Application of cyclic amide-tetrahydroisoquinoline compound in preparation of anti-pancreatic cancer drugs

Abstract

The invention discloses an application of a cyclic amide-tetrahydroisoquinoline compound in preparation of a medicine for resisting pancreatic cancer. The compound has a remarkable inhibition effect on pancreatic cancer cells, has low toxicity to organisms, not only expands the variety of medicines for clinically treating pancreatic cancer, but also is suitable for large-scale production.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technologies, and particularly to the application of a cyclic amide-tetrahydroisoquinoline compound in the preparation of an anti-pancreatic cancer drug. Background Art

[0002] Pancreatic cancer is a tumor with extremely high malignancy. Due to its difficult early diagnosis and extremely poor prognosis, it is known as the "king of cancers" in the medical field. Data shows that the five-year survival rate of pancreatic cancer patients is less than 7%, and according to the prediction of the World Health Organization, by 2030, the mortality rate of pancreatic cancer may jump to the second place in the global cancer mortality ranking. Most patients are already in the advanced stage at the time of diagnosis. The tumor not only infiltrates locally severely but also often metastasizes distantly, which is the core cause of its high mortality rate. In addition, the high drug resistance of pancreatic cancer to existing treatment methods and the high recurrence rate after surgery further exacerbate the lethality of this disease.

[0003] Currently, the clinical treatment of pancreatic cancer still mainly relies on chemotherapy, and the commonly used drug is Gemcitabine. At the same time, there are also targeted treatment strategies for epidermal growth factor receptor (EGFR), angiogenesis, tumor microenvironment, and hypoxia status. However, the effects of these treatment methods are not ideal, and the survival benefit of patients is limited. Surgical resection is currently an effective way to potentially cure pancreatic cancer. However, due to the high invasiveness and high metastatic ability of pancreatic cancer, even after successful surgery, more than 76% of patients will have distant tumor metastasis in a short time, resulting in a high recurrence rate.

[0004] In view of the limitations of existing treatment methods, the medical field urgently needs to explore new treatment mechanisms and drug research and development directions to provide new options for the treatment of pancreatic cancer. Summary of the Invention

[0005] In view of the deficiencies in the prior art, the present invention proposes the application of a cyclic amide-tetrahydroisoquinoline compound in the preparation of an anti-pancreatic cancer drug.

[0006] The present invention provides the application of a cyclic amide-tetrahydroisoquinoline compound in the preparation of an anti-pancreatic cancer drug, and the cyclic amide-tetrahydroisoquinoline compound has the following structure of formula (I):

[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, where R2 is an H atom, C 1～12 alkyl, C 1～12 alkylamino, C1～12 an alkoxy group, C 1～12 an alkanoyl group, C 1～12 an alkoxycarbonylamino group, C 1～12 any one of an alkoxy group;

[0011] Y is a C or N atom;

[0012] R1 is wherein A1 is any one of a C, O, S atom or -NH, A2, A3, A4, A5 and A6 are the same or different and are C or N atoms, R 11 is mono-substituted or multi-substituted and is selected from an H atom, C 1～12 alkyl group, a halogen atom, C 1～12 alkoxy group, C 1～12 alkylamino group, C 1～12 alkanoyl group, C 1～12 of an alkoxycarbonylamino group, C 1～12 of an alkoxy group, an amino group, a hydroxyl group, an unsubstituted or substituted aromatic ring, an unsubstituted or substituted aliphatic ring.

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

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

[0015] Z is an O or N atom;

[0016] X is -N-R2, where R2 is an H atom or C 1～3 alkyl group;

[0017] Y is a C or N atom;

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

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

[0020] Z is an O atom;

[0021] X is -N-R2, where R2 is an H atom or a C 1～3 alkyl group;

[0022] Y is a C or N atom;

[0023] R1 is where A1 is an S atom or -NH, and A2, A3, A4, A5, and A6 are the same or different and are C or N atoms, and R 11 is mono-substituted or multi-substituted and is selected from an H atom, a C 1～3 alkyl group, a halogen atom, a C 1～3 alkoxy group, a C 1～3 alkylamino group, amino, hydroxyl, unsubstituted or substituted piperazine, indole, morpholine, and one or more of them, where the substituent of the substituted piperazine is a C 1～6 alkyl group, a halogen, a C 1～6 alkoxy group, hydroxyl, or amino.

[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, where R2 is an H atom or a C 1～3 alkyl group;

[0027] Y is a C atom;

[0028] R1 is where A1 is -NH; A2, A3, A4, A5, and A6 are the same or different and are C or N atoms, and R 11 is mono-substituted or multi-substituted and is selected from an H atom, a C 1～3 alkyl group, a halogen atom, unsubstituted or substituted piperazine, morpholine, and one or more of them, where the substituent of the substituted piperazine is a C 1～3 alkyl group, a C 1～3 alkoxy group, hydroxyl, or amino.

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

[0030]

[0031]

[0032]

[0033] Further, 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, 104.

[0034] Further, 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, 100.

