Cyclic amide-tetrahydroisoquinoline compound

Abstract

The invention discloses a cyclic amide-tetrahydroisoquinoline compound and a preparation method thereof. The compound has a remarkable inhibition effect on pancreatic cancer cells, has low toxicity to organisms, not only expands the variety of compounds capable of treating pancreatic cancer, but also is suitable for large-scale production.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to a cyclic amide-tetrahydroisoquinoline compound. Background Art

[0002] Pancreatic cancer is a highly malignant tumor, known in the medical community as the "king of cancers" due to its difficulty in early diagnosis and extremely poor prognosis. Data show that the five-year survival rate for pancreatic cancer patients is less than 7%, and the World Health Organization predicts that by 2030, pancreatic cancer mortality may jump to the second highest ranking among cancer deaths worldwide. Most patients are diagnosed in the advanced stage, with not only severe local tumor infiltration but also frequent distant metastasis, which is the core factor contributing to its high mortality rate. Furthermore, pancreatic cancer's high resistance to existing treatments and high recurrence rate after surgery further exacerbate the disease's lethality.

[0003] Currently, the clinical treatment of pancreatic cancer is still mainly chemotherapy, with gemcitabine being the most commonly used drug. There are also targeted treatment strategies targeting epidermal growth factor receptor (EGFR), angiogenesis, tumor microenvironment, and hypoxia. However, the effects of these treatments are not ideal, and the survival benefits for patients are limited. Surgical resection is currently an effective way to cure pancreatic cancer, but due to the high invasiveness and high metastasis of pancreatic cancer, even after successful surgery, more than 76% of patients will develop distant metastasis of the tumor within a short period of time, resulting in a high recurrence rate.

[0004] Given the limitations of existing treatments, the medical community urgently needs to explore new treatment mechanisms and drug development directions to provide new options for pancreatic cancer treatment. Summary of the Invention

[0005] In view of the defects in the prior art, the present invention proposes a cyclic amide-tetrahydroisoquinoline compound.

[0006] The present invention provides a cyclic amide-tetrahydroisoquinoline compound having the following structure:

[0007]

[0008] Wherein, ring A is a cyclic amide structure;

[0009] Z is any one of O, N or S atoms;

[0010] X is an O atom or -N-R2, wherein R2 is a H atom, C 1～12 Alkyl, C 1～12 Alkylamino, C 1～12 Alkoxy, C 1～12 Alkanoyl, C 1～12Alkylamide, C 1～12 Any one of the alkyl ester groups;

[0011] Y is a C or N atom;

[0012] R1 is wherein A1 is any one of C, O, S or -NH, A2, A3, A4, A5 and A6 are the same or different and are C or N atoms, R 11 is monosubstituted or polysubstituted, selected from H atoms, C 1～12 Alkyl, halogen atom, C 1～12 Alkoxy, C 1～12 Alkylamino, C 1～12 Alkanoyl, C 1～12 Alkylamide, C 1～12 One or more of an alkyl ester group, an amino group, a hydroxyl group, an unsubstituted or substituted aromatic ring, and an unsubstituted or substituted aliphatic ring.

[0013] Ferroptosis, as a newly discovered programmed cell death, has excellent effects in treating cancer. By regulating the ferroptosis process, the inventors have discovered a series of drugs targeting pancreatic cancer cells, providing new options for the treatment of pancreatic cancer. The cyclic amide-tetrahydroisoquinoline compounds of the present invention can inhibit iron autophagy by coactivating nuclear receptor 4, thereby regulating ferroptosis. At the same time, the cyclic amide structure can effectively complex iron ions and prevent the occurrence of ferroptosis. Therefore, the proliferation of tumor cells is inhibited, especially the inhibitory effect on pancreatic cancer cells is significant. The compound structure provided by the present invention is different from the existing drug structure on the market, expands the types of drugs for the clinical treatment of pancreatic cancer, and is suitable for large-scale production.

[0014] Furthermore, the ring A is an aliphatic ring or an aromatic ring amide;

[0015] Z is an O or N atom;

[0016] X is -N-R2, wherein R2 is a hydrogen atom or a C 1～3 Alkyl;

[0017] Y is a C or N atom;

[0018] R1 is wherein A1 is any one of O, S or -NH, A2, A3, A4, A5 and A6 are the same or different and are C or N atoms, R 11 is monosubstituted or polysubstituted, selected from H atoms, C 1～3 Alkyl, halogen atom, C 1～3 Alkoxy, C 1～3 Any one or more of alkylamino, amino, hydroxyl, unsubstituted or substituted piperazine, indole, and morpholine.

[0019] Furthermore, the ring A is a 4-7 membered aliphatic cyclic amide;

[0020] Z is an O atom;

[0021] X is -N-R2, wherein R2 is a hydrogen atom or a C 1～3 Alkyl;

[0022] Y is a C or N atom;

[0023] R1 is wherein A1 is a S atom or -NH, A2, A3, A4, A5 and A6 are the same or different and are C or N atoms, R 11 is monosubstituted or polysubstituted, selected from H atoms, C 1～3 Alkyl, halogen atom, C 1～3 Alkoxy, C 1～3 One or more of alkylamino, amino, hydroxyl, unsubstituted or substituted piperazine, indole, and morpholine, wherein the substituent of the substituted piperazine is C 1～6 Alkyl, halogen, C 1～6 Any of an alkoxy group, a hydroxy group or an amino group.

[0024] Furthermore, the ring A is a 4- to 6-membered aliphatic cyclic amide;

[0025] Z is an O atom;

[0026] X is -N-R2, wherein R2 is a hydrogen atom or a C 1～3 Alkyl;

[0027] Y is a C atom;

[0028] R1 is wherein A1 is -NH; A2, A3, A4, A5 and A6 are the same or different C or N atoms, R 11 is monosubstituted or polysubstituted, selected from H atoms, C 1～3 One or more of an alkyl group, a halogen atom, a non-substituted or substituted piperazine, and a morpholine group, wherein the substituent of the substituted piperazine is C 1～3 Alkyl, C 1～3 Any of an alkoxy group, a hydroxy group or an amino group.

[0029] Furthermore, the cyclic amide-tetrahydroisoquinoline compound has any one of the following structural formulas:

[0030]

[0031]

[0032]

[0033] Furthermore, the cyclic amide-tetrahydroisoquinoline compound is selected from any one of the above compounds 2, 5, 10, 17, 18, 19, 22, 25, 26, 27, 28, 32, 33, 34, 36, 37, 38, 39, 41, 46, 47, 49, 50, 52, 53, 58, 61, 62, 64, 68, 70, 75, 76, 77, 78, 79, 85, 92, 94, 97, 100, 102, and 104.

[0034] Furthermore, the cyclic amide-tetrahydroisoquinoline compound is selected from any one of the above compounds 2, 17, 18, 19, 26, 28, 32, 39, 41, 46, 47, 49, 52, 62, 64, 85, and 100.

[0035] Furthermore, the cyclic amide-tetrahydroisoquinoline compound is selected from any one of the above compounds 2, 18, 28, 47, 39, 41, 46, 64, and 85.

[0036] Furthermore, the cyclic amide-tetrahydroisoquinoline compound is selected from the above compound 39.

[0037] The following is an exemplary synthesis route of a cyclic amide-tetrahydroisoquinoline compound. Ring A of the exemplary compound 25 is a 6-membered aliphatic cyclic amide; Z is an O atom; X is -N-R2, R2 is an H atom; Y is a C atom; R1 is A1 is a S atom, A2 is a N atom, A3, A4, A5 and A6 are all C atoms, R 11 For substituted piperazine, the substituent is methyl:

[0038] The synthetic route of the cyclic amide-tetrahydroisoquinoline compound 25 is given below as an example:

[0039]

[0040] The following is a method for preparing exemplary compound 25, comprising the following steps:

[0041] Compound 1a (0.9-1.1 mmol), TBTU (0.9-1.1 mmol), and K2CO3 (1.4-1.6 mmol) were added to a round-bottom flask in sequence, followed by the addition of dry N,N-dimethylformamide (9-11 mL). The mixture was stirred at room temperature for 55-68 min, followed by the addition of compound 2a (0.9-1.1 mmol). The mixture was stirred at 60°C for 11-13 hours under magnetic stirring, and then extracted with ethyl acetate 2-4 times, each time using 130-160 mL. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The solid obtained by spin drying was separated and purified by column chromatography to obtain a yellow solid to obtain compound 3a (yield: 63-65%).

[0042] Compound 3a (1-1.3 mmol) was added to 4-6 mL of methanol, followed by 1-2 mL of TFA. The mixture was stirred at room temperature for 2.5-3 hours, and then a saturated magnesium carbonate solution was added to adjust the pH to about 8. The mixture was then extracted with ethyl acetate 2-4 times, using 130-160 mL each time. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude compound 4a. Compound 5a (0.9-1.1 mmol) and DBU (1.0-1.2 mmol) were then added and dissolved in N,N-dimethylformamide (7-10 mL). The mixture was stirred under magnetic stirring at 60° C. for 7-9 hours, and then extracted with ethyl acetate 2-4 times, using 150 mL each time. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The solid obtained by spin drying was separated and purified by column chromatography to obtain a yellow solid to obtain compound 6a (yield 58-60%).

[0043] Compound 6a (0.9-1.1 mmol), compound 7a (0.9-1.1 mmol), cesium carbonate (1.1-1.3 mmol) and Pd(OAc)2 (0.9-1.1 mmol) were added to 9-10 mL of methanol and stirred at 80°C for 11-12 h. After the reaction, the solid was filtered out and rinsed with methanol 2-4 times, each time with 9-12 mL. The filtrate was then dried and purified by column chromatography to obtain a yellow solid to obtain compound 25 (yield 66-68%).

