HH = 6.0 Hz, 2H), 3.70 - 3.80 (m, 4H), 3.52 (t,<00003​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​H NMR(400MHzCDCl3),δ9.34(s,1H,py-H),8.41(d, 3 J HH N9.0Hz,1H,py-H),8.00-8.10(m,3H,2py-H+Ar-H),7.89(s,1H,Ar-H),7.77(d, 3 J HH N9.0Hz,1H,Ar-H),7.45(d, 3 J HH N9.0Hz,1H,Ar-H),6.70(d, 3 J HH N9.0Hz,1H,Ar-H),4.30(t, 3 J HH N6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H).

[0088] Picture E10, 1 H NMR(400MHzCDCl3),δ9.30(s,1H,py-H),8.39(d, 3 J HH N9.0Hz,1H,foot-H),8.31(d, 3 J HH N9.0Hz,1H,ft-H),8.00-8.10(m,2H,2ft-H),7.91(d, 3 J HH 9.0Hz,1H,Ar-H),7.74(s,1H,Ar-H),7.45(d, 3 J HH N9.0Hz,1H,Ar-H),6.74(d, 3 J HH N9.0Hz,1H,Ar-H),4.35(t, 3 J HH N6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H).

[0089] Environment E11, 1 H NMR(400MHzCDCl3),δ9.35(s,1H,py-H),8.38(d, 3 J HH N9.0Hz,1H,foot-H),8.27(d, 3 J HH=9.0Hz,1H,py-H),8.00-8.10(m,3H,2py-H+Ar-H),7.40-7.50(m,2H,py-H+Ar-H),6.70(d, 3 J HH =9.0Hz,1H,Ar-H),4.31(t, 3 J HH =6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H).

[0090] Example 8 Preparation of Compounds F4-H7 Series (Compound II)

[0091]

[0092] General synthesis procedures for compound F4-H7: 1.0 mmol of compound C4-E7, 1.2 equivalents of Ts-Cl, 3.0 equivalents of Et3N, and 5.0 ml of CH2Cl2 were used. The reaction mixture was stirred overnight 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 then drained, and the crude product was separated using a silica gel column.

[0093] Compound F4, 1 H NMR (400MHz; CDCl3), δ9.51 (s, 1H, py-H), 8.78 (d, 3 J HH =9.0Hz,1H,py-H),8.00-8.10(m,2H,py-H),7.70-7.90(m,5H,py-H+4Ar-H),7.57(t,1H, 3 J HH =9.0Hz,py-H),7.45(d, 3 J HH =9.0Hz,2H,Ar-H),6.70(d, 3 J HH =9.0Hz,1H,Ar-H),4.31(t, 3 J HH =6.0Hz,2H),3.96(t, 3 J HH =6.0Hz,2H),2.44(s,3H,CH3).

[0094] Compound F5, 1 H NMR (400MHz; CDCl3), δ9.48 (s, 1H, py-H), 8.70 (d, 3 J HH= 9.0 Hz, 1H, py-H), 8.00 - 8.10 (m, 2H, py-H), 7.70 - 7.90 (m, 5H, py-H + 4Ar-H), 7.45 (d, 3 J HH = 9.0 Hz, 2H, Ar-H), 6.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.34 (t, 3 J HH = 6.0 Hz, 2H), 3.92 (t, 3 J HH = 6.0 Hz, 2H), 2.45 (s, 3H, CH3).

[0095] Compound F6, 1 1H NMR (400 MHz; CDCl3), δ 9.53 (s, 1H, py-H), 8.71 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.00 - 8.10 (m, 3H, 2py-H + Ar-H), 7.70 - 7.90 (m, 5H, py-H + 4Ar-H), 7.45 (d, 3 J HH = 9.0 Hz, 2H, Ar-H), 6.75 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.31 (t, 3 J HH = 6.0 Hz, 2H), 3.93 (t, 3 J HH = 6.0 Hz, 2H), 2.43 (s, 3H, CH3).

[0096] Compound F7, 1 1H NMR (400 MHz; CDCl3), δ 9.50 (s, 1H, py-H), 8.69 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.00 - 8.10 (m, 4H, 2py-H + 2Ar-H), 7.86 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 7.75 (d, 3 J HH = 9.0 Hz, 2H, Ar-H), 7.40 - 7.50 (m, 3H, Ar-H), 6.71 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.34 (t,3 J HH = 6.0 Hz, 2H), 3.95 (t, 3 J HH = 6.0 Hz, 2H), 2.44 (s, 3H, CH3).

[0097] Compound G4, 1 1H NMR (400 MHz; CDCl3), δ 9.49 (s, 1H, py-H), 8.71 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.00 - 8.10 (m, 2H, py-H), 7.70 - 7.90 (m, 5H, py-H + 4Ar-H), 7.54 (t, 1H, 3 J HH = 9.0 Hz, py-H), 7.43 (d, 3 J HH = 9.0 Hz, 2H, Ar-H), 6.71 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.30 (t, 3 J HH = 6.0 Hz, 2H), 3.70 - 3.80 (m, 4H), 3.50 (t, 3 J HH = 6.0 Hz, 2H), 2.43 (s, 3H, CH3).