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

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

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

[0038] The following gives an exemplary synthesis route of the cyclic amide-tetrahydroisoquinoline compound 25:

[0039]

[0040] The following is a preparation method of the example compound 25, which includes 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 successively added into a round-bottom flask, and dry N,N-dimethylformamide (9 - 11 mL) was added. The mixture was stirred at room temperature for 55 - 68 min, then compound 2a (0.9 - 1.1 mmol) was added, and the reaction was magnetically stirred at 60 °C for 11 - 13 h. Then, it was extracted with ethyl acetate 2 - 4 times, 130 - 160 mL each time. After the organic layer was dried over anhydrous magnesium sulfate, it was concentrated under reduced pressure. The solid obtained by rotary evaporation was separated and purified by column chromatography to obtain a yellow solid, and compound 3a was obtained (yield 63 - 65%);

[0042] Compound 3a (1 - 1.3 mmol) was added to 4 - 6 mL of methanol, then 1 - 2 mL of TFA was added. After stirring at room temperature for 2.5 - 3 h, saturated magnesium carbonate solution was added to adjust the pH to about 8. Then, it was extracted with ethyl acetate 2 - 4 times, 130 - 160 mL each time. After the organic layer was dried over anhydrous magnesium sulfate, it was concentrated under reduced pressure to obtain crude compound 4a. Subsequently, compound 5a (0.9 - 1.1 mmol) and DBU (1.0 - 1.2 mmol) were added, dissolved in N,N-dimethylformamide (7 - 10 mL), and the reaction was magnetically stirred at 60 °C for 7 - 9 h. Then, it was extracted with ethyl acetate 2 - 4 times, 150 mL each time. After the organic layer was dried over anhydrous magnesium sulfate, it was concentrated under reduced pressure. The solid obtained by rotary evaporation was separated and purified by column chromatography to obtain a yellow solid, and compound 6a was obtained (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 the mixture was stirred at 80 °C for 11 - 12 h. After the reaction was completed, the solid was filtered off, and the solid was rinsed with methanol 2 - 4 times, 9 - 12 mL each time. Subsequently, the filtrate was rotary evaporated, and the residue was separated and purified by column chromatography to obtain a yellow solid, and compound 25 was obtained (yield 66 - 68%).

[0044] Furthermore, the cyclic amide - tetrahydroisoquinoline compound can be applied in any form of its pharmaceutically acceptable salts, solvates or chiral isomers.

[0045] Furthermore, the pharmaceutically acceptable salt is obtained by reacting the cyclic amide - tetrahydroisoquinoline compound with an inorganic acid or an organic acid.

[0046] Further, the organic acid is any one of citric acid, acetic acid, oxalic acid, isonicotinic acid, lactic acid, salicylic acid, acid citrate, tartaric acid, oleic acid, tannic acid, pantothenic acid, tartaric acid, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or pamoic acid.

[0047] Further, the inorganic acid is any one of hydrochloric acid, phosphoric acid, sulfuric acid or nitric acid.

[0048] Further, the drug is any one of oral preparations, injections, topical agents or inhalants.

[0049] Further, the oral preparation is any one of capsules, tablets, pills or granules; the inhalant is a spray.

[0050] In summary, compared with the prior art, the present invention achieves the following technical effects:

[0051] (1) The cyclic amide-tetrahydroisoquinoline compounds provided by the present invention can significantly inhibit the proliferation of pancreatic cancer cells;

[0052] (2) The cyclic amide-tetrahydroisoquinoline compounds provided by the present invention have low toxicity to organisms;

[0053] (3) The preparation process of the cyclic amide-tetrahydroisoquinoline compounds provided by the present invention is simple and easy to mass-produce. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the attached tables and drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following attached tables and drawings only show some embodiments of the present invention, and therefore should not be regarded as limiting the scope. For those of ordinary skill in the art, other related drawings can also be obtained based on these attached tables and drawings without creative efforts.

[0055] Figure 1 It is a statistical chart of the effect of the compound prepared in Example 39 of the present invention on the iron ion concentration in PANC-1 cells;

[0056] Figure 2 It is a statistical chart of the effect of the compound prepared in Example 39 of the present invention on the iron ion concentration in PaTu-8988T cells;

[0057] Figure 3 It is the acute toxicity test results of the compounds prepared in Examples 35, 39 and 75 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0058] In order to enable those skilled in the art to better understand the solution of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the scope of protection of the present invention.

[0059] Embodiment

[0060] The present invention will be further described below in conjunction with specific embodiments and comparative embodiments. The following specific embodiments are all preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the following embodiments, especially not limited to the models of the various component raw materials used in the following specific embodiments.

[0061] I. The raw material sources of the embodiments and comparative examples are as follows:

[0062] Unless otherwise specified, the raw material substances used in the embodiments of the present invention are all commercially available.

[0063] The preparation method of the cyclic amide-tetrahydroisoquinoline compounds in the embodiments of the present invention is similar to the synthesis route of the above compound 25 and includes the following steps:

[0064] Add the cyclic amide carboxylic acid derivative (1.0 mmol), TBTU (1.0 mmol) and K2CO3 (1.5 mmol) into a round-bottom flask in sequence, add dry N, N-dimethylformamide (10 mL), stir at room temperature for 1 hour, then add the Boc-tetrahydroisoquinoline containing amino or hydroxyl (compound 2a series) (1.0 mmol), magnetically stir and react at 60 °C for 12 hours, then extract with ethyl acetate (3 × 150 mL, that is, extract three times with 150 mL of ethyl acetate). After the organic layer is dried over anhydrous magnesium sulfate, it is concentrated under reduced pressure. The solid obtained by rotary evaporation is separated and purified by column chromatography to obtain a yellow solid, and the compound 3a series is obtained (yield 60% - 88%);

[0065] The compound 3a series (1.0 mmol) was added to 5 mL of methanol, and then 1 mL of TFA was added. After stirring at room temperature for 3 hours, saturated magnesium carbonate solution was added to adjust the pH to about 8. Then, it was extracted with ethyl acetate (3×150 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the crude compound 4a series. Subsequently, the compound 5a series (1.0 mmol) and DBU (1.2 mmol) were added and dissolved in N,N-dimethylformamide (10 mL). The reaction was stirred magnetically 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 rotary evaporation was separated and purified by column chromatography to obtain a yellow solid, and the compound 6a series was obtained (yield 59% - 77%);

[0066] The compound 6a series (1.0 mmol), the 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, the solid was filtered off, and the solid was rinsed with methanol (3×10 mL). Subsequently, the filtrate was rotary evaporated, separated and purified by column chromatography to obtain a yellow solid, and the final product was obtained.