[0044] In summary, compared with the prior art, the present invention achieves the following technical effects:

[0045] (1) The cyclic amide-tetrahydroisoquinoline compounds provided by the present invention can significantly inhibit the proliferation of pancreatic cancer cells;

[0046] (2) The cyclic amide-tetrahydroisoquinoline compounds provided by the present invention have low toxicity to organisms;

[0047] (3) The preparation process of the cyclic amide-tetrahydroisoquinoline compounds provided by the present invention is simple and easy to produce on a large scale. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the appendixes and drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following appendixes and drawings only illustrate certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other relevant drawings can be obtained based on these appendixes and drawings without making any creative efforts.

[0049] Figure 1This is a statistical graph showing the effect of the compound prepared in Example 39 of the present invention on the iron ion concentration in PANC-1 cells;

[0050] Figure 2 This is a statistical graph showing the effect of the compound prepared in Example 39 of the present invention on the iron ion concentration in PaTu-8988T cells;

[0051] Figure 3 These are the results of acute toxicity experiments on the compounds prepared in Examples 35, 39, and 75 of the present invention. DETAILED DESCRIPTION

[0052] In order to help those skilled in the art better understand the solutions of the present invention, the technical solutions in the embodiments of the present invention are clearly and completely described below. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without making any creative efforts should fall within the scope of protection of the present invention.

[0053] Example

[0054] The present invention is further described below with reference to specific examples and comparative examples. The following specific examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the following examples, and are particularly not limited to the types of the various component raw materials used in the following specific examples.

[0055] 1. The sources of raw materials for the embodiments and comparative examples are as follows:

[0056] Unless otherwise specified, the raw materials used in the examples of the present invention are commercially available.

[0057] The preparation method of the cyclic amide-tetrahydroisoquinoline compound of the embodiment of the present invention is similar to the synthetic route of the above-mentioned compound 25, comprising the following steps:

[0058] To a round-bottom flask were added a cyclic amide carboxylic acid derivative (1.0 mmol), TBTU (1.0 mmol), and K2CO3 (1.5 mmol) in sequence, followed by the addition of dry N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 1 hour. Subsequently, Boc-tetrahydroisoquinoline (compound 2a series) (1.0 mmol) containing an amino or hydroxyl group was added, and the mixture was reacted at 60°C with magnetic stirring for 12 hours. The mixture was then extracted with ethyl acetate (3 × 150 mL, i.e., three times with 150 mL of ethyl acetate). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The solid obtained by spin drying was separated and purified by column chromatography to obtain a yellow solid, thereby obtaining compound 3a series (yield 60% to 88%).

[0059] Compound 3a series (1.0 mmol) was added to 5 mL of methanol, followed by 1 mL of TFA. After stirring at room temperature for 3 hours, a saturated magnesium carbonate solution was added to adjust the pH to about 8, and then extracted with ethyl acetate (3×150 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain crude compound 4a series. Compound 5a series (1.0 mmol) and DBU (1.2 mmol) were then added and dissolved in N,N-dimethylformamide (10 mL). The mixture was stirred under magnetic stirring at 60°C for 8 hours, and then extracted with ethyl acetate (3×150 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The solid obtained by spin drying was separated and purified by column chromatography to obtain a yellow solid to obtain compound 6a series (yield 59% to 77%).

[0060] Compound 6a series (1.0 mmol), compound 7a series (1.0 mmol), cesium carbonate (1.2 mmol) and Pd(OAc)2 (1.0 mmol) were added to 10 mL of methanol and stirred at 60 °C for 8 h. After the reaction was completed, the solid was filtered out and rinsed with methanol (3×10 mL). The filtrate was then dried and purified by column chromatography to obtain a yellow solid to obtain the final product.

[0061] The structures of the compounds obtained in Example 1-104 are as follows:

[0062]

[0063]

[0064] Example 1

[0065] The characterization data of Example 1 are: 1H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7.64(d,J=8.8H z,1H),7.51(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.76(d,J=8.8Hz,1H),5.53(s,3H) ,4.51(s,2H),4.49(q,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),3.47(t,J=6.0Hz,4H),2.87(t,J=6.0Hz,2H),2.2 4(t,J=6.0Hz,2H),1.78(q,J=6.0Hz,2H),1.59(p,J=6.0Hz,4H),1.57(p,J=6.0Hz,2H),1.31(p,J=6.0Hz,2H).

[0066] Example 2

[0067] The characterization data of Example 2 are: 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,J=8.8Hz,1H),7.6 4(d,J=8.8Hz,,1H),7.51(d,J=8.8Hz,,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.76(d,J=8.8Hz ,1H),5.53(s,3H),4.51(s,2H),3.66(t,J=6.0Hz,2H),3.47(t,J=6.0Hz,4H),2.87(t,J=6.0Hz,2H),2.78( t,J=6.0Hz,1H),2.24(t,J=6.0Hz,2H),1.59(p,J=6.0Hz,4H),1.57(p,J=6.0Hz,2H),1.51(q,J=6.0Hz,2H).

[0068] Example 3

[0069] The characterization data of Example 3 are: 1H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7.64(d,J= 8.8Hz,,1H),7.51(d,J=8.8Hz,,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,,1H),6.76(d,J=8.8Hz,1H) ,5.53(s,3H),4.51(s,2H),4.37(t,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),3.47(t,J=6.0Hz,4H),2.87(t, J=6.0Hz,2H),2.55(t,J=6.0Hz,2H),1.91(q,J=6.0Hz,2H),1.59(p,J=6.0Hz,4H),1.57(p,J=6.0Hz,2H).

[0070] Example 4

[0071] The characterization data of Example 4 are: 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,,1H),7.84(d,J=8.8Hz,1H),7 .64(d,J=8.8Hz,,1H),7.51(s,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,,1H),6.76(d,J=8.8 Hz,1H),5.53(s,3H),4.51(s,2H),3.66(t,J=6.0Hz,2H),3.47(t,J=6.0Hz,4H),2.87(t,J=6.0Hz ,2H),2.78(t,J=6.0Hz,1H),2.38(d,J=6.0Hz,2H),1.59(p,J=6.0Hz,4H),1.57(p,J=6.0Hz,2H).

[0072] Example 5

[0073] The characterization data of Example 5 are: 1H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,,1H),7.84(d,J=8.8Hz,1J=8.8Hz,H),7.64( d,J=8.8Hz,,1H),7.24(t,J=8.8Hz,1H),7.21(t,,1H),6.83(d,J=8.8Hz,1H),6.76(d,J=8.8Hz,1H),5.53(s,3 H),4.51(s,2H),3.66(t,J=6.0Hz,2H),3.47(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.86(t,J=6.0Hz,4H),2. 78(t,J=6.0Hz,1H),2.35(t,J=6.0Hz,4H),2.27(s,J=6.0Hz,3H),1.57(p,J=6.0Hz,2H),1.51(q,J=6.0Hz,2H).

[0074] Example 6

[0075] The characterization data of Example 6 are: 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H), 7.64(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(s,1H) ,5.53(s,2H),4.51(q,J=6.0Hz,2H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.86(t,J= 6.0Hz,4H),2.79(t,J=6.0Hz,1H),2.66(t,J=6.0Hz,3H),2.35(t,J=6.0Hz,4H),2.27(s,3H).

[0076] Example 7

[0077] The characterization data of Example 7 are: 1H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7.64(d,J =8.8Hz,1H),7.51(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.76(d,J=8.8Hz1H),5 .53(s,3H),4.51(s,J=6.0Hz,2H),4.37(q,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H), 2.86(t,J=6.0Hz,4H),2.55(t,J=6.0Hz,2H),2.35(t,J=6.0Hz,4H),2.27(s,3H),1.91(q,J=6.0Hz,2H).

[0078] Example 8

[0079] The characterization data of Example 8 are: 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H) ,7.64(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(d,J= 8.8Hz1H),5.53(s,3H),4.51(s,2H),3.66(t,J=6.0Hz,2H),3.56(t,J=6.0Hz,2H),2.87(t,J= 6.0Hz,2H),2.86(t,J=6.0Hz,4H),2.78(t,J=6.0Hz,1H),2.35(t,J=6.0Hz,4H),2.27(s,3H).

[0080] Example 9

[0081] The characterization data of Example 9 are: 1H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz ,1H),7.64(d,J=8.8Hz,1H),7.51(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8. 8Hz,1H),6.64(d,1H),5.53(s,3H),4.51(s,2H),4.00(s,2H),3.66(t,J=6.0Hz,2H),2. 87(t,J=6.0Hz,2H),2.78(t,J=6.0Hz,1H),2.24(t,J=6.0Hz,2H),1.51(q,J=6.0Hz,2H).

[0082] Example 10

[0083] The characterization data of Example 10 are: 1 H NMR (400MHz, CD3OD) δ8.15(s,2H),8.04(d,J=8.8Hz,1H),7.69(s,1H),7.64(d,J=8.8Hz, 1H),7.51(d,J=8.8Hz,1H),7.44(d,J=8.8Hz,1H),7.29(d,J=8.8Hz,1H),7.24(t,J=8.8Hz ,1H),7.21(d,J=8.8Hz,1H),5.53(s,3H),4.51(d,J=6.0Hz,2H),3.66(t,J=6.0Hz,2H),2 .87(t,J=6.0Hz,2H),2.78(t,J=6.0Hz,1H),2.24(t,J=6.0Hz,2H),1.51(q,J=6.0Hz,2H).

[0084] Example 11

[0085] The characterization data of Example 11 are: 1H NMR (400MHz, CD3OD) δ8.15(s,2H),8.04(d,J=8.8Hz,1H),7.64(d,J=8.8Hz,1H),7. 51(d,J=8.8Hz,1H),7.47(d,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),7.1 1(d,1H),6.88(t,1H),5.53(d,3H),4.51(s,2H),3.84(s,3H),3.66(s,2H),2.87(t ,J=6.0Hz,2H),2.78(t,J=6.0Hz,1H),2.24(t,J=6.0Hz,2H),1.51(q,J=6.0Hz,2H).

[0086] Example 12

[0087] The characterization data of Example 12 are: 1 H NMR (400MHz, CD3OD) δ8.15(s,2H),8.04(d,J=8.8Hz,1H),7.64(d,J=8.8Hz,1H),7.51 (d,J=8.8Hz,1H),7.47(d,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),7.11(t, 1H),6.95(d,1H),5.53(s,3H),5.37(s,1H),4.51(s,2H),3.66(t,J=6.0Hz,2H),2.87 (t,J=6.0Hz,2H),2.78(t,J=6.0Hz,1H),2.24(t,J=6.0Hz,2H),1.51(q,J=6.0Hz,2H).