[0098] Compound G5, 1 1H NMR (400 MHz; CDCl3), δ 9.55 (s, 1H, py-H), 8.74 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.00 - 8.10 (m, 2H, py-H), 7.70 - 7.90 (m, 6H, py-H + 5Ar-H), 7.45 (d, 3 J HH = 9.0 Hz, 2H, Ar-H), 6.71 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.33 (t, 3 J HH = 6.0 Hz, 2H), 3.70 - 3.80 (m, 4H), 3.52 (t, 3 J HH = 6.0 Hz, 2H), 2.44 (s, 3H, CH3).

[0099] Compound G6, 11H NMR (400 MHz; CDCl3), δ 9.51 (s, 1H, py-H), 8.69 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.00 - 8.10 (m, 3H, 2py-H + Ar-H), 7.70 - 7.90 (m, 5H, py-H + 4Ar-H), 7.43 (d, 3 J HH = 9.0 Hz, 2H, Ar-H), 6.71 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.34 (t, 3 J HH = 6.0 Hz, 2H), 3.70 - 3.80 (m, 4H), 3.50 (t, 3 J HH = 6.0 Hz, 2H), 2.42 (s, 3H, CH3).

[0100] Compound G7, 1 1H NMR (400 MHz; CDCl3), δ 9.51 (s, 1H, py-H), 8.75 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.00 - 8.10 (m, 4H, 2py-H + 2Ar-H), 7.86 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 7.71 (d, 3 J HH = 9.0 Hz, 2H, Ar-H), 7.40 - 7.50 (m, 3H, Ar-H), 6.74 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.30 (t, 3 J HH = 6.0 Hz, 2H), 3.70 - 3.80 (m, 4H), 3.51 (t, 3 J HH = 6.0 Hz, 2H), 2.44 (s, 3H, CH3).

[0101] Compound H4, 1 1H NMR (400 MHz; CDCl3), δ 9.53 (s, 1H, py-H), 8.75 (d, 3 J HH=9.0Hz,1H,py-H),8.00-8.10(m,2H,py-H),7.70-7.90(m,5H,py-H+4Ar-H),7.58(t,1H, 3 J HH =9.0Hz,py-H),7.45(d, 3 J HH =9.0Hz,2H,Ar-H),6.74(d, 3 J HH =9.0Hz,1H,R-H),4.34(t, 3 J HH =6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H),2.44(s,3H,CH3)。

[0102] H5, 1 H NMR(400MHz;CDCl3), δ9.51(s,1H,py-H),8.69(d, 3 J HH =9.0Hz,1H,py-H),8.00-8.10(m,2H,py-H),7.70-7.90(m,6H,py-H+5Ar-H),7.44(d, 3 J HH (9.0Hz,2H,Ar-H),6.73(d, 3 J HH =9.0Hz,1H,R-H),4.30(t, 3 J HH =6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H),2.43(s,3H,CH3)。

[0103] H6, 1 H NMR(400MHz;CDCl3), δ9.54(s,1H,py-H),8.75(d, 3 J HH =9.0Hz,1H,py-H),8.00-8.10(m,3H,2py-H+Ar-H),7.70-7.90(m,5H,py-H+4Ar-H),7.45(d, 3 J HH (9.0Hz,2H,Ar-H),6.73(d, 3 J HH 9.0Hz,1H,R-H),4.35(t, 3 J HH=6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H),2.44(s,3H,CH3).

[0104] Compound H7, 1 H NMR(400MHz; CDCl3), δ9.53(s,1H,py-H),8.71(d, 3 J HH =9.0Hz,1H,py-H),8.00-8.10(m,4H,2py-H+2Ar-H),7.84(d, 3 J HH =9.0Hz,1H,Ar-H),7.73(d, 3 J HH =9.0Hz,2H,Ar-H),7.40-7.50(m,3H,Ar-H),6.71(d, 3 J HH =9.0Hz,1H,Ar-H),4.30(t, 3 J HH =6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H),2.43(s,3H,CH3).

[0105] Example 9 Preparation of Compounds F8-H11 Series (Compound II)

[0106]

[0107] General synthesis procedures for compound F8-H11: 1.0 mmol of compound C8-E11, 2.4 equivalents of Ts-Cl, 5.0 equivalents of Et3N, and 5.0 ml of CH2Cl2 were stirred at room temperature overnight 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 then drained, and the crude product was separated using a silica gel column.