[0067] The structures of the compounds prepared in Examples 1 - 104 are as follows:

[0068]

[0069]

[0070] Example 1

[0071] The characterization data of Example 1 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.49 (q, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.24 (t, J = 6.0 Hz, 2H), 1.78 (q, J = 6.0 Hz, 2H), 1.59 (p, J = 6.0 Hz, 4H), 1.57 (p, J = 6.0 Hz, 2H), 1.31 (p, J = 6.0 Hz, 2H).

[0072] Example 2

[0073] The characterization data of Example 2 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz,, 1H), 7.51 (d, J = 8.8 Hz,, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 5.53 (s, 3H), 4.51 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 1H), 2.24 (t, J = 6.0 Hz, 2H), 1.59 (p, J = 6.0 Hz, 4H), 1.57 (p, J = 6.0 Hz, 2H), 1.51 (q, J = 6.0 Hz, 2H).

[0074] Example 3

[0075] The characterization data of Example 3 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.37 (t, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.55 (t, J = 6.0 Hz, 2H), 1.91 (q, J = 6.0 Hz, 2H), 1.59 (p, J = 6.0 Hz, 4H), 1.57 (p, J = 6.0 Hz, 2H).

[0076] Example 4

[0077] The characterization data of Example 4 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 5.53 (s, 3H), 4.51 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 1H), 2.38 (d, J = 6.0 Hz, 2H), 1.59 (p, J = 6.0 Hz, 4H), 1.57 (p, J = 6.0 Hz, 2H).

[0078] Example 5

[0079] The characterization data of Example 5 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (t, 1H), 6.83 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 5.53 (s, 3H), 4.51 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.78 (t, J = 6.0 Hz, 1H), 2.35 (t, J = 6.0 Hz, 4H), 2.27 (s, J = 6.0 Hz, 3H), 1.57 (p, J = 6.0 Hz, 2H), 1.51 (q, J = 6.0 Hz, 2H).

[0080] Example 6

[0081] The characterization data of Example 6 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (s, 1H), 5.53 (s, 2H), 4.51 (q, J = 6.0 Hz, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.79 (t, J = 6.0 Hz, 1H), 2.66 (t, J = 6.0 Hz, 3H), 2.35 (t, J = 6.0 Hz, 4H), 2.27 (s, 3H).

[0082] Example 7

[0083] The characterization data of Example 7 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, J = 6.0 Hz, 2H), 4.37 (q, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.55 (t, J = 6.0 Hz, 2H), 2.35 (t, J = 6.0 Hz, 4H), 2.27 (s, 3H), 1.91 (q, J = 6.0 Hz, 2H).

[0084] Example 8

[0085] The characterization data of Example 8 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 3.56 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.78 (t, J = 6.0 Hz, 1H), 2.35 (t, J = 6.0 Hz, 4H), 2.27 (s, 3H).

[0086] Example 9

[0087] The characterization data of Example 9 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.64 (d, 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.00 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 1H), 2.24 (t, J = 6.0 Hz, 2H), 1.51 (q, J = 6.0 Hz, 2H).

[0088] Example 10

[0089] The characterization data of Example 10 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.69 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 5.53 (s, 3H), 4.51 (d, J = 6.0 Hz, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 1H), 2.24 (t, J = 6.0 Hz, 2H), 1.51 (q, J = 6.0 Hz, 2H).

[0090] Example 11

[0091] The characterization data of Example 11 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.47 (d, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 7.11 (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 = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 1H), 2.24 (t, J = 6.0 Hz, 2H), 1.51 (q, J = 6.0 Hz, 2H).

[0092] Example 12

[0093] The characterization data of Example 12 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.47 (d, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 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 = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 1H), 2.24 (t, J = 6.0 Hz, 2H), 1.51 (q, J = 6.0 Hz, 2H).

[0094] Example 13

[0095] The characterization data of Example 13 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.69 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.24 (t, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.00 (d, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.85 (t, J = 6.0 Hz, 2H), 2.79 (s, 1H).

[0096] Example 14

[0097] The characterization data of Example 14 are as follows: 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).

[0098] Example 15

[0099] The characterization data of Example 15 are as follows: 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).

[0100] Example 16

[0101] The characterization data of Example 16 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.59 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 7.20 (d, 1H), 7.04 (d, 1H), 5.53 (s, 3H), 4.37 (t, J = 6.0 Hz, 1H), 3.97 (s, J = 6.0 Hz, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 1.90 (d, J = 6.0 Hz, 2H).

[0102] Example 17

[0103] The characterization data of Example 17 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.37 (t, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 1.90 (d, J = 6.0 Hz, 2H), 1.59 (p, J = 6.0 Hz, 4H), 1.57 (p, J = 6.0 Hz, 2H).