[0088] Example 13

[0089] The characterization data of Example 13 are: 1 H NMR (400MHz, CD3OD) δ8.15(s,1H),8.04(d,J=8.8Hz,1H),7.69(s,1H),7.44(d,J=8.8Hz,1H),7.29(d,J=8.8Hz,1H),7.26(d,J=8.8Hz,2H),7.24(t ,J=8.8Hz,2H),7.21(d,J=8.8Hz,1H),5.53(s,2H),4.51(s,2H),4.00(d, J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),2.85(t,J=6.0Hz,2H),2.79(s,1H).

[0090] Example 14

[0091] The characterization data of Example 14 are: 1 H NMR(400MHz,CD3OD)δ8.15(s,1H),8.04(d,J=8.8Hz,1H),7.69(s,1H),7.44(d,J =8.8Hz,1H),7.29(d,J=8.8Hz,1H),7.26(d,J=8.8Hz,2H),7.24(t,J=8.8Hz,2H), 7.21(d,J=8.8Hz,1H),5.53(s,3H),4.51(s,2H),3.66(t,J=6.0Hz,2H),3.45(d,J =6.0Hz,2H),2.85(t,J=6.0Hz,2H),2.78(p,J=6.0Hz,1H),2.38(d,J=6.0Hz,2H).

[0092] Example 15

[0093] The characterization data of Example 15 are: 1 H NMR(400MHz,CD3OD)δ8.15(s,1H),8.04(d,J=8.8Hz,1H),7.69(s,1H),7.44(d,J =8.8Hz,1H),7.29(d,J=8.8Hz,1H),7.26(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,2H), 7.21(d,J=8.8Hz,1H),7.20(d,1H),5.53(s,3H),4.37(t,J=6.0Hz,1H),3.97(s,J =6.0Hz,2H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),1.90(d,J=6.0Hz,2H).

[0094] Example 16

[0095] The characterization data of Example 16 are: 1H NMR (400MHz, CD3OD) δ8.15 (s, 1H), 8.04 (d, J = 8.8Hz, 1H), 7.59 (s, 1H), 7.44 (d ,J=8.8Hz,1H),7.26(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,2H),7.21(d,J=8.8Hz, 1H),7.20(d,1H),7.04(d,1H),5.53(s,3H),4.37(t,J=6.0Hz,1H),3.97(s,J=6 .0Hz,2H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),1.90(d,J=6.0Hz,2H).

[0096] Example 17

[0097] The characterization data of Example 17 are: 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7 .64(d,J=8.8Hz,1H),7.51(s,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.76(d,J=8.8H z1H),5.53(s,3H),4.51(s,2H),4.37(t,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),3.47(t,J=6.0Hz, 4H), 2.87 (t, J = 6.0Hz, 2H), 1.90 (d, J = 6.0Hz, 2H), 1.59 (p, J = 6.0Hz, 4H), 1.57 (p, J = 6.0Hz, 2H).

[0098] Example 18

[0099] The characterization data of Example 18 are: 1H NMR(400MHz,CD3OD)δ8.15(s,2H),8.04(d,J=8.8Hz,1H),7.64(d,J=8.8Hz,1H),7 .51(d,J=8.8Hz,1H),7.34(d,1H),7.24(t,J=8.8Hz,2H),7.21(d,J=8.8Hz,1H),7. 17(d,1H),5.53(s,3H),4.51(s,2H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H) ,2.78(t,J=6.0Hz,1H),2.29(d,J=6.0Hz,3H),2.24(t,2H),1.51(q,J=6.0Hz,2H).

[0100] Example 19

[0101] The characterization data of Example 19 are: 1 H NMR (400MHz, CD3OD) δ8.15 (s, 1H), 8.04 (d, J = 8.8Hz, 1H), 7.69 (s, 1H), 7.44 (d, J = 8. 8Hz,1H),7.29(d,J=8.8Hz,1H),7.26(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,2H),7.21(d ,J=8.8Hz,1H),7.20(d,1H),5.53(s,3H),4.37(d,J=6.0Hz,1H),3.97(s,2H),3.66( t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.55(t,J=6.0Hz,2H),1.91(q,J=6.0Hz,2H).

[0102] Example 20

[0103] The characterization data of Example 20 are: 1H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7.64(d,J =8.8Hz,1H),7.51(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.76(d,J=8.8Hz,1H), 4.51(s,2H),4.49(t,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.86(t,J=6.0Hz,4H), 2.35(t,J=6.0Hz,4H),2.25(s,3H),2.20(t,J=6.0Hz,2H),1.76(q,J=6.0Hz,2H),1.31(p,J=6.0Hz,4H).

[0104] Example 21

[0105] The characterization data of Example 21 are: 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7.64(d,J =8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(d,J=8.8Hz1H),5.53(s,3H ),4.51(q,J=6.0Hz,2H),3.67(t,J=6.0Hz,4H),3.66(t,J=6.0Hz,2H),3.47(q,J=6.0Hz,2H),3.27(t,J =6.0Hz,4H),2.87(t,J=6.0Hz,2H),2.78(t,J=6.0Hz,1H),1.57(p,J=6.0Hz,2H),1.51(q,J=6.0Hz,2H).

[0106] Example 22

[0107] The characterization data of Example 22 are: 1H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8 Hz,1H),7.64(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d, 1H),6.76(d,J=8.8Hz1H),5.53(s,2H),4.51(s,2H),3.67(t,J=6.0Hz,4H),3.66(t,J =6.0Hz,2H),3.27(t,J=6.0Hz,4H),2.87(t,J=6.0Hz,2H),2.79(s,1H),2.66(s,3H).

[0108] Example 23

[0109] The characterization data of Example 23 are: 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7.6 4(d,J=8.8Hz,1H),7.51(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.76(d,J= 8.8Hz1H),5.53(s,3H),4.51(s,2H),4.37(q,J=6.0Hz,1H),3.67(t,J=6.0Hz,4H),3.66(t,J=6.0H z,2H),3.27(t,J=6.0Hz,4H),2.87(t,J=6.0Hz,2H),2.55(t,J=6.0Hz,2H),1.91(q,J=6.0Hz,2H).

[0110] Example 24

[0111] The characterization data of Example 24 are: 1H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1 H),7.64(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76 (d,J=8.8Hz1H),5.53(s,3H),4.51(s,2H),3.67(t,J=6.0Hz,4H),3.66(t,J=6.0Hz,2H),3 .56(t,J=6.0Hz,2H),3.27(t,J=6.0Hz,4H),2.87(t,J=6.0Hz,2H),2.78(t,J=6.0Hz,1H).

[0112] Example 25

[0113] The characterization data of Example 25 are: 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7.64(d,J=8. 8Hz,1H),7.51(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.76(d,J=8.8Hz1H),5.53(s ,3H),4.51(s,2H),4.49(q,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.86(t,J=6.0Hz,4 H),2.35(t,J=6.0Hz,4H),2.27(s,3H),2.24(t,J=6.0Hz,2H),1.78(q,J=6.0Hz,2H),1.31(p,J=6.0Hz,2H).

[0114] Example 26

[0115] The characterization data of Example 26 are: 1H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7.64(d ,J=8.8Hz,1H),7.51(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.76(d,J=8.8Hz1 H),5.53(s,3H),4.51(s,2H),4.49(s,1H),3.67(t,J=6.0Hz,4H),3.66(t,J=6.0Hz,2H),3.27(t,J=6 .0Hz,4H),2.87(t,J=6.0Hz,2H),2.24(t,J=6.0Hz,2H),1.78(t,J=6.0Hz,2H),1.31(p,J=6.0Hz,2H).

[0116] Example 27

[0117] The characterization data of Example 27 are: 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H) ,7.64(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(d,J= 8.8Hz1H),5.53(s,3H),4.51(s,2H),4.37(t,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),2.87(t,J= 6.0Hz,2H),2.86(t,J=6.0Hz,4H),2.35(t,4J=6.0Hz,H),2.27(s,3H),1.90(d,J=6.0Hz,2H).

[0118] Example 28

[0119] The characterization data of Example 28 are: 1H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7.64 (d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(d,J=8.8Hz1H),5 .53(s,3H),4.51(s,2H),4.37(t,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.86 (t,J=6.0Hz,4H),2.55(t,J=6.0Hz,2H),2.35(t,J=6.0Hz,4H),2.27(s,3H),1.91(q,J=6.0Hz,2H).

[0120] Example 29

[0121] The characterization data of Example 29 are: 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1 H),7.64(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76 (d,J=8.8Hz1H),5.53(s,3H),4.51(s,2H),4.37(q,J=6.0Hz,1H),3.67(t,J=6.0Hz,4H),3 .66(t,J=6.0Hz,2H),3.27(t,J=6.0Hz,4H),2.87(t,J=6.0Hz,2H),1.90(d,J=6.0Hz,2H).

[0122] Example 30

[0123] The characterization data of Example 30 are: 1H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7 .64(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(d,J=8.8H z1H),5.53(s,3H),4.51(s,2H),4.37(t,J=6.0Hz,1H),3.67(t,J=6.0Hz,4H),3.66(t,J=6.0Hz, 2H), 3.27 (t, J = 6.0Hz, 4H), 2.87 (t, J = 6.0Hz, 2H), 2.55 (t, J = 6.0Hz, 2H), 1.91 (q, J = 6.0Hz, 2H).

[0124] Example 31

[0125] The characterization data of Example 31 are: 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7 .64(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(d,J=8.8H z1H),5.53(s,3H),4.51(s,2H),4.37(q,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),3.47(t,J=6.0Hz, 4H), 2.87 (t, J = 6.0Hz, 2H), 1.90 (d, J = 6.0Hz, 2H), 1.59 (p, J = 6.0Hz, 4H), 1.57 (p, J = 6.0Hz, 2H).