[0108] Compound F8, 1 H NMR(400MHz; CDCl3), δ9.32(s,1H,py-H),8.35(d, 3 J HH =9.0Hz,1H,py-H),8.00-8.10(m,3H,2py-H+Ar-H),7.75(d, 3 J HH =9.0Hz,4H,Ar-H),7.40-7.50(m,6H,py-H+5Ar-H),6.71(d, 3 J HH= 9.0 Hz, 1H, Ar-H), 4.33 (t, 3 J HH = 6.0 Hz, 2H), 3.91 (t, 3 J HH = 6.0 Hz, 2H), 2.44 (s, 6H, CH3).

[0109] Compound F9, 1 1H NMR (400 MHz; CDCl3), δ 9.35 (s, 1H, py-H), 8.30 - 8.40 (m, 3H, py-H + 2Ar-H), 8.00 - 8.10 (m, 3H, 2py-H + Ar-H), 7.73 (d, 3 J HH = 9.0 Hz, 4H, Ar-H), 7.40 - 7.50 (m, 5H, py-H + 4Ar-H), 6.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.31 (t, 3 J HH = 6.0 Hz, 2H), 3.95 (t, 3 J HH = 6.0 Hz, 2H), 2.43 (s, 6H, CH3).

[0110] Compound F10, 1 1H NMR (400 MHz; CDCl3), δ 9.31 (s, 1H, py-H), 8.62 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.34 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.21 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.00 - 8.15 (m, 3H, 2py-H + Ar-H), 7.74 (d, 3 J HH = 9.0 Hz, 4H, Ar-H), 7.40 - 7.50 (m, 5H, py-H + 4Ar-H), 6.71 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.34 (t, 3 J HH = 6.0 Hz, 2H), 3.91 (t, 3 J HH = 6.0 Hz, 2H), 2.44 (s, 6H, CH3).

[0111] Compound F11, 1 H NMR (400 MHz; CDCl3), δ 9.34 (s, 1H, py-H), 8.62 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.30 - 8.40 (m, 2H, Ar-H), 8.00 - 8.10 (m, 2H, py-H + Ar-H), 7.76 (d, 3 J HH = 9.0 Hz, 4H, Ar-H), 7.40 - 7.50 (m, 6H, py-H + 5Ar-H), 6.72 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.31 (t, 3 J HH = 6.0 Hz, 2H), 3.89 (t, 3 J HH = 6.0 Hz, 2H), 2.43 (s, 6H, CH3).

[0112] Compound G8, 1 H NMR (400 MHz; CDCl3), δ 9.35 (s, 1H, py-H), 8.31 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.11 (d, 3 J HH = 9.0 Hz, 1H, py-H), 8.00 - 8.10 (m, 3H, 2py-H + Ar-H), 7.74 (d, 3 J HH = 9.0 Hz, 4H, Ar-H), 7.40 - 7.50 (m, 6H, py-H + 5Ar-H), 6.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.30 (t, 3 J HH = 6.0 Hz, 2H), 3.70 - 3.80 (m, 4H), 3.52 (t, 3 J HH = 6.0 Hz, 2H), 2.42 (s, 6H, CH3).

[0113] Compound G9, 1 H NMR (400 MHz; CDCl3), δ 9.32 (s, 1H, py-H), 8.30 - 8.40 (m, 3H, py-H + 2Ar-H), 8.00 - 8.15 (m, 3H, 2py-H + Ar-H), 7.74 (d,3 J HH = 9.0 Hz, 4H, Ar-H), 7.40 - 7.50 (m, 5H, py-H + 4Ar-H), 6.73 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.29 (t, 3 J HH = 6.0 Hz, 2H), 3.70 - 3.80 (m, 4H), 3.52 (t, 3 J HH = 6.0 Hz, 2H), 2.42 (s, 6H, CH3).

[0114] Compound G10, 1 1H NMR (400 MHz; CDCl3), δ 9.33 (s, 1H, py-H), 8.60 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.32 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.22 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.00 - 8.15 (m, 3H, 2py-H + Ar-H), 7.74 (d, 3 J HH = 9.0 Hz, 4H, Ar-H), 7.40 - 7.50 (m, 5H, py-H + 4Ar-H), 6.74 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.28 (t, 3 J HH = 6.0 Hz, 2H), 3.70 - 3.80 (m, 4H), 3.54 (t, 3 J HH = 6.0 Hz, 2H), 2.43 (s, 6H, CH3).