[0104] Example 18

[0105] The characterization data of Example 18 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.34 (d, 1H), 7.24 (t, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 7.17 (d, 1H), 5.53 (s, 3H), 4.51 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 1H), 2.29 (d, J = 6.0 Hz, 3H), 2.24 (t, 2H), 1.51 (q, J = 6.0 Hz, 2H).

[0106] Example 19

[0107] The characterization data of Example 19 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.69 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 7.20 (d, 1H), 5.53 (s, 3H), 4.37 (d, J = 6.0 Hz, 1H), 3.97 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.55 (t, J = 6.0 Hz, 2H), 1.91 (q, J = 6.0 Hz, 2H).

[0108] Example 20

[0109] The characterization data of Example 20 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 4.51 (s, 2H), 4.49 (t, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.35 (t, J = 6.0 Hz, 4H), 2.25 (s, 3H), 2.20 (t, J = 6.0 Hz, 2H), 1.76 (q, J = 6.0 Hz, 2H), 1.31 (p, J = 6.0 Hz, 4H).

[0110] Example 21

[0111] The characterization data of Example 21 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (q, J = 6.0 Hz, 2H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.47 (q, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 1H), 1.57 (p, J = 6.0 Hz, 2H), 1.51 (q, J = 6.0 Hz, 2H).

[0112] Example 22

[0113] The characterization data of Example 22 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.79 (s, 1H), 2.66 (s, 3H).

[0114] Example 23

[0115] The characterization data of Example 23 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.37 (q, J = 6.0 Hz, 1H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.55 (t, J = 6.0 Hz, 2H), 1.91 (q, J = 6.0 Hz, 2H).

[0116] Example 24

[0117] The characterization data of Example 24 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.56 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 1H).

[0118] Example 25

[0119] The characterization data of Example 25 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.49 (q, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.35 (t, J = 6.0 Hz, 4H), 2.27 (s, 3H), 2.24 (t, J = 6.0 Hz, 2H), 1.78 (q, J = 6.0 Hz, 2H), 1.31 (p, J = 6.0 Hz, 2H).

[0120] Example 26

[0121] The characterization data of Example 26 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.49 (s, 1H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.24 (t, J = 6.0 Hz, 2H), 1.78 (t, J = 6.0 Hz, 2H), 1.31 (p, J = 6.0 Hz, 2H).

[0122] Example 27

[0123] The characterization data of Example 27 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.37 (t, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.35 (t, 4J = 6.0 Hz, H), 2.27 (s, 3H), 1.90 (d, J = 6.0 Hz, 2H).

[0124] Example 28

[0125] The characterization data of Example 28 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.37 (t, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.55 (t, J = 6.0 Hz, 2H), 2.35 (t, J = 6.0 Hz, 4H), 2.27 (s, 3H), 1.91 (q, J = 6.0 Hz, 2H).

[0126] Example 29

[0127] The characterization data of Example 29 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.37 (q, J = 6.0 Hz, 1H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 1.90 (d, J = 6.0 Hz, 2H).

[0128] Example 30

[0129] The characterization data of Example 30 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.37 (t, J = 6.0 Hz, 1H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.55 (t, J = 6.0 Hz, 2H), 1.91 (q, J = 6.0 Hz, 2H).

[0130] Example 31

[0131] The characterization data of Example 31 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.37 (q, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 1.90 (d, J = 6.0 Hz, 2H), 1.59 (p, J = 6.0 Hz, 4H), 1.57 (p, J = 6.0 Hz, 2H).

[0132] Example 32

[0133] The characterization data of Example 32 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.37 (t, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.55 (t, J = 6.0 Hz, 2H), 1.91 (q, J = 6.0 Hz, 2H), 1.59 (p, J = 6.0 Hz, 4H), 1.57 (p, J = 6.0 Hz, 2H).

[0134] Example 33

[0135] The characterization data of Example 33 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.00 (s, 1H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.79 (d, J = 6.0 Hz, 1H).

[0136] Example 34

[0137] The characterization data of Example 34 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.24 (d, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.00 (d, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.79 (d, J = 6.0 Hz, 1H).

[0138] Example 35

[0139] The characterization data of Example 35 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.00 (d, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.79 (d, J = 6.0 Hz, 1H), 1.59 (p, J = 6.0 Hz, 4H), 1.57 (p, J = 6.0 Hz, 2H).

[0140] Example 36

[0141] The characterization data of Example 36 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.59 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 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 = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.79 (d, J = 6.0 Hz, 1H).

[0142] Example 37

[0143] The characterization data of Example 37 are as follows: 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=6.0Hz,1H),3.66(t,J=6.0Hz,2H),2.87(t,J=6.0Hz,2H),1.90(d,J=6.0Hz,2H).

[0144] Example 38

[0145] The characterization data of Example 38 are as follows: 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).

[0146] Example 39

[0147] The characterization data of Example 39 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.49 (q, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.35 (t, J = 6.0 Hz, 4H), 2.27 (s, 3H), 2.24 (t, J = 6.0 Hz, 2H), 1.78 (q, J = 6.0 Hz, 2H), 1.31 (p, J = 6.0 Hz, 2H).

[0148] Example 40

[0149] The characterization data of Example 40 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.24 (d, 1H), 7.21 (t, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.49 (d, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.24 (t, J = 6.0 Hz, 2H), 1.78 (q, J = 6.0 Hz, 2H), 1.59 (p, J = 6.0 Hz, 4H), 1.57 (p, J = 6.0 Hz, 2H), 1.31 (p, J = 6.0 Hz, 2H).