[0126] Example 32

[0127] The characterization data of Example 32 are: 1H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7.64(d ,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(d,J=8.8Hz1H),5.53( s,3H),4.51(s,2H),4.37(t,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),3.47(t,J=6.0Hz,4H),2.87(t,J=6 .0Hz,2H),2.55(t,J=6.0Hz,2H),1.91(q,J=6.0Hz,2H),1.59(p,J=6.0Hz,4H),1.57(p,J=6.0Hz,2H).

[0128] Example 33

[0129] The characterization data of Example 33 are: 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz ,1H),7.64(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H), 6.76(d,J=8.8Hz1H),5.53(s,2H),4.51(s,2H),4.00(s,1H),3.67(t,J=6.0Hz,4H),3.6 6(t,J=6.0Hz,2H),3.27(t,J=6.0Hz,4H),2.87(t,J=6.0Hz,2H),2.79(d,J=6.0Hz,1H).

[0130] Example 34

[0131] The characterization data of Example 34 are: 1H NMR (400MHz, CD3OD) δ8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8Hz, 1H), 7.84 (d,J=8.8Hz,1H),7.64(d,J=8.8Hz,1H),7.24(d,1H),7.21(d,J=8.8Hz,1H), 6.83(d,1H),6.76(d,J=8.8Hz1H),5.53(s,2H),4.51(s,2H),4.00(d,J=6.0 Hz,1H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.79(d,J=6.0Hz,1H).

[0132] Example 35

[0133] The characterization data of Example 35 are: 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7 .64(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(d,J=8.8H z1H),5.53(s,2H),4.51(s,2H),4.00(d,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),3.47(t,J=6.0Hz, 4H), 2.87 (t, J = 6.0Hz, 2H), 2.79 (d, J = 6.0Hz, 1H), 1.59 (p, J = 6.0Hz, 4H), 1.57 (p, J = 6.0Hz, 2H).

[0134] Example 36

[0135] The characterization data of Example 36 are: 1 H NMR (400MHz, CD3OD) δ8.15(s,2H),8.04(d,J=8.8Hz,1H),7.64(d,J=8.8Hz, 1H),7.59(s,1H),7.44(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8. 8Hz,1H),7.04(d,1H),6.83(d,1H),5.53(s,2H),4.51(s,2H),4.00(d,J=6.0 Hz,1H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.79(d,J=6.0Hz,1H).

[0136] Example 37

[0137] The characterization data of Example 37 are: 1 H NMR (400MHz, CD3OD) δ8.15(s,2H),8.04(d,J=8.8Hz,1H),7.64(d,J=8.8Hz, 1H),7.59(d,1H),7.44(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8. 8Hz,1H),7.04(d,1H),6.83(d,1H),5.53(s,3H),4.51(s,2H),4.37(q,J=6.0 Hz,1H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),1.90(d,J=6.0Hz,2H).

[0138] Example 38

[0139] The characterization data of Example 38 are: 1 H NMR(400MHz,CD3OD)δ8.15(s,2H),8.04(d,J=8.8Hz,1H),7.64(d,J=8.8Hz,1H),7 .59(s,1H),7.44(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),7. 04(d,1H),6.83(d,1H),5.53(s,3H),4.51(s,2H),4.37(q,J=6.0Hz,1H),3.66(t, J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.55(t,J=6.0Hz,2H),1.91(q,J=6.0Hz,2H).

[0140] Example 39

[0141] The characterization data of Example 39 are: 1H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7.64(d,J= 8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(d,J=8.8Hz1H),5.53(s,3H) ,4.51(s,2H),4.49(q,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.86(t,J=6.0Hz,4H) ,2.35(t,J=6.0Hz,4H),2.27(s,3H),2.24(t,J=6.0Hz,2H),1.78(q,J=6.0Hz,2H),1.31(p,J=6.0Hz,2H).

[0142] Example 40

[0143] The characterization data of Example 40 are: 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7.64(d, J=8.8Hz,1H),7.24(d,1H),7.21(t,1H),6.83(d,1H),6.76(d,J=8.8Hz1H),5.53(s,3H),4.51(s,2H), 4.49(d,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),3.47(t,J=6.0Hz,4H),2.87(t,J=6.0Hz,2H),2.24(t,J= 6.0Hz,2H),1.78(q,J=6.0Hz,2H),1.59(p,J=6.0Hz,4H),1.57(p,J=6.0Hz,2H),1.31(p,J=6.0Hz,2H).

[0144] Example 41

[0145] The characterization data of Example 41 are: 1H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7.64(d ,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(d,J=8.8Hz1H),5.53( s,3H),4.51(s,2H),4.49(d,J=6.0Hz,1H),3.67(t,J=6.0Hz,4H),3.66(t,J=6.0Hz,2H),3.27(t,J=6 .0Hz,4H),2.87(t,J=6.0Hz,2H),2.24(t,J=6.0Hz,2H),1.78(q,J=6.0Hz,2H),1.31(p,J=6.0Hz,2H).

[0146] Example 42

[0147] The characterization data of Example 42 are: 1 H NMR (400MHz, CD3OD) δ8.15(s,2H),8.04(d,J=8.8Hz,1H),7.64(d,J=8.8Hz,1H),7.59(d ,1H),7.44(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),7.04(d,1H), 6.83(d,1H),5.53(s,3H),4.51(s,2H),4.49(d,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),2. 87(t,J=6.0Hz,2H),2.24(t,J=6.0Hz,2H),1.78(q,J=6.0Hz,2H),1.31(p,J=6.0Hz,2H).

[0148] Example 43

[0149] The characterization data of Example 43 are: 1H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7 .64(d,J=8.8Hz,1H),7.51(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.76( d,J=8.8Hz1H),5.53(s,2H),4.51(s,2H),4.00(d,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),2.87(t, J=6.0Hz,2H),2.86(t,J=6.0Hz,4H),2.79(d,J=6.0Hz,1H),2.35(t,J=6.0Hz,4H),2.27(s,3H).

[0150] Example 44

[0151] The characterization data of Example 44 are: 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H) ,7.64(d,J=8.8Hz,1H),7.51(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H), 6.76(d,J=8.8Hz1H),5.53(s,2H),4.51(s,2H),4.00(d,J=6.0Hz,1H),3.67(t,J=6.0Hz,4H) ,3.66(t,J=6.0Hz,2H),3.27(t,J=6.0Hz,4H),2.87(t,J=6.0Hz,2H),2.79(d,J=6.0Hz,1H).

[0152] Example 45

[0153] The characterization data of Example 45 are: 1H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7 .64(d,J=8.8Hz,1H),7.51(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.76( d,J=8.8Hz1H),5.53(s,3H),4.51(s,2H),4.37(q,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),2.87(t, J=6.0Hz,2H),2.86(t,J=6.0Hz,4H),2.35(t,J=6.0Hz,4H),2.27(s,3H),1.90(d,J=6.0Hz,2H).

[0154] Example 46

[0155] The characterization data of Example 46 are: 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,2H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1 H),7.64(d,J=8.8Hz,1H),7.51(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz, 1H),6.76(d,J=8.8Hz1H),5.53(s,3H),4.51(s,2H),4.37(q,J=6.0Hz,1H),3.67(t,J=6.0 Hz, 4H), 3.66 (t, J = 6.0Hz, 2H), 3.27 (t, J = 6.0Hz, 4H), 2.87 (t, J = 6.0Hz, 2H), 1.90 (s, 2H).

[0156] Example 47

[0157] The characterization data of Example 47 are: 1H NMR (400MHz, CD3OD) δ8.15(s,2H),8.04(d,J=8.8Hz,1H),7.64(d,J=8.8Hz,1H ),7.59(s,1H),7.51(d,J=8.8Hz,1H),7.44(d,J=8.8Hz,1H),7.24(t,J=8.8Hz, 1H),7.21(d,J=8.8Hz,1H),7.04(d,1H),5.53(s,3H),4.51(s,2H),4.37(q,J=6 .0Hz,1H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),1.90(d,J=6.0Hz,2H).

[0158] Example 48

[0159] The characterization data of Example 48 are: 1 H NMR (400MHz, CD3OD) δ8.15(s,2H),8.04(d,J=8.8Hz,1H),7.64(d,J=8.8Hz,1H),7.51(d,J= 8.8Hz,1H),7.47(d,1H),7.31(t,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.80(d ,1H),5.53(s,3H),4.51(s,2H),4.49(q,J=6.0Hz,1H),4.00(s,2H),3.66(t,J=6.0Hz,2H), 2.87(t,J=6.0Hz,2H), 2.24(t,J=6.0Hz,2H), 1.78(q,J=6.0Hz,2H), 1.31(p,J=6.0Hz,2H).

[0160] Example 49

[0161] The characterization data of Example 49 are: 1H NMR(400MHz,CD3OD)δ8.15(s,2H),8.04(d,J=8.8Hz,1H),7.64(d,J=8.8Hz,1H) ,7.51(d,J=8.8Hz,1H),7.47(d,1H),7.31(t,1H),7.24(t,J=8.8Hz,1H),7.21(d ,J=8.8Hz,1H),6.80(d,1H),5.53(s,3H),4.51(s,2H),4.00(s,2H),3.66(t,J= 6.0Hz,2H),3.56(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.78(t,J=6.0Hz,1H).

[0162] Example 50

[0163] The characterization data of Example 50 are: 1 H NMR (400MHz, CD3OD) δ8.15(s,2H),8.04(d,J=8.8Hz,1H),7.64(d,J=8.8Hz,1H),7.51(d,J=8.8Hz,1H),7.47(d,1H),7.31(t,1H),7.24(t,J=8.8Hz, 1H),7.21(d,J=8.8Hz,1H),6.80(d,1H),5.53(s,2H),4.51(s,2H),4.00(s ,3H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.79(d,J=6.0Hz,1H).