[0115] Compound G11, 1 1H NMR (400 MHz; CDCl3), δ 9.31 (s, 1H, py-H), 8.66 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.30 - 8.40 (m, 2H, Ar-H), 8.00 - 8.10 (m, 2H, py-H + Ar-H), 7.74 (d, 3 J HH=9.0Hz,4H,Ar-H),7.40-7.50(m,6H,py-H+5Ar-H),6.71(d, 3 J HH =9.0Hz,1H,R-H),4.29(t, 3 J HH =6.0Hz,2H),3.70–3.80(m,4H),3.52(t, 3 J HH [6.0Hz,2H),2.42(s,6H,CH3)。

[0116] H8, 1 H NMR(400MHz;CDCl3), δ9.31(s,1H,py-H),8.30(d, 3 J HH =9.0Hz,1H,py-H),8.10(d, 3 J HH (9.0Hz,1H,py-H),8.00-8.10(m,3H,2py-H+Ar-H),7.73(d), 3 J HH =9.0Hz,4H,Ar–H),7.40–7.50(m, 6H,py−H+5Ar−H),6.74(d, 3 J HH =9.0Hz,1H,R-H),4.32(t, 3 J HH =6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H),2.44(s,6H,CH3)。

[0117] H9, 1 H NMR(400MHz;CDCl3),δ9.34(s,1H,py-H),8.30-8.40(m,3H,py-H+2Ar-H),8.00-8.15(m,3H,2py-H+Ar-H),7.76(d, 3 J HH =9.0Hz,4H,Ar-H),7.40-7.50(m,5H,py-H+4Ar-H),6.70(d, 3 J HH =9.0Hz,1H,R-H),4.30(t, 3 J HH =6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H),2.43(s,6H,CH3)。

[0118] Compound H10, 1 H NMR(400MHz; CDCl3), δ9.31(s,1H,py-H),8.63(d, 3 J HH =9.0Hz,1H,Ar-H),8.29(d, 3 J HH =9.0Hz,1H,Ar-H),8.21(d, 3 J HH =9.0Hz,1H,Ar-H),8.00-8.15(m,3H,2py-H+Ar-H),7.76(d, 3 J HH =9.0Hz,4H,Ar-H),7.40-7.50(m,5H,py-H+4Ar-H),6.70(d, 3 J HH =9.0Hz,1H,Ar-H),4.31(t, 3 J HH =6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H),2.42(s,6H,CH3).

[0119] Compound H11, 1 H NMR(400MHz; CDCl3), δ9.34(s,1H,py-H),8.61(d, 3 J HH =9.0Hz,1H,Ar-H),8.30-8.40(m,2H,Ar-H),8.00-8.10(m,2H,py-H+Ar-H),7.76(d, 3 J HH =9.0Hz,4H,Ar-H),7.40-7.50(m,6H,py-H+5Ar-H),6.74(d, 3 J HH =9.0Hz,1H,Ar-H),4.35(t, 3 J HH =6.0Hz,2H),3.70-3.80(m,4H),3.50-3.60(m,6H),2.42(s,6H,CH3).

[0120] Example 10 Preparation of Compounds L4-LLL7 Series (Compound I)

[0121]

[0122] General synthesis steps for compound L4-LLL7: 1.0 mmol of compound F4-H7 and 1.5 equivalents of CsF were dissolved in 5 ml of DMF. The reaction mixture was stirred overnight at 120°C 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 drained, and the crude product was separated using a silica gel column.

[0123] Compound L4, 1 H NMR(400MHz; CDCl3), δ9.52(s,1H,py-H),8.70(d, 3 J HH =9.0Hz,1H,Ar-H),8.00-8.10(m,2H,py-H+Ar-H),7.80-7.90(m,2H,py-H+Ar-H),7.70(d, 3 J HH =9.0Hz,4H,Ar-H),7.57(t, 3 J HH =9.0Hz,1H,Ar-H),6.71(d, 3 J HH =9.0Hz,1H,Ar-H),4.51(dt, 2 J HF =46Hz, 3 J HH =7.1Hz,2H),4.12(dt, 3 J HF =25Hz, 3 J HH =7.1 Hz, 2H).

[0124] Compound L5, 1 H NMR(400MHz; CDCl3), δ9.49(s,1H,py-H),8.72(d, 3 J HH =9.0Hz,1H,Ar-H),8.00-8.10(m,2H,py-H+Ar-H),7.80-7.90(m,4H,2py-H+2Ar-H),7.70(d, 3 J HH =9.0Hz,4H,Ar-H),7.57(t, 3 J HH =9.0Hz,1H,Ar-H),6.73(d, 3 J HH =9.0Hz,1H,Ar-H),4.49(dt, 2 J HF =46Hz, 3J HH = 7.1 Hz, 2H), 4.17 (dt, 3 J HF = 25 Hz, 3 J HH = 7.1 Hz, 2H).

[0125] Compound L6, 1 H NMR (400 MHz; CDCl3), δ 9.52 (s, 1H, py-H), 8.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.00 - 8.10 (m, 3H, 2py-H + Ar-H), 7.80 - 7.90 (m, 3H, py-H + 2Ar-H), 6.75 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.53 (dt, 2 J HF = 46 Hz, 3 J HH = 7.1 Hz, 2H), 4.21 (dt, 3 J HF = 25 Hz, 3 J HH = 7.1 Hz, 2H).