[0150] Example 41

[0151] The characterization data of Example 41 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.49 (d, J = 6.0 Hz, 1H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.24 (t, J = 6.0 Hz, 2H), 1.78 (q, J = 6.0 Hz, 2H), 1.31 (p, J = 6.0 Hz, 2H).

[0152] Example 42

[0153] The characterization data of Example 42 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.59 (d, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 7.04 (d, 1H), 6.83 (d, 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.49 (d, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.24 (t, J = 6.0 Hz, 2H), 1.78 (q, J = 6.0 Hz, 2H), 1.31 (p, J = 6.0 Hz, 2H).

[0154] Example 43

[0155] The characterization data of Example 43 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.00 (d, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.79 (d, J = 6.0 Hz, 1H), 2.35 (t, J = 6.0 Hz, 4H), 2.27 (s, 3H).

[0156] Example 44

[0157] The characterization data of Example 44 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.00 (d, J = 6.0 Hz, 1H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.79 (d, J = 6.0 Hz, 1H).

[0158] Example 45

[0159] The characterization data of Example 45 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.37 (q, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.35 (t, J = 6.0 Hz, 4H), 2.27 (s, 3H), 1.90 (d, J = 6.0 Hz, 2H).

[0160] Example 46

[0161] The characterization data of Example 46 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.37 (q, J = 6.0 Hz, 1H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 1.90 (s, 2H).

[0162] Example 47

[0163] The characterization data of Example 47 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.59 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 7.04 (d, 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.37 (q, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 1.90 (d, J = 6.0 Hz, 2H).

[0164] Example 48

[0165] The characterization data of Example 48 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.47 (d, 1H), 7.31 (t, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.80 (d, 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.49 (q, J = 6.0 Hz, 1H), 4.00 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.24 (t, J = 6.0 Hz, 2H), 1.78 (q, J = 6.0 Hz, 2H), 1.31 (p, J = 6.0 Hz, 2H).

[0166] Example 49

[0167] The characterization data of Example 49 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.47 (d, 1H), 7.31 (t, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.80 (d, 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.00 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 3.56 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 1H).

[0168] Example 50

[0169] The characterization data of Example 50 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.47 (d, 1H), 7.31 (t, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.80 (d, 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.00 (s, 3H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.79 (d, J = 6.0 Hz, 1H).

[0170] Example 51

[0171] The characterization data of Example 51 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.47 (d, 1H), 7.31 (t, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.80 (d, 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.37 (t, J = 6.0 Hz, 1H), 4.00 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.55 (t, J = 6.0 Hz, 2H), 1.91 (q, J = 6.0 Hz, 2H).

[0172] Example 52

[0173] The characterization data of Example 52 are as follows: 1 H NMR (400 MHz, CD3OD) δ 8.15 (s, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.47 (d, 1H), 7.31 (t, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.80 (d, 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.00 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.96 (q, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 1H), 2.00 (q, J = 6.0 Hz, 2H).

[0174] Example 53

[0175] The characterization data of Example 53 are as follows: 1 H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (t, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 1H), 1.57 (p, J = 6.0 Hz,, 2H), 1.51 (q, J = 6.0 Hz, 2H).

[0176] Example 54

[0177] The characterization data of Example 54 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz, 1H), 5.53 (s, 2H), 4.51 (s, 2H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 1H), 1.57 (p, J = 6.0 Hz, 2H), 1.51 (q, J = 6.0 Hz, 2H).

[0178] Example 55

[0179] The characterization data of Example 55 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.37 (q, J = 6.0 Hz, 1H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.55 (t, J = 6.0 Hz, 2H), 1.91 (q, J = 6.0 Hz, 2H).

[0180] Example 56

[0181] The characterization data of Example 56 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.56 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 1H).

[0182] Example 57

[0183] The characterization data of Example 57 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (s, 1H), 5.53 (s, 2H), 4.51 (q, J = 6.0 Hz, 2H), 4.49 (t, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.35 (t, J = 6.0 Hz, 4H), 2.27 (s, J = 6.0 Hz, 3H), 2.24 (t, J = 6.0 Hz, 2H), 1.78 (q, J = 6.0 Hz, 2H), 1.31 (p, J = 6.0 Hz, 2H).

[0184] Example 58

[0185] The characterization data of Example 58 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.49 (q, J = 6.0 Hz, 1H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.24 (t, J = 6.0 Hz, 2H), 1.78 (q, J = 6.0 Hz, 2H), 1.31 (p, J = 6.0 Hz, 2H).

[0186] Example 59

[0187] The characterization data of Example 59 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.37 (q, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.35 (t, J = 6.0 Hz, 4H), 2.27 (s, 3H), 1.90 (d, J = 6.0 Hz, 2H).

[0188] Example 60

[0189] The characterization data of Example 60 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.37 (q, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.55 (t, J = 6.0 Hz, 2H), 2.35 (t, J = 6.0 Hz, 4H), 2.27 (s, 3H), 1.91 (q, J = 6.0 Hz, 2H).

[0190] Example 61

[0191] The characterization data of Example 61 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.37 (q, J = 6.0 Hz, 1H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 1.90 (d, J = 6.0 Hz, 2H).

[0192] Example 62

[0193] The characterization data of Example 62 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (d, 1H), 7.21 (t, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.37 (s, 1H), 3.67 (q, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.55 (t, J = 6.0 Hz, 2H), 1.91 (q, J = 6.0 Hz, 2H).