[0164] Example 51

[0165] The characterization data of Example 51 are: 1 H NMR (400MHz, CD3OD) δ8.15(s,2H),8.04(d,J=8.8Hz,1H),7.64(d,J=8.8Hz,1H),7.51 (d,J=8.8Hz,1H),7.47(d,1H),7.31(t,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz, 1H),6.80(d,1H),5.53(s,3H),4.51(s,2H),4.37(t,J=6.0Hz,1H),4.00(s,2H),3.66 (t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.55(t,J=6.0Hz,2H),1.91(q,J=6.0Hz,2H).

[0166] Example 52

[0167] The characterization data of Example 52 are: 1 H NMR (400MHz, CD3OD) δ8.15(s,2H),8.04(d,J=8.8Hz,1H),7.64(d,J=8.8Hz,1H),7.51 (d,J=8.8Hz,1H),7.47(d,1H),7.31(t,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz, 1H),6.80(d,1H),5.53(s,3H),4.51(s,2H),4.00(s,2H),3.66(t,J=6.0Hz,2H),2.96 (q,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.78(t,J=6.0Hz,1H),2.00(q,J=6.0Hz,2H).

[0168] Example 53

[0169] The characterization data of Example 53 are: 1 H NMR (400MHz, CD3OD) δ8.39(s,1H),8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.44(d,J=8.8 Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(t,1H),6.76(d,J=8.8Hz1H),5.53(s,2H ),4.51(s,2H),3.67(t,J=6.0Hz,4H),3.66(t,J=6.0Hz,2H),3.47(t,J=6.0Hz,2H),3.27(t,J=6.0H z,4H),2.87(t,J=6.0Hz,2H),2.78(t,J=6.0Hz,1H),1.57(p,J=6.0Hz,,2H),1.51(q,J=6.0Hz,2H).

[0170] Example 54

[0171] The characterization data of Example 54 are: 1H NMR (400MHz, CD3OD) δ8.39(s,1H),8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.44(d,J=8.8 Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(d,J=8.8Hz,1H),5.53(s,2 H),4.51(s,2H),3.67(t,J=6.0Hz,4H),3.66(t,J=6.0Hz,2H),3.47(t,J=6.0Hz,2H),3.27(t,J=6.0 Hz, 4H), 2.87 (t, J = 6.0Hz, 2H), 2.78 (t, J = 6.0Hz, 1H), 1.57 (p, J = 6.0Hz, 2H), 1.51 (q, J = 6.0Hz, 2H).

[0172] Example 55

[0173] The characterization data of Example 55 are: 1 H NMR (400MHz, CD3OD) δ8.39(s,1H),8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.51(d,J= 8.8Hz,1H),7.44(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.76(d,J=8.8H z1H),5.53(s,2H),4.51(s,2H),4.37(q,J=6.0Hz,1H),3.67(t,J=6.0Hz,4H),3.66(t,J=6.0Hz, 2H), 3.27 (t, J = 6.0Hz, 4H), 2.87 (t, J = 6.0Hz, 2H), 2.55 (t, J = 6.0Hz, 2H), 1.91 (q, J = 6.0Hz, 2H).

[0174] Example 56

[0175] The characterization data of Example 56 are: 1H NMR (400MHz, CD3OD) δ8.39(s,1H),8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.4 4(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(d,J =8.8Hz1H),5.53(s,2H),4.51(s,2H),3.67(t,J=6.0Hz,4H),3.66(t,J=6.0Hz,2H),3.5 6(t,J=6.0Hz,2H),3.27(t,J=6.0Hz,4H),2.87(t,J=6.0Hz,2H),2.78(t,J=6.0Hz,1H).

[0176] Example 57

[0177] The characterization data of Example 57 are: 1 H NMR (400MHz, CD3OD) δ8.39(s,1H),8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.51(d,J=8.8Hz,1H), 7.44(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.76(s,1H),5.53(s,2H),4.51(q,J=6. 0Hz,2H),4.49(t,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.86(t,J=6.0Hz,4H),2.35( t,J=6.0Hz,4H),2.27(s,J=6.0Hz,3H),2.24(t,J=6.0Hz,2H),1.78(q,J=6.0Hz,2H),1.31(p,J=6.0Hz,2H).

[0178] Example 58

[0179] The characterization data of Example 58 are: 1H NMR (400MHz, CD3OD) δ8.39(s,1H),8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.51(d,J=8.8Hz ,1H),7.44(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.76(d,J=8.8Hz1H),5.53( s,2H),4.51(s,2H),4.49(q,J=6.0Hz,1H),3.67(t,J=6.0Hz,4H),3.66(t,J=6.0Hz,2H),3.27(t,J=6 .0Hz,4H),2.87(t,J=6.0Hz,2H),2.24(t,J=6.0Hz,2H),1.78(q,J=6.0Hz,2H),1.31(p,J=6.0Hz,2H).

[0180] Example 59

[0181] The characterization data of Example 59 are: 1 H NMR (400MHz, CD3OD) δ8.39(s,1H),8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.44( d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(d,J=8.8H z1H),5.53(s,2H),4.51(s,2H),4.37(q,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),2.87(t,J=6. 0Hz, 2H), 2.86 (t, J = 6.0Hz, 4H), 2.35 (t, J = 6.0Hz, 4H), 2.27 (s, 3H), 1.90 (d, J = 6.0Hz, 2H).

[0182] Example 60

[0183] The characterization data of Example 60 are: 1H NMR (400MHz, CD3OD) δ8.39(s,1H),8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.44(d,J=8 .8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(d,J=8.8Hz1H),5.53( s,2H),4.51(s,2H),4.37(q,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.86(t ,J=6.0Hz,4H),2.55(t,J=6.0Hz,2H),2.35(t,J=6.0Hz,4H),2.27(s,3H),1.91(q,J=6.0Hz,2H).

[0184] Example 61

[0185] The characterization data of Example 61 are: 1 H NMR (400MHz, CD3OD) δ8.39(s,1H),8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.4 4(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(d,J =8.8Hz1H),5.53(s,2H),4.51(s,2H),4.37(q,J=6.0Hz,1H),3.67(t,J=6.0Hz,4H),3.6 6(t,J=6.0Hz,2H),3.27(t,J=6.0Hz,4H),2.87(t,J=6.0Hz,2H),1.90(d,J=6.0Hz,2H).

[0186] Example 62

[0187] The characterization data of Example 62 are: 1H NMR(400MHz,CD3OD)δ8.39(s,1H),8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7 .44(d,J=8.8Hz,1H),7.24(d,1H),7.21(t,1H),6.83(d,1H),6.76(d,J=8.8Hz1H),5.5 3(s,2H),4.51(s,2H),4.37(s,1H),3.67(q,J=6.0Hz,4H),3.66(t,J=6.0Hz,2H),3.27 (t,J=6.0Hz,4H),2.87(t,J=6.0Hz,2H),2.55(t,J=6.0Hz,2H),1.91(q,J=6.0Hz,2H).

[0188] Example 63

[0189] The characterization data of Example 63 are: 1 H NMR (400MHz, CD3OD) δ8.39(s,1H),8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.44(d, J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(d,J=8.8Hz1H) ,5.53(s,2H),4.51(s,2H),4.37(q,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),3.47(t,J=6.0Hz,4H ),2.87(t,J=6.0Hz,2H),1.90(d,J=6.0Hz,2H),1.59(t,J=6.0Hz,4H),1.57(p,J=6.0Hz,2H).

[0190] Example 64

[0191] The characterization data of Example 64 are: 1H NMR (400MHz, CD3OD) δ8.39(s,1H),8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.44(d,J=8 .8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(d,J=8.8Hz1H),5.53( s,2H),4.51(s,2H),4.37(t,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),3.47(t,J=6.0Hz,4H),2.87(t ,J=6.0Hz,2H),2.55(t,J=6.0Hz,2H),1.91(q,J=6.0Hz,2H),1.59(p,J=6.0Hz,4H),1.57(p,2H).

[0192] Example 65

[0193] The characterization data of Example 65 are: 1 H NMR (400MHz, CD3OD) δ8.39(s,1H),8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.4 4(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(d,J =8.8Hz1H),5.53(s,1H),4.51(s,2H),4.00(d,J=6.0Hz,1H),3.67(t,J=6.0Hz,4H),3.6 6(t,J=6.0Hz,2H),3.27(t,J=6.0Hz,4H),2.87(t,J=6.0Hz,2H),2.79(d,J=6.0Hz,1H).

[0194] Example 66

[0195] The characterization data of Example 66 are: 1H NMR(400MHz,CD3OD)δ8.39(s,1H),8.15(s,2H),7.88(d,1H),7.64(d,J=8.8 Hz,1H),7.44(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H), 6.83(d,1H),6.76(d,J=8.8Hz1H),5.53(s,1H),4.51(s,2H),4.00(d,J=6.0 Hz,1H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.79(d,J=6.0Hz,1H).

[0196] Example 67

[0197] The characterization data of Example 67 are: 1 H NMR (400MHz, CD3OD) δ8.39(s,1H),8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.44(d, J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(d,J=8.8Hz1H) ,5.53(s,1H),4.51(s,2H),4.00(d,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),3.47(t,J=6.0Hz,4H ),2.87(t,J=6.0Hz,2H),2.79(d,J=6.0Hz,1H),1.59(p,J=6.0Hz,4H),1.57(p,J=6.0Hz,2H).

[0198] Example 68

[0199] The characterization data of Example 68 are: 1 H NMR (400MHz, CD3OD) δ8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.44(d,J=8.8Hz,1H),7.40(s,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz, 1H),7.04(d,1H),6.83(d,1H),5.53(s,1H),4.51(s,2H),4.00(d,J=6.0Hz ,1H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.79(d,J=6.0Hz,1H).

[0200] Example 69

[0201] The characterization data of Example 69 are: 1 H NMR (400MHz, CD3OD) δ8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.44(d,J=8.8Hz,1H),7.40(s,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz, 1H),7.04(d,1H),6.83(d,1H),5.53(s,2H),4.51(s,2H),4.37(q,J=6.0Hz ,1H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),1.90(d,J=6.0Hz,2H).