[0126] Compound L7, 1 H NMR (400 MHz; CDCl3), δ 9.55 (s, 1H, py-H), 8.72 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.00 - 8.10 (m, 4H, 2py-H + 2Ar-H), 7.86 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 7.51 (t, 3 J HH = 9.0 Hz, 1H, Ar-H), 6.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.55 (dt, 2 J HF = 46 Hz, 3 J HH = 7.1 Hz, 2H), 4.11 (dt, 3 J HF = 25 Hz, 3 J HH = 7.1 Hz, 2H).

[0127] Compound LL4,1 1H NMR (400 MHz; CDCl3), δ 9.49 (s, 1H, py-H), 8.72 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.00 - 8.10 (m, 2H, py-H + Ar-H), 7.80 - 7.90 (m, 2H, py-H + Ar-H), 7.71 (d, 3 J HH = 9.0 Hz, 4H, Ar-H), 7.55 (t, 3 J HH = 9.0 Hz, 1H, Ar-H), 6.74 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.20 - 4.30 (m, 4H), 3.77 (t, 3 J HH = 7.1 Hz, 2H), 3.54 (dt, 3 J HF = 25 Hz, 3 J HH = 7.1 Hz, 2H).

[0128] Compound LL5, 1 1H NMR (400 MHz; CDCl3), δ 9.54 (s, 1H, py-H), 8.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.00 - 8.10 (m, 2H, py-H + Ar-H), 7.80 - 7.90 (m, 4H, py-H + 3Ar-H), 6.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.20 - 4.30 (m, 4H), 3.81 (t, 3 J HH = 7.1 Hz, 2H), 3.50 (dt, 3 J HF = 25 Hz, 3 J HH = 7.1 Hz, 2H).

[0129] Compound LL6, 1 1H NMR (400 MHz; CDCl3), δ 9.50 (s, 1H, py-H), 8.68 (d, 3 J HH= 9.0 Hz, 1H, Ar-H), 8.00 - 8.10 (m, 3H, 2py-H + Ar-H), 7.80 - 7.90 (m, 3H, py-H + 2Ar-H), 6.71 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.20 - 4.30 (m, 4H), 3.71 (t, 3 J HH = 7.1 Hz, 2H), 3.49 (dt, 3 J HF = 25 Hz, 3 J HH = 7.1 Hz, 2H).

[0130] Compound LL7, 1 1H NMR (400 MHz; CDCl3), δ 9.50 (s, 1H, py-H), 8.69 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.00 - 8.10 (m, 4H, 2py-H + 2Ar-H), 7.84 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 7.54 (t, 3 J HH = 9.0 Hz, 1H, Ar-H), 6.76 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.20 - 4.30 (m, 4H), 3.75 (t, 3 J HH = 7.1 Hz, 2H), 3.59 (dt, 3 J HF = 25 Hz, 3 J HH = 7.1 Hz, 2H).

[0131] Compound LLL4, 1 1H NMR (400 MHz; CDCl3), δ 9.53 (s, 1H, py-H), 8.76 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.00 - 8.10 (m, 2H, py-H + Ar-H), 7.80 - 7.90 (m, 2H, py-H + Ar-H), 7.65 (d, 3 J HH = 9.0 Hz, 4H, Ar-H), 7.54 (t, 3 J HH= 9.0 Hz, 1H, Ar-H), 6.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.20 - 4.30 (m, 4H), 3.79 (t, 3 J HH = 7.1 Hz, 2H), 3.50 - 3.60 (m, 6H).

[0132] Compound LLL5, 1 1H NMR (400 MHz; CDCl3), δ 9.50 (s, 1H, py-H), 8.72 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.00 - 8.10 (m, 2H, py-H + Ar-H), 7.80 - 7.90 (m, 4H, py-H + 3Ar-H), 6.73 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.20 - 4.30 (m, 4H), 3.72 (t, 3 J HH = 7.1 Hz, 2H), 3.50 - 3.60 (m, 6H).

[0133] Compound LLL6, 1 1H NMR (400 MHz; CDCl3), δ 9.53 (s, 1H, py-H), 8.78 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.00 - 8.10 (m, 3H, 2py-H + Ar-H), 7.80 - 7.90 (m, 3H, py-H + 2Ar-H), 6.75 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.20 - 4.30 (m, 4H), 3.81 (t, 3 J HH = 7.1 Hz, 2H), 3.50 - 3.60 (m, 6H).

[0134] Compound LLL7, 1 1H NMR (400 MHz; CDCl3), δ 9.55 (s, 1H, py-H), 8.74 (d, 3 J HH = 9. 0 Hz, 1H, Ar-H), 8.00 - 8.10 (m, 4H, 2py-H + 2Ar-H), 7.85 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 7.51 (t,3 J HH =9.0Hz,1H,Ar-H),6.71(d, 3 J HH =9.0Hz,1H,Ar-H),4.20-4.30(m,4H),3.75(t, 3 J HH =7.1Hz,2H),3.50-3.60(m,6H).