[0194] Example 63

[0195] The characterization data of Example 63 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.37 (q, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 1.90 (d, J = 6.0 Hz, 2H), 1.59 (t, J = 6.0 Hz, 4H), 1.57 (p, J = 6.0 Hz, 2H).

[0196] Example 64

[0197] The characterization data of Example 64 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.37 (t, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.55 (t, J = 6.0 Hz, 2H), 1.91 (q, J = 6.0 Hz, 2H), 1.59 (p, J = 6.0 Hz, 4H), 1.57 (p, 2H).

[0198] Example 65

[0199] The characterization data of Example 65 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 1H), 4.51 (s, 2H), 4.00 (d, J = 6.0 Hz, 1H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.79 (d, J = 6.0 Hz, 1H).

[0200] Example 66

[0201] The characterization data of Example 66 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 1H), 4.51 (s, 2H), 4.00 (d, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.79 (d, J = 6.0 Hz, 1H).

[0202] Example 67

[0203] The characterization data of Example 67 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 1H), 4.51 (s, 2H), 4.00 (d, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.79 (d, J = 6.0 Hz, 1H), 1.59 (p, J = 6.0 Hz, 4H), 1.57 (p, J = 6.0 Hz, 2H).

[0204] Example 68

[0205] The characterization data of Example 68 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.40 (s, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 7.04 (d, 1H), 6.83 (d, 1H), 5.53 (s, 1H), 4.51 (s, 2H), 4.00 (d, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.79 (d, J = 6.0 Hz, 1H).

[0206] Example 69

[0207] The characterization data of Example 69 are as follows: 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).

[0208] Example 70

[0209] The characterization data of Example 70 are as follows: 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).

[0210] Example 71

[0211] The characterization data of Example 71 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.49 (d, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.35 (t, J = 6.0 Hz, 4H), 2.27 (s, 3H), 2.24 (t, J = 6.0 Hz, 2H), 1.78 (q, J = 6.0 Hz, 2H), 1.31 (p, J = 6.0 Hz, 2H).

[0212] Example 72

[0213] The characterization data of Example 72 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.49 (d, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.24 (t, J = 6.0 Hz, 2H), 1.78 (t, J = 6.0 Hz, 2H), 1.59 (p, J = 6.0 Hz, 4H), 1.57 (p, J = 6.0 Hz, 2H), 1.31 (p, J = 6.0 Hz, 2H).

[0214] Example 73

[0215] The characterization data of Example 73 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.83 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.49 (d, J = 6.0 Hz, 1H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.24 (t, J = 6.0 Hz, 2H), 1.78 (q, J = 6.0 Hz, 2H), 1.31 (p, J = 6.0 Hz, 2H).

[0216] Example 74

[0217] The characterization data of Example 74 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.40 (s, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 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 = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.24 (t, J = 6.0 Hz, 2H), 1.78 (t, J = 6.0 Hz, 2H), 1.31 (p, J = 6.0 Hz, 2H).

[0218] Example 75

[0219] The characterization data of Example 75 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 1H), 4.51 (s, 2H), 4.00 (d, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.79 (d, J = 6.0 Hz, 1H), 2.35 (t, J = 6.0 Hz, 4H), 2.27 (s, 3H).

[0220] Example 76

[0221] The characterization data of Example 76 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 1H), 4.51 (s, 2H), 4.00 (d, J = 6.0 Hz, 1H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.79 (d, J = 6.0 Hz, 1H).

[0222] Example 77

[0223] The characterization data of Example 77 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.37 (q, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.35 (t, J = 6.0 Hz, 4H), 2.27 (s, 3H), 1.90 (d, J = 6.0 Hz, 2H).

[0224] Example 78

[0225] The characterization data of Example 78 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.37 (q, J = 6.0 Hz, 1H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 1.90 (d, J = 6.0 Hz, 2H).

[0226] Example 79

[0227] The characterization data of Example 79 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.15 (s, 2H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.40 (d, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 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 = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 1.90 (d, J = 6.0 Hz, 2H).

[0228] Example 80

[0229] The characterization data of Example 80 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 2H), 7.95 (d, 1H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.31 (t, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.78 (d, 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.49 (q, J = 6.0 Hz, 1H), 4.00 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.24 (t, J = 6.0 Hz, 2H), 1.78 (q, J = 6.0 Hz, 2H), 1.31 (p, J = 6.0 Hz, 2H).

[0230] Example 81

[0231] The characterization data of Example 81 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 2H), 7.95 (d, 1H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.31 (t, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.78 (d, 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.00 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 3.56 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 1H).

[0232] Example 82

[0233] The characterization data of Example 82 are as follows: 1 H NMR (400 MHz, CD3OD) δ 8.15 (s, 2H), 7.95 (d, 1H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.31 (t, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.78 (d, 1H), 5.53 (s, 1H), 4.51 (s, 2H), 4.00 (s, s, d, 3H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.79 (d, J = 6.0 Hz, 1H).

[0234] Example 83

[0235] The characterization data of Example 83 are as follows: 1 H NMR (400 MHz, CD3OD) δ 8.15 (s, 2H), 7.95 (d, 1H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.31 (t, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.78 (d, 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.37 (q, J = 6.0 Hz, 1H), 4.00 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.55 (t, J = 6.0 Hz, 2H), 1.91 (q, J = 6.0 Hz, 2H).

[0236] Example 84

[0237] The characterization data of Example 84 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.15 (s, 2H), 7.95 (d, 1H), 7.88 (d, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.31 (t, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.78 (d, 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.00 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.96 (q, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 1H), 2.00 (q, J = 6.0 Hz, 2H).