[0202] Example 70

[0203] The characterization data of Example 70 are: 1 H NMR (400MHz, CD3OD) δ8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8Hz, 1H), 7.44 (d, J=8.8Hz,1H),7.40(s,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),7.04(d ,1H),6.83(d,1H),5.53(s,2H),4.51(s,2H),4.37(q,J=6.0Hz,1H),3.66(t,J= 6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.55(t,J=6.0Hz,2H),1.91(q,J=6.0Hz,2H).

[0204] Example 71

[0205] The characterization data of Example 71 are: 1H NMR (400MHz, CD3OD) δ8.39(s,1H),8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.44(d,J=8.8Hz, 1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(d,J=8.8Hz1H),5.53(s,2H),4.5 1(s,2H),4.49(d,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.86(t,J=6.0Hz,4H),2 .35(t,J=6.0Hz,4H),2.27(s,3H),2.24(t,J=6.0Hz,2H),1.78(q,J=6.0Hz,2H),1.31(p,J=6.0Hz,2H).

[0206] Example 72

[0207] The characterization data for Example 72 are: 1 H NMR (400MHz, CD3OD) δ8.39(s,1H),8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.44(d,J=8.8Hz,1H ),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(d,J=8.8Hz1H),5.53(s,2H),4.51(s, 2H),4.49(d,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),3.47(t,J=6.0Hz,4H),2.87(t,J=6.0Hz,2H),2.24(t, J=6.0Hz,2H),1.78(t,J=6.0Hz,2H),1.59(p,J=6.0Hz,4H),1.57(p,J=6.0Hz,2H),1.31(p,J=6.0Hz,2H).

[0208] Example 73

[0209] The characterization data of Example 73 are: 1H NMR (400MHz, CD3OD) δ8.39(s,1H),8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.44(d,J=8.8 Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.83(d,1H),6.76(d,J=8.8Hz1H),5.53(s,2H ),4.51(s,2H),4.49(d,J=6.0Hz,1H),3.67(t,J=6.0Hz,4H),3.66(t,J=6.0Hz,2H),3.27(t,J=6.0 Hz, 4H), 2.87 (t, J = 6.0Hz, 2H), 2.24 (t, J = 6.0Hz, 2H), 1.78 (q, J = 6.0Hz, 2H), 1.31 (p, J = 6.0Hz, 2H).

[0210] Example 74

[0211] The characterization data for Example 74 are: 1 H NMR (400MHz, CD3OD) δ8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.44(d,J=8 .8Hz,1H),7.40(s,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),7.04(d,1H), 6.83(d,1H),5.53(s,2H),4.51(s,2H),4.49(s,1H),3.66(t,J=6.0Hz,2H),2.87(t ,J=6.0Hz,2H),2.24(t,J=6.0Hz,2H),1.78(t,J=6.0Hz,2H),1.31(p,J=6.0Hz,2H).

[0212] Example 75

[0213] The characterization data of Example 75 are: 1H NMR (400MHz, CD3OD) δ8.39(s,1H),8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.51(d, J=8.8Hz,1H),7.44(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.76(d,J= 8.8Hz1H),5.53(s,1H),4.51(s,2H),4.00(d,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),2.87(t,J= 6.0Hz,2H),2.86(t,J=6.0Hz,4H),2.79(d,J=6.0Hz,1H),2.35(t,J=6.0Hz,4H),2.27(s,3H).

[0214] Example 76

[0215] The characterization data for Example 76 are: 1 H NMR (400MHz, CD3OD) δ8.39(s,1H),8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.51( d,J=8.8Hz,1H),7.44(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.76 (d,J=8.8Hz1H),5.53(s,1H),4.51(s,2H),4.00(d,J=6.0Hz,1H),3.67(t,J=6.0Hz,4H),3 .66(t,J=6.0Hz,2H),3.27(t,J=6.0Hz,4H),2.87(t,J=6.0Hz,2H),2.79(d,J=6.0Hz,1H).

[0216] Example 77

[0217] The characterization data for Example 77 are: 1H NMR (400MHz, CD3OD) δ8.39(s,1H),8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.51( s,1H),7.44(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.76(d,J=8.8H z1H),5.53(s,2H),4.51(s,2H),4.37(q,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),2.87(t,J=6. 0Hz, 2H), 2.86 (t, J = 6.0Hz, 4H), 2.35 (t, J = 6.0Hz, 4H), 2.27 (s, 3H), 1.90 (d, J = 6.0Hz, 2H).

[0218] Example 78

[0219] The characterization data of Example 78 are: 1 H NMR (400MHz, CD3OD) δ8.39(s,1H),8.15(s,2H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.51( d,J=8.8Hz,1H),7.44(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.76 (d,J=8.8Hz1H),5.53(s,2H),4.51(s,2H),4.37(q,J=6.0Hz,1H),3.67(t,J=6.0Hz,4H),3 .66(t,J=6.0Hz,2H),3.27(t,J=6.0Hz,4H),2.87(t,J=6.0Hz,2H),1.90(d,J=6.0Hz,2H).

[0220] Example 79

[0221] The characterization data of Example 79 are: 1H NMR (400MHz, CD3OD) δ8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8Hz, 1H), 7.51 (d,J=8.8Hz,1H),7.44(d,J=8.8Hz,1H),7.40(d,1H),7.24(t,J=8.8Hz,1H), 7.21(d,J=8.8Hz,1H),7.04(d,1H),5.53(s,2H),4.51(s,2H),4.37(q,J=6.0 Hz,1H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),1.90(d,J=6.0Hz,2H).

[0222] Example 80

[0223] The characterization data of Example 80 are: 1 H NMR(400MHz,CD3OD)δ8.15(s,2H),7.95(d,1H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.51 (d,J=8.8Hz,1H),7.31(t,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.78(d,1H) ,5.53(s,2H),4.51(s,2H),4.49(q,J=6.0Hz,1H),4.00(s,2H),3.66(t,J=6.0Hz,2H),2. 87(t,J=6.0Hz,2H),2.24(t,J=6.0Hz,2H),1.78(q,J=6.0Hz,2H),1.31(p,J=6.0Hz,2H).

[0224] Example 81

[0225] The characterization data of Example 81 are: 1 H NMR(400MHz,CD3OD)δ8.15(s,2H),7.95(d,1H),7.88(d,1H),7.64(d,J=8.8H z,1H),7.51(d,J=8.8Hz,1H),7.31(t,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8 .8Hz,1H),6.78(d,1H),5.53(s,2H),4.51(s,2H),4.00(s,2H),3.66(t,J=6. 0Hz, 2H), 3.56 (t, J = 6.0Hz, 2H), 2.87 (t, J = 6.0Hz, 2H), 2.78 (t, J = 6.0Hz, 1H).

[0226] Example 82

[0227] The characterization data of Example 82 are: 1 H NMR (400MHz, CD3OD) δ8.15(s,2H),7.95(d,1H),7.88(d,1H),7.64(d,J=8.8Hz,1H),7.51(d,J=8.8Hz,1H),7.31(t,1H),7.24(t,J=8.8Hz,1H),7. 21(d,J=8.8Hz,1H),6.78(d,1H),5.53(s,1H),4.51(s,2H),4.00(s,s,d, 3H), 3.66(t,J=6.0Hz,2H), 2.87(t,J=6.0Hz,2H), 2.79(d,J=6.0Hz,1H).

[0228] Example 83

[0229] The characterization data of Example 83 are: 1 H NMR(400MHz,CD3OD)δ8.15(s,2H),7.95(d,1H),7.88(d,1H),7.64(d,J=8.8Hz,1H) ,7.51(d,J=8.8Hz,1H),7.31(t,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H), 6.78(d,1H),5.53(s,2H),4.51(s,2H),4.37(q,J=6.0Hz,1H),4.00(s,2H),3.66(t ,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.55(t,J=6.0Hz,2H),1.91(q,J=6.0Hz,2H).

[0230] Example 84

[0231] The characterization data of Example 84 are: 1H NMR(400MHz,CD3OD)δ8.15(s,2H),7.95(d,1H),7.88(d,1H),7.64(d,J=8.8Hz,1H) ,7.51(d,J=8.8Hz,1H),7.31(t,1H),7.24(t,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H), 6.78(d,1H),5.53(s,2H),4.51(s,2H),4.00(s,2H),3.66(t,J=6.0Hz,2H),2.96(q ,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.78(t,J=6.0Hz,1H),2.00(q,J=6.0Hz,2H).

[0232] Example 85

[0233] The characterization data of Example 85 are: 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,1H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8H z,1H),7.26(d,J=8.8Hz,2H),7.24(t,J=8.8Hz,2H),7.21(d,J=8.8Hz,1H),6.76(d,J= 8.8Hz1H),5.53(s,2H),4.51(s,2H),4.00(d,J=6.0Hz,1H),3.67(t,J=6.0Hz,4H),3.6 6(t,J=6.0Hz,2H),3.27(t,J=6.0Hz,4H),2.85(t,J=6.0Hz,2H),2.79(d,J=6.0Hz,1H).

[0234] Example 86

[0235] The characterization data of Example 86 are: 1H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,1H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H) ,7.26(d,J=8.8Hz,2H),7.24(t,J=8.8Hz,2H),7.21(d,J=8.8Hz,1H),6.76(d,J=8.8Hz1H),5 .53(s,3H),4.51(s,2H),3.67(t,J=6.0Hz,4H),3.66(t,J=6.0Hz,2H),3.45(t,J=6.0Hz,2H) ,3.27(t,J=6.0Hz,4H),2.85(t,J=6.0Hz,2H),2.78(p,J=6.0Hz,1H),2.38(d,J=6.0Hz,2H).

[0236] Example 87

[0237] The characterization data of Example 87 are: 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,1H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H) ,7.26(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,2H),7.21(d,J=8.8Hz,1H),7.20(d,1H),6.76(d,J =8.8Hz1H),5.53(s,3H),4.37(q,J=6.0Hz,1H),3.97(s,J=6.0Hz,2H),3.67(t,J=6.0Hz,4H) ,3.66(t,J=6.0Hz,2H),3.27(t,J=6.0Hz,4H),2.87(t,J=6.0Hz,2H),1.90(d,J=6.0Hz,2H).