[0135] Example 11 Preparation of Compounds L8-LLL11 Series (Compound I)

[0136]

[0137] General synthetic procedures for compound L8-LLL11: 1.0 mmol of compound F8-H11 and 3.0 equivalents of CsF were dissolved in 5 ml of DMF. The reaction mixture was stirred at 120°C overnight until the reaction was complete. The reaction mixture was partitioned between ethyl acetate and saturated brine. The organic solvent phase was dried over magnesium sulfate. The solvent was then drained, and the crude product was separated using a silica gel column.

[0138] Compound L8, 1 H NMR(400MHz; CDCl3), δ9.32(s,1H,py-H),8.40(d, 3 J HH =9.0Hz,1H,Ar-H),8.00-8.10(m,2H,py-H+Ar-H),7.91(d, 3 J HH =9.0Hz,4H,Ar-H),7.72(d, 3 J HH =9.0Hz,4H,Ar-H),7.50-7.60(m,2H,py-H+Ar-H),6.70(d, 3 J HH =9.0Hz,1H,Ar-H),4.55(dt, 2 J HF =46Hz, 3 J HH =7.1Hz,2H),4.22(dt, 3 J HF =25Hz, 3 J HH =7.1 Hz, 2H).

[0139] Compound L9, 1 H NMR(400MHz; CDCl3), δ9.30(s,1H,py-H),8.37(d,3 J HH = 9.0 Hz, 1H, Ar-H), 8.00 - 8.10 (m, 4H, 2py-H + 2Ar-H), 7.75 (d, 3 J HH = 9.0 Hz, 4H, Ar-H), 7.45 (d, 3 J HH = 9.0 Hz, 4H, Ar-H), 6.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.47 (dt, 2 J HF = 46 Hz, 3 J HH = 7.1 Hz, 2H), 4.16 (dt, 3 J HF = 25 Hz, 3 J HH = 7.1 Hz, 2H).

[0140] Compound L10, 1 1H NMR (400 MHz; CDCl3), δ 9.36 (s, 1H, py-H), 8.47 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.33 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.00 - 8.10 (m, 2H, py-H + Ar-H), 7.90 (d, 3 J HH = 9.0 Hz, 4H, Ar-H), 7.74 (s, 1H, Ar-H), 7.45 (d, 3 J HH = 9.0 Hz, 4H, Ar-H), 6.73 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.57 (dt, 2 J HF = 46 Hz, 3 J HH = 7.1 Hz, 2H), 4.26 (dt, 3 J HF = 25 Hz, 3 J HH = 7.1 Hz, 2H).

[0141] Compound L11, 1 1H NMR (400 MHz; CDCl3), δ 9.34 (s, 1H, py-H), 8.37 (d,3 J HH = 9.0 Hz, 1H, Ar-H), 8.28 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.00 - 8.10 (m, 3H, 2py-H + Ar-H), 7.40 - 7.50 (m, 2H, py-H + Ar-H), 6.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.50 (dt, 2 J HF = 46 Hz, 3 J HH = 7.1 Hz, 2H), 4.16 (dt, 3 J HF = 25 Hz, 3 J HH = 7.1 Hz, 2H).

[0142] Compound LL8, 1 1H NMR (400 MHz; CDCl3), δ 9.31 (s, 1H, py-H), 8.29 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.00 - 8.10 (m, 2H, py-H + Ar-H), 7.90 (d, 3 J HH = 9.0 Hz, 4H, Ar-H), 7.71 (d, 3 J HH = 9.0 Hz, 4H, Ar-H), 7.50 - 7.60 (m, 2H, py-H + Ar-H), 6.74 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.20 - 4.30 (m, 4H), 3.75 (t, 3 J HH = 7.1 Hz, 2H), 3.55 (dt, 3 J HF = 25 Hz, 3 J HH = 7.1 Hz, 2H).

[0143] Compound LL9, 1 1H NMR (400 MHz; CDCl3), δ 9.30 (s, 1H, py-H), 8.37 (d, 3 J HH= 9.0 Hz, 1H, Ar-H), 8.00 - 8.10 (m, 4H, 2py-H + 2Ar-H), 7.89 (s, 1H, Ar-H), 7.75 (d, 3 J HH = 9.0 Hz, 4H, Ar-H), 7.45 (d, 3 J HH = 9.0 Hz, 4H, Ar-H), 6.69 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.20 - 4.30 (m, 4H), 3.79 (t, 3 J HH = 7.1 Hz, 2H), 3.53 (dt, 3 J HF = 25 Hz, 3 J HH = 7.1 Hz, 2H).