[0238] Example 85

[0239] The characterization data of Example 85 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.24 (t, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.00 (d, J = 6.0 Hz, 1H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.85 (t, J = 6.0 Hz, 2H), 2.79 (d, J = 6.0 Hz, 1H).

[0240] Example 86

[0241] The characterization data of Example 86 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.24 (t, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.45 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.85 (t, J = 6.0 Hz, 2H), 2.78 (p, J = 6.0 Hz, 1H), 2.38 (d, J = 6.0 Hz, 2H).

[0242] Example 87

[0243] The characterization data of Example 87 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 7.20 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.37 (q, J = 6.0 Hz, 1H), 3.97 (s, J = 6.0 Hz, 2H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 1.90 (d, J = 6.0 Hz, 2H).

[0244] Example 88

[0245] The characterization data of Example 88 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 7.20 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.00 (d, J = 6.0 Hz, 1H), 3.97 (s, 2H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.87 (t, J = 6.0 Hz, 2H), 2.79 (d, J = 6.0 Hz, 1H).

[0246] Example 89

[0247] The characterization data of Example 89 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.24 (t, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.37 (q, J = 6.0 Hz, 1H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.85 (t, J = 6.0 Hz, 2H), 2.55 (t, J = 6.0 Hz, 2H), 1.91 (q, J = 6.0 Hz, 2H).

[0248] Example 90

[0249] The characterization data of Example 90 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.24 (t, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 3.67 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.0 Hz, 4H), 2.96 (q, J = 6.0 Hz, 2H), 2.85 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 1H), 2.00 (q, J = 6.0 Hz, 2H).

[0250] Example 91

[0251] The characterization data of Example 91 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.24 (t, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.37 (q, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.85 (t, J = 6.0 Hz, 2H), 2.55 (t, J = 6.0 Hz, 2H), 2.35 (t, J = 6.0 Hz, 4H), 2.27 (d, J = 6.0 Hz, 3H), 1.91 (q, J = 6.0 Hz, 2H).

[0252] Example 92

[0253] The characterization data of Example 92 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.24 (t, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 3.66 (q, J = 6.0 Hz, 2H), 2.96 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.85 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 1H), 2.35 (t, J = 6.0 Hz, 4H), 2.27 (s, 3H), 2.00 (q, J = 6.0 Hz, 2H).

[0254] Example 93

[0255] The characterization data of Example 93 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.24 (t, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.00 (d, J = 6.0 Hz, 1H), 3.66 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.85 (t, J = 6.0 Hz, 2H), 2.79 (d, J = 6.0 Hz, 1H), 2.35 (t, J = 6.0 Hz, 4H), 2.27 (s, 3H).

[0256] Example 94

[0257] The characterization data of Example 94 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.24 (t, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.51 (s, 2H), 3.66 (t, 2H), 3.45 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.85 (t, J = 6.0 Hz, 2H), 2.78 (p, J = 6.0 Hz, 1H), 2.38 (d, J = 6.0 Hz, 2H), 2.35 (t, J = 6.0 Hz, 4H), 2.27 (s, 3H).

[0258] Example 95

[0259] The characterization data of Example 95 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 7.20 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 3H), 4.37 (q, J = 6.0 Hz, 1H), 3.97 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.35 (t, J = 6.0 Hz, 4H), 2.27 (s, 3H), 1.90 (d, J = 6.0 Hz, 2H).

[0260] Example 96

[0261] The characterization data of Example 96 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 7.20 (d, 1H), 6.76 (d, J = 8.8 Hz 1H), 5.53 (s, 2H), 4.00 (d, J = 6.0 Hz, 1H), 3.97 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 4H), 2.79 (d, J = 6.0 Hz, 1H), 2.35 (t, J = 6.0 Hz, 4H), 2.27 (d, J = 6.0 Hz, 3H).

[0262] Example 97

[0263] The characterization data of Example 97 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.47 (d, 1H), 7.31 (t, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.24 (t, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 6.80 (d, 1H), 5.53 (s, 2H), 4.51 (s, 2H), 4.00 (s, s, d, 3H), 3.66 (t, J = 6.0 Hz, 2H), 2.85 (t, J = 6.0 Hz, 2H), 2.79 (d, J = 6.0 Hz, 1H).

[0264] Example 98

[0265] The characterization data of Example 98 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.47 (d, 1H), 7.31 (t, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.24 (t, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 6.80 (d, 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.00 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 3.45 (t, J = 6.0 Hz, 2H), 2.85 (t, J = 6.0 Hz, 2H), 2.78 (q, J = 6.0 Hz, 1H), 2.38 (d, J = 6.0 Hz, 2H).

[0266] Example 99

[0267] The characterization data of Example 99 are as follows: 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),1.90(d,J=6.0Hz,2H).

[0268] Example 100

[0269] The characterization data of Example 100 are as follows: 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,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).

[0270] Example 101

[0271] The characterization data of Example 101 are as follows: 11H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.47 (d, 1H), 7.31 (t, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.24 (t, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 6.80 (d, 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.37 (q, J = 6.0 Hz, 1H), 4.00 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.85 (t, J = 6.0 Hz, 2H), 2.55 (t, J = 6.0 Hz, 2H), 1.91 (q, J = 6.0 Hz, 2H).

[0272] Example 102

[0273] The characterization data of Example 102 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.47 (d, 1H), 7.31 (t, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.24 (t, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 6.80 (d, 1H), 5.53 (s, 3H), 4.51 (s, 2H), 4.00 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.96 (q, J = 6.0 Hz, 2H), 2.85 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 1H), 2.00 (q, J = 6.0 Hz, 2H).

[0274] Example 103

[0275] The characterization data of Example 103 are as follows: 1 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.47 (d, 1H), 7.31 (t, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 7.20 (d, 1H), 6.80 (d, 1H), 5.53 (s, 3H), 4.37 (q, J = 6.0 Hz, 1H), 4.00 (s, 2H), 3.97 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.55 (t, J = 6.0 Hz, 2H), 1.91 (q, J = 6.0 Hz, 2H).

[0276] Example 104

[0277] The characterization data of Example 104 are as follows: 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).

[0278] Example 105

[0279] Preparation of injection

[0280] The compound 1 prepared in Example 1 was dissolved in a small amount of DMSO, and then conventional injection water was added, followed by fine filtration, filling and sterilization to prepare an injection.

[0281] Example 106

[0282] Preparation of tablets

[0283] The compound 1 prepared in Example 1 and cyclodextrin were granulated and tabletted according to a weight ratio of 6:1 to obtain tablets.

[0284] Example 107

[0285] Preparation of capsules

[0286] The compound 1 prepared in Example 1 and microcrystalline cellulose were made into capsules according to a weight ratio of 6:1.

[0287] Example 108

[0288] Test the inhibitory effect of the compounds of Examples 1 - 104 on pancreatic cancer cells

[0289] 1. Experimental method

[0290] Cell source: The cell lines used in this study were human pancreatic cancer cells PANC-1 and PaTu-8988T, and the cells were from ATCC.

[0291] Cell culture: Cells were cultured in an incubator at 37 °C with 5% CO2. After being taken out from the cryopreservation tank, the cells were thawed as quickly as possible in a 37 °C water bath, and then immediately placed into IMDM medium supplemented with 20% fetal bovine serum, and DNase I at a concentration of 10 μg / mL was added. The cells were centrifuged at 1500 rpm for 5 minutes, and then resuspended in complete medium at a concentration of 2 - 5×10 6 cells / mL. The thawed cells were subsequently cultured in complete medium. The IMDM medium was supplemented with 10% fetal bovine serum (FBS) and BIT (4 g / L bovine serum albumin, 5 μg / mL insulin, 60 μg / mL transferrin, 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 stimulating factor (G - CSF). In addition, the medium also contained 50 μM β - mercaptoethanol (Sigma - Aldrich).

[0292] Testing method: The MTT method was used to detect cell mortality. Cells were seeded at 1×10 5 / mL in H4230 medium supplemented with 10% IMDM, divided into a control group and a dosing group with a dosing concentration of 1 μM. On the second day, 10 μL of the prepared MTT solution was added to each well and 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 mixture was shaken on a shaker for 15 min. The absorbance at 492 nm was measured using an enzyme - linked immunosorbent assay (ELISA) reader.

[0293] 2. Experimental results

[0294] Table 1 Inhibitory activity of the compounds in the examples on the growth of pancreatic cancer cells

[0295]

[0296]

[0297] 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 on reducing the colony formation of pancreatic cancer cells (Table 1). Among them, the compound prepared in Example 39 had the best comprehensive effect. Further tests were conducted on the compound in Example 39 (hereinafter referred to as Compound 39):

[0298] Example 109

[0299] Effect of Test Compound 39 on Intracellular Iron Ion Level

[0300] 1. Experimental Method

[0301] Intracellular Fe 2+ Level determination: Seed PANC-1 and PaTu-8988T cells in a 96-well confocal laser scanning microscopy (CLSM) special culture plate, with 5000 cells in 100 μL of medium per well. After the cells have incubated overnight in the medium, discard the old medium. Treat the cells with medium containing 0.5 μM of Compound 39 for 6 hours. Prepare a probe working solution containing 1 μM of FerroOrange and 1 μg / mL of Hoechst 33342 in serum-free medium, then add it to the 96-well plate and incubate the cells in a 37 °C incubator for 30 min. Subsequently, wash the cells once with 1×PBS and perform cell detection using an FV3000 CLSM or a Cellomics ArrayScan Vti high-content screening system.

[0302] 2. Experimental Results

[0303] The results showed that Compound 39 could significantly reduce the concentration of iron ions in pancreatic cancer cells ( Figure 1 and Figure 2 ).

[0304] Example 110

[0305] Acute Toxicity Experiments of Test Compounds 39, 35 and 75

[0306] 1. Experimental Method

[0307] SPF-grade C57BL / 6 mice (6 - 7 weeks old) were used in the experiment. They were housed in an SPF-grade animal facility at a temperature of 21 - 24 °C and a humidity of 50 - 70%, fed with SPF-grade mouse feed and given sterile water to drink. After being purchased and housed in the animal facility for 1 week without any abnormalities, 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, 75 - 400 mg / kg), with 6 mice in each group, half male and half female, and they were housed separately in cages. Among them, 39 - 100 mg / kg, 39 - 200 mg / kg, and 39 - 400 mg / kg represent the dosages of Compound 39, 35 - 400 mg / kg represents the dosage of Compound 35, and 75 - 400 mg / kg represents the dosage of Compound 75.

[0308] Fast the mice for 12 h before dosing, allow free access to water, then administer the drugs by gavage, and give normal feeding 4 h after dosing. Within one week after dosing