[0238] Example 88

[0239] The characterization data of Example 88 are: 1H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,1H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1 H),7.26(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,2H),7.21(d,J=8.8Hz,1H),7.20(d,1H),6.76 (d,J=8.8Hz1H),5.53(s,2H),4.00(d,J=6.0Hz,1H),3.97(s,2H),3.67(t,J=6.0Hz,4H),3 .66(t,J=6.0Hz,2H),3.27(t,J=6.0Hz,4H),2.87(t,J=6.0Hz,2H),2.79(d,J=6.0Hz,1H).

[0240] Example 89

[0241] The characterization data of Example 89 are: 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,1H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H) ,7.26(d,J=8.8Hz,2H),7.24(t,J=8.8Hz,2H),7.21(d,J=8.8Hz,1H),6.76(d,J=8.8Hz1H),5 .53(s,3H),4.51(s,2H),4.37(q,J=6.0Hz,1H),3.67(t,J=6.0Hz,4H),3.66(t,J=6.0Hz,2H) ,3.27(t,J=6.0Hz,4H),2.85(t,J=6.0Hz,2H),2.55(t,J=6.0Hz,2H),1.91(q,J=6.0Hz,2H).

[0242] Example 90

[0243] The characterization data of Example 90 are: 1H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,1H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H) ,7.26(d,J=8.8Hz,2H),7.24(t,J=8.8Hz,2H),7.21(d,J=8.8Hz,1H),6.76(d,J=8.8Hz1H),5 .53(s,3H),4.51(s,2H),3.67(t,J=6.0Hz,4H),3.66(t,J=6.0Hz,2H),3.27(t,J=6.0Hz,4H) ,2.96(q,J=6.0Hz,2H),2.85(t,J=6.0Hz,2H),2.78(t,J=6.0Hz,1H),2.00(q,J=6.0Hz,2H).

[0244] Example 91

[0245] The characterization data of Example 91 are: 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,1H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7.2 6(d,J=8.8Hz,2H),7.24(t,J=8.8Hz,2H),7.21(d,J=8.8Hz,1H),6.76(d,J=8.8Hz1H),5.53(s,3H) ,4.51(s,2H),4.37(q,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),2.86(t,J=6.0Hz,4H),2.85(t,J=6.0H z,2H),2.55(t,J=6.0Hz,2H),2.35(t,J=6.0Hz,4H),2.27(d,J=6.0Hz,3H),1.91(q,J=6.0Hz,2H).

[0246] Example 92

[0247] The characterization data of Example 92 are: 1H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,1H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7 .26(d,J=8.8Hz,2H),7.24(t,J=8.8Hz,2H),7.21(d,J=8.8Hz,1H),6.76(d,J=8.8Hz1H),5.53(s ,3H),4.51(s,2H),3.66(q,J=6.0Hz,2H),2.96(t,J=6.0Hz,2H),2.86(t,J=6.0Hz,4H),2.85(t, J=6.0Hz,2H),2.78(t,J=6.0Hz,1H),2.35(t,J=6.0Hz,4H),2.27(s,3H),2.00(q,J=6.0Hz,2H).

[0248] Example 93

[0249] The characterization data of Example 93 are: 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,1H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1 H),7.26(d,J=8.8Hz,2H),7.24(t,J=8.8Hz,2H),7.21(d,J=8.8Hz,1H),6.76(d,J=8.8Hz1 H),5.53(s,2H),4.51(s,2H),4.00(d,J=6.0Hz,1H),3.66(t,J=6.0Hz,2H),2.86(t,J=6.0 Hz, 4H), 2.85 (t, J = 6.0Hz, 2H), 2.79 (d, J = 6.0Hz, 1H), 2.35 (t, J = 6.0Hz, 4H), 2.27 (s, 3H).

[0250] Example 94

[0251] The characterization data of Example 94 are: 1H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,1H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H) ,7.26(d,J=8.8Hz,2H),7.24(t,J=8.8Hz,2H),7.21(d,J=8.8Hz,1H),6.76(d,J=8.8Hz1H),5. 53(s,3H),4.51(s,2H),3.66(t,2H),3.45(t,J=6.0Hz,2H),2.86(t,J=6.0Hz,4H),2.85(t,J= 6.0Hz, 2H), 2.78 (p, J = 6.0Hz, 1H), 2.38 (d, J = 6.0Hz, 2H), 2.35 (t, J = 6.0Hz, 4H), 2.27 (s, 3H).

[0252] Example 95

[0253] The characterization data of Example 95 are: 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,1H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H) ,7.26(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,2H),7.21(d,J=8.8Hz,1H),7.20(d,1H),6.76(d,J= 8.8Hz1H),5.53(s,3H),4.37(q,J=6.0Hz,1H),3.97(s,2H),3.66(t,J=6.0Hz,2H),2.87(t,J= 6.0Hz,2H),2.86(t,J=6.0Hz,4H),2.35(t,J=6.0Hz,4H),2.27(s,3H),1.90(d,J=6.0Hz,2H).

[0254] Example 96

[0255] The characterization data of Example 96 are: 1H NMR (400MHz, CD3OD) δ8.57(s,1H),8.15(s,1H),8.04(d,J=8.8Hz,1H),7.84(d,J=8.8Hz,1H),7 .26(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,2H),7.21(d,J=8.8Hz,1H),7.20(d,1H),6.76(d,J=8.8H z1H),5.53(s,2H),4.00(d,J=6.0Hz,1H),3.97(s,2H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz, 2H), 2.86 (t, J = 6.0Hz, 4H), 2.79 (d, J = 6.0Hz, 1H), 2.35 (t, J = 6.0Hz, 4H), 2.27 (d, J = 6.0Hz, 3H).

[0256] Example 97

[0257] The characterization data of Example 97 are: 1 H NMR (400MHz, CD3OD) δ8.15(s,1H),8.04(d,J=8.8Hz,1H),7.47(d,1H),7.31(t,1H),7.26(d,J=8.8Hz,2H),7.24(t,J=8.8Hz,2H),7.21(d,J =8.8Hz,1H),6.80(d,1H),5.53(s,2H),4.51(s,2H),4.00(s,s,d,3H),3.66(t,J=6.0Hz,2H),2.85(t,J=6.0Hz,2H),2.79(d,J=6.0Hz,1H).

[0258] Example 98

[0259] The characterization data of Example 98 are: 1 H NMR(400MHz,CD3OD)δ8.15(s,1H),8.04(d,J=8.8Hz,1H),7.47(d,1H),7.31(t, 1H),7.26(d,J=8.8Hz,2H),7.24(t,J=8.8Hz,2H),7.21(d,J=8.8Hz,1H),6.80(d ,1H),5.53(s,3H),4.51(s,2H),4.00(s,2H),3.66(t,J=6.0Hz,2H),3.45(t,J= 6.0Hz,2H),2.85(t,J=6.0Hz,2H),2.78(q,J=6.0Hz,1H),2.38(d,J=6.0Hz,2H).

[0260] Example 99

[0261] The characterization data of Example 99 are: 1 H NMR(400MHz,CD3OD)δ8.15(s,1H),8.04(d,J=8.8Hz,1H),7.47(d,1H),7.31( t,1H),7.26(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,2H),7.21(d,J=8.8Hz,1H),7. 20(d,1H),6.80(d,1H),5.53(s,3H),4.37(q,J=6.0Hz,1H),4.00(s,2H),3.9 7(s,2H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),1.90(d,J=6.0Hz,2H).

[0262] Example 100

[0263] The characterization data of Example 100 are: 1 H NMR (400MHz, CD3OD) δ8.15(s,1H),8.04(d,J=8.8Hz,1H),7.47(d,1H),7.31(t,1H),7.26(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,2H),7.21(d,J=8.8H z,1H),7.20(d,1H),6.80(d,1H),5.53(s,2H),4.00(s,s,d3H),3.97(s, 2H), 3.66(t,J=6.0Hz,2H), 2.87(t,J=6.0Hz,2H), 2.79(d,J=6.0Hz,1H).

[0264] Example 101

[0265] The characterization data of Example 101 are: 1H NMR(400MHz,CD3OD)δ8.15(s,1H),8.04(d,J=8.8Hz,1H),7.47(d,1H),7.31(t, 1H),7.26(d,J=8.8Hz,2H),7.24(t,J=8.8Hz,2H),7.21(d,J=8.8Hz,1H),6.80(d ,1H),5.53(s,3H),4.51(s,2H),4.37(q,J=6.0Hz,1H),4.00(s,2H),3.66(t,J= 6.0Hz,2H),2.85(t,J=6.0Hz,2H),2.55(t,J=6.0Hz,2H),1.91(q,J=6.0Hz,2H).

[0266] Example 102

[0267] The characterization data of Example 102 are: 1 H NMR(400MHz,CD3OD)δ8.15(s,1H),8.04(d,J=8.8Hz,1H),7.47(d,1H),7.31(t, 1H),7.26(d,J=8.8Hz,2H),7.24(t,J=8.8Hz,2H),7.21(d,J=8.8Hz,1H),6.80(d ,1H),5.53(s,3H),4.51(s,2H),4.00(s,2H),3.66(t,J=6.0Hz,2H),2.96(q,J= 6.0Hz,2H),2.85(t,J=6.0Hz,2H),2.78(t,J=6.0Hz,1H),2.00(q,J=6.0Hz,2H).

[0268] Example 103

[0269] The characterization data of Example 103 are: 1 H NMR(400MHz,CD3OD)δ8.15(s,1H),8.04(d,J=8.8Hz,1H),7.47(d,1H),7.31(t,1H) ,7.26(d,J=8.8Hz,1H),7.24(t,J=8.8Hz,2H),7.21(d,J=8.8Hz,1H),7.20(d,1H), 6.80(d,1H),5.53(s,3H),4.37(q,J=6.0Hz,1H),4.00(s,2H),3.97(s,2H),3.66(t ,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),2.55(t,J=6.0Hz,2H),1.91(q,J=6.0Hz,2H).