[0144] Compound LL10, 1 1H NMR (400 MHz; CDCl3), δ 9.33 (s, 1H, py-H), 8.42 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.31 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.00 - 8.10 (m, 2H, py-H + Ar-H), 7.89 (d, 3 J HH = 9.0 Hz, 4H, Ar-H), 7.72 (s, 1H, Ar-H), 7.42 (d, 3 J HH = 9.0 Hz, 4H, Ar-H), 6.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.20 - 4.30 (m, 4H), 3.71 (t, 3 J HH = 7.1 Hz, 2H), 3.55 (dt, 3 J HF = 25 Hz, 3 J HH = 7.1 Hz, 2H).

[0145] Compound LL11, 1 1H NMR (400 MHz; CDCl3), δ 9.31 (s, 1H, py-H), 8.30 (d, 3 J HH= 9.0 Hz, 1H, Ar-H), 8.24 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.00 - 8.10 (m, 3H, 2py-H + Ar-H), 7.40 - 7.50 (m, 2H, py-H + Ar-H), 6.74 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.20 - 4.30 (m, 4H), 3.76 (t, 3 J HH = 7.1 Hz, 2H), 3.51 (dt, 3 J HF = 25 Hz, 3 J HH = 7.1 Hz, 2H).

[0146] Compound LLL8, 1 1H NMR (400 MHz; CDCl3), δ 9.35 (s, 1H, py-H), 8.33 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.00 - 8.10 (m, 2H, py-H + Ar-H), 7.89 (d, 3 J HH = 9.0 Hz, 4H, Ar-H), 7.68 (d, 3 J HH = 9.0 Hz, 4H, Ar-H), 7.55 (t, 3 J HH = 9.0 Hz, 1H, Ar-H), 7.45 (t, 3 J HH = 9.0 Hz, 1H, Ar-H), 6.70 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 4.20 - 4.30 (m, 4H), 3.75 (t, 3 J HH = 7.1 Hz, 2H), 3.50 - 3.60 (m, 6H).

[0147] Compound LLL9, 1 1H NMR (400 MHz; CDCl3), δ 9.31 (s, 1H, py-H), 8.47 (d, 3 J HH = 9.0 Hz, 1H, Ar-H), 8.00 - 8.10 (m, 3H, 2py-H + Ar-H), 7.85 (s, 1H, Ar-H), 7.75 (d, 3 JHH =9.0Hz,4H,Ar-H),7.43(d, 3 J HH =9.0Hz,4H,Ar-H),6.75(d, 3 J HH =9.0Hz,1H,Ar-H),4.20-4.30(m,4H),3.76(t, 3 J HH =7.1Hz,2H),3.50-3.60(m,6H).

[0148] Compound LLL10, 1 H NMR(400MHz; CDCl3), δ9.31(s,1H,py-H),8.32(d, 3 J HH =9.0Hz,1H,Ar-H),8.00-8.10(m,3H,2py-H+Ar-H),7.75-7.85(m,3H,py-H+2Ar-H),6.72(d, 3 J HH =9.0Hz,1H,Ar-H),4.20-4.30(m,4H),3.74(t, 3 J HH =7.1Hz,2H),3.50-3.60(m,6H).

[0149] Compound LLL11, 1 H NMR(400MHz; CDCl3), δ9.34(s,1H,py-H),8.34(d, 3 J HH =9.0Hz,1H,Ar-H),8.22(d, 3 J HH =9.0Hz,1H,Ar-H),8.00-8.10(m,3H,2py-H+Ar-H),7.40-7.50(m,2H,py-H+Ar-H),6.71(d, 3 J HH =9.0Hz,1H,Ar-H),4.20-4.30(m,4H),3.79(t, 3 J HH =7.1Hz,2H),3.50-3.60(m,6H).

[0150] Effect Example 1

[0151] In vitro binding assay

[0152] Human AD brain tissue homogenate was diluted in PBS at a dilution of 1:500, with 800 μL used in each tube. [3H]BTA-1 (tritiated BTA-1) was diluted from a 1 mCi / mL stock solution to 1 μCi / 100 μL using ethanol. It was further diluted to 2.7×10 -2 μCi / 100 μL, 100 μL is used in each tube. "Cold" 6-OH-BTA-1 or other test compound (such as compound I of the present invention) is dissolved in dimethyl sulfoxide to obtain 1×10 -3 M solution, prepared with dimethyl sulfoxide to prepare 1×10 -4 to 1×10 -10 M solution, using 10 μL per tube. After assembly, vortex the tubes and incubate at 37°C for 2 hours. Separate the cells using a cell harvester and wash the filter paper with PBS containing 10% ethanol. Place the filter paper in a 4 mL plastic vial and add 2 mL of scintillation fluid. Count the sample. Analyze the data using GraphPad to determine the binding constant.