[0270] Example 104

[0271] The characterization data of Example 104 are: 1 H NMR(400MHz,CD3OD)δ8.15(s,1H),8.04(d,J=8.8Hz,1H),7.47(d,1H),7.31(t,1H),7.26 (d,J=8.8Hz,1H),7.24(t,J=8.8Hz,2H),7.21(d,J=8.8Hz,1H),7.20(d,1H),6.80(d,1H) ,5.53(s,3H),4.49(q,J=6.0Hz,1H),4.00(s,2H),3.97(s,2H),3.66(t,J=6.0Hz,2H),2. 87(t,J=6.0Hz,2H),2.24(t,J=6.0Hz,2H),1.78(q,J=6.0Hz,2H),1.31(p,J=6.0Hz,2H).

[0272] Example 105

[0273] Preparation of injection solution

[0274] Compound 1 prepared in Example 1 was dissolved in a small amount of DMSO, and then added with water for injection according to conventional methods. The mixture was finely filtered, sealed and sterilized to prepare an injection solution.

[0275] Example 106

[0276] Preparation of tablets

[0277] The compound 1 prepared in Example 1 and cyclodextrin were granulated and tableted at a weight ratio of 6:1 to obtain tablets.

[0278] Example 107

[0279] Preparation of capsules

[0280] The compound 1 prepared in Example 1 and microcrystalline cellulose were prepared into capsules at a weight ratio of 6:1.

[0281] Example 108

[0282] Test the inhibitory effect of the compounds of Examples 1-104 on pancreatic cancer cells

[0283] 1. Experimental methods

[0284] Cell source: The cell lines used in the present invention are human pancreatic cancer cells PANC-1 and PaTu-8988T, which are obtained from ATCC.

[0285] Cell culture: Cells were cultured in a 37°C, 5% CO2 incubator. After removal from the cryostat, cells were thawed as quickly as possible in a 37°C water bath and immediately placed in IMDM medium supplemented with 20% fetal bovine serum and 10 μg / mL DNASE I. Cells were centrifuged at 1500 rpm for 5 minutes and then resuspended in complete culture medium at a concentration of 2-5 × 10 6 cells / mL; the thawed cells were then cultured in complete medium. IMDM medium was supplemented with 10% fetal bovine serum (FBS) and BIT (bovine serum albumin 4 g / L, insulin 5 μg / mL, transferrin 60 μg / mL, all from Sigma-Aldrich). To promote cell growth and maintenance, some specific cytokines and components were added: 50 ng / mL FLT3 ligand, 10 ng / mL IL-6, 50 ng / mL stem cell factor (SCF), 25 ng / mL thrombopoietin (TPO), 10 ng / mL IL-3, and 10 ng / mL granulocyte colony factor (G-CSF). In addition, the culture medium also contained 50 μM β-mercaptoethanol (Sigma-Aldrich).

[0286] Test method: MTT method was used to detect cell death rate. 5 / mL was inoculated in H4230 culture medium, 10% IMDM was added to the culture medium, and the cells were divided into a control group and a drug-treated group. The drug-treated group had a concentration of 1 μM. On the second day, 10 μL of prepared MTT solution was added to each well, and the cells were incubated in a 37°C incubator for 4 h. Then, the liquid in the wells was carefully discarded, 120 μL of dimethyl sulfoxide was added to each well, and the cells were shaken on a shaker for 15 min. The absorbance at 492 nm was detected using a microplate reader.

[0287] 2. Experimental results

[0288] Table 1 Inhibitory activity of the compounds in the examples on pancreatic cancer cell growth

[0289]

[0290]

[0291] L-CFU analysis showed that the compounds prepared in Examples 1-104 all had the effect of inhibiting the colony formation of pancreatic cancer cells. Among them, the compounds prepared in Examples 2, 18, 28, 47, 39, 41, 46, 64 and 85 had a better effect of reducing the colony formation of pancreatic cancer cells (Table 1). Among them, the compound prepared in Example 39 had the best overall effect. The compound of Example 39 (hereinafter referred to as Compound 39) was further tested below:

[0292] Example 109

[0293] Effects of test compound 39 on intracellular iron ion levels

[0294] 1. Experimental methods

[0295] Intracellular Fe 2+ Level determination: PANC-1 and PaTu-8988T cells were seeded in 96-well laser confocal microscopy culture plates, with 5000 cells per well in 100 μL of culture medium. After the cells were cultured overnight in the culture medium, the old culture medium was discarded and the cells were treated with culture medium containing 0.5 μM compound 39 for 6 hours. The probe working solution containing 1 μM FerroOrange and 1 μg / mL Hoechst 33342 was prepared in serum-free culture medium and then added to the 96-well plate. The cells were incubated in a 37°C incubator for 30 minutes, and then the cells were washed once with 1× PBS. Cell detection was performed using an FV3000 laser confocal microscope or a Cellomics ArrayScan Vti high-content system.

[0296] 2. Experimental results

[0297] The results showed that compound 39 could significantly reduce the concentration of iron ions in pancreatic cancer cells ( Figure 1 and Figure 2 ).

[0298] Example 110

[0299] Acute toxicity test of compound 39, compound 35 and compound 75

[0300] 1. Experimental methods

[0301] The experiment used SPF-grade C57BL / 6 mice (6-7 weeks old), which were raised in an SPF-grade animal room at a temperature of 21-24°C and a humidity of 50-70%. They were fed SPF-grade mouse feed and sterile drinking water. After being purchased and raised in the animal room for 1 week, no abnormalities were observed. They were randomly divided into 6 groups (control group, 39-100 mg / kg, 39-200 mg / kg, 39-400 mg / kg, 35-400 mg / kg, and 75-400 mg / kg), with 6 mice in each group, half male and half female, and half female, and were fed in separate cages at the same time; 39-100 mg / kg, 39-200 mg / kg, and 39-400 mg / kg represent the dosage of compound 39, 35-400 mg / kg represents the dosage of compound 35, and 75-400 mg / kg represents the dosage of compound 75;

[0302] The mice were fasted for 12 hours before administration and allowed to drink water freely. The mice were then gavage-administered and fed normally 4 hours after administration. Within one week of administration, the mice were weighed on days 0, 3, 5, and 7, and their abnormal behavior and death were observed.

[0303] 2. Experimental results

[0304] like Figure 3 As shown, compared with the control group, the mice in the drug-treated group did not show obvious weight changes, nor did they experience acute toxic phenomena such as mouse death, abnormal behavior, and decreased appetite.

[0305] Based on the test data on the inhibitory effect of cyclic amide-tetrahydroisoquinoline compounds on pancreatic cancer cells, the effect on intracellular iron ion levels, and acute toxicity, it is sufficient to show that the cyclic amide-tetrahydroisoquinoline compounds prepared by Examples 1-104 have significant inhibitory effects on pancreatic cancer cells and low toxicity to organisms. They not only expand the types of drugs for the clinical treatment of pancreatic cancer, but are also suitable for large-scale production.

[0306] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A cyclic amide-tetrahydroisoquinoline compound, characterized in that The compound has the following formula (I): Wherein, ring A is a cyclic amide structure; Z is any one of O, N or S atoms; X is an O atom or -N-R2, wherein R2 is a H atom, C 1～12 Alkyl, C 1～12 Alkylamino, C 1～12 Alkoxy, C 1～12 Alkanoyl, C 1～12 Alkylamide, C 1～12 Any one of the alkyl ester groups; Y is a C or N atom; R1 is wherein A1 is any one of C, O, S or -NH, A2, A3, A4, A5 and A6 are the same or different and are C or N atoms, R 11 is monosubstituted or polysubstituted, selected from H atoms, C 1～12 Alkyl, halogen atom, C 1～12 Alkoxy, C 1～12 Alkylamino, C 1～12 Alkanoyl, C 1～12 Alkylamide, C 1～12 One or more of an alkyl ester group, an amino group, a hydroxyl group, an unsubstituted or substituted aromatic ring, and an unsubstituted or substituted aliphatic ring.

2. The compound according to claim 1, characterized in that The ring A is an aliphatic ring or an aromatic ring amide; Z is an O or N atom; X is -N-R2, wherein R2 is a hydrogen atom or a C 1～3 Alkyl; Y is a C or N atom; R1 is wherein A1 is any one of O, S or -NH, A2, A3, A4, A5 and A6 are the same or different and are C or N atoms, R 11 is monosubstituted or polysubstituted, selected from H atoms, C 1～3 Alkyl, halogen atom, C 1～3 Alkoxy, C 1～3 Any one or more of alkylamino, amino, hydroxyl, unsubstituted or substituted piperazine, indole, and morpholine.

3. The compound according to claim 2, characterized in that The ring A is a 4-7 membered aliphatic cyclic amide; Z is an O atom; X is -N-R2, wherein R2 is a hydrogen atom or a C 1～3 Alkyl; Y is a C or N atom; R1 is wherein A1 is a S atom or -NH, A2, A3, A4, A5 and A6 are the same or different and are C or N atoms, R 11 is monosubstituted or polysubstituted, selected from H atoms, C 1～3 Alkyl, halogen atom, C 1～3 Alkoxy, C 1～3 One or more of alkylamino, amino, hydroxyl, unsubstituted or substituted piperazine, indole, and morpholine, wherein the substituent of the substituted piperazine is C 1～6 Alkyl, halogen, C 1～6 Any of an alkoxy group, a hydroxy group or an amino group.

4. The compound according to claim 3, characterized in that The ring A is a 4- to 6-membered aliphatic cyclic amide; Z is an O atom; X is -N-R2, wherein R2 is a hydrogen atom or a C 1～3 Alkyl; Y is a C atom; R1 is wherein A1 is -NH; A2, A3, A4, A5 and A6 are the same or different C or N atoms, R 11 is monosubstituted or polysubstituted, selected from H atoms, C 1～3 One or more of an alkyl group, a halogen atom, a non-substituted or substituted piperazine, and a morpholine group, wherein the substituent of the substituted piperazine is C 1～3 Alkyl, C 1～3 Any of an alkoxy group, a hydroxy group or an amino group.

5. The compound according to claim 1, characterized in that The cyclic amide-tetrahydroisoquinoline compound has any one of the following structural formulas:

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