[0153] The binding constants Ki of the compounds I of the present invention are listed in Table 1:

[0154] Table 1

[0155] Compound X / n <![CDATA[cLogD 7.4 ]]> Ki(nM) L4 O / 0 2.5 2.8 L5 O / 0 2.5 5.5 L6 O / 0 2.5 7.7 L7 O / 0 2.5 12 LL4 O / 1 2.3 1.2 LL5 O / 1 2.3 4.1 LL6 O / 1 2.3 5.7 LL7 O / 1 2.3 8.3 LLL4 O / 2 2.2 1.2 LLL5 O / 2 2.2 3.9 LLL6 O / 2 2.2 6.0 LLL7 O / 2 2.2 8.7 L8 NH / 0 2.4 2.8 L9 NH / 0 2.4 5.2 L10 NH / 0 2.4 7.5 L11 NH / 0 2.4 13 LL8 NH / 1 2.3 0.8 LL9 NH / 1 2.3 3.5 LL10 NH / 1 2.3 4.7 LL11 NH / 1 2.3 7.3 LLL8 NH / 2 2.1 1.0 LLL9 NH / 2 2.1 4.5 LLL10 NH / 2 2.2 4.9 LLL11 NH / 2 2.1 9.1 [3H]BTA-1 37

[0156] Effect Example 2

[0157] The results of the autoradiographic study of brain tissue sections from human AD patients are shown in Figure 1 The first row of images shows autoradiography of AD patient brain tissue sections using radioactive LL8 staining. The upper left image shows autoradiography of AD patient brain tissue sections in the presence of 1 μM non-radioactive 6-OH-BTA-1 (PIB) using non-radioactive 6-OH-BTA-1 as a space-occupying agent. The lower left image shows autoradiography of brain tissue sections in the second row of images, in the absence of a space-occupying agent and in the absence of radioactive LL8 staining and non-radioactive 6-OH-BTA-1 as a space-occupying agent.

[0158] from Figure 1 As can be seen above, the radiolabeled molecule LL8 clearly reveals spots of amyloid deposits in the cerebral cortex. These spots are no longer visible after pretreatment with 6-OH-BTA-1. Therefore, the radiolabeled molecule LL8 is capable of characteristically revealing amyloid deposits.

[0159] in conclusion

[0160] This invention describes the synthesis of a new class of radiolabeled compounds. These radiolabeled compounds show characteristic absorption in brain slices of AD patients and are good imaging agents, which are expected to provide sensitive molecular probes for the early diagnosis of Alzheimer's disease.

Claims

1. A tricyclic compound of Formula I or a pharmaceutically acceptable salt thereof; in, M is O or NH, R 1 、R 2 、R 3 and R 4 One of the The remaining three are H, and n is 0, 1, or 2.

2. The tricyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The tricyclic compound shown in Formula I is a compound shown in Formula Ia:

3. The tricyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The tricyclic compound shown in Formula I is a compound shown in Formula Ib:

4. The tricyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The tricyclic compound shown in Formula I is:

5. A tricyclic compound of Formula I or a pharmaceutically acceptable salt thereof; in, M is O or NH, R 1 、R 2 、R 3 and R 4 One of the The remaining three are H, and n is 0, 1, or 2.

6. The tricyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 5, wherein: The tricyclic compound shown in Formula I is a compound shown in Formula Ia:

7. The tricyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 5, wherein: The tricyclic compound shown in Formula I is a compound shown in Formula Ib:

8. The tricyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 5, wherein: The tricyclic compound shown in Formula I is:

9. A method for preparing the tricyclic compound of Formula I or a pharmaceutically acceptable salt thereof as claimed in claim 2, comprising the steps of: reacting the compound of Formula II-a with CsF in a solvent to obtain the compound of Formula Ia; R 5 、R 6 、R 7 and R 8 One of the The remaining three are H; accordingly, R 1 、R 2 、R 3 and R 4 One of the The remaining three are H.

10. The preparation method according to claim 9, characterized in that The solvent is a highly polar aprotic solvent; And / or, the preparation method of the compound as shown in Formula I is carried out by the following route:

11. A method for preparing the tricyclic compound of Formula I or a pharmaceutically acceptable salt thereof as claimed in claim 3, comprising the steps of: reacting the compound of Formula II-b with CsF in a solvent to obtain the compound of Formula Ib; R 5 、R 6 、R 7 and R 8 One of the The remaining three are H; accordingly, R 1 、R 2 、R 3 and R 4 One of the The remaining three are H.

12. The preparation method according to claim 11, characterized in that The solvent is a highly polar aprotic solvent; And / or, the preparation method of the compound as shown in Formula I is carried out by the following route:

13. The preparation method according to claim 12, wherein The highly polar aprotic solvent is dichloromethane or DMF.

14. A compound or a pharmaceutically acceptable salt thereof:

15. Use of a tricyclic compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8 for preparing a fluorescent colorimetric agent for in vitro tissues or for preparing a drug for treating a disease caused by hyperphosphorylated amyloid protein aggregation.

16. Use of the tricyclic compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 in the preparation of a positron emission tomography agent.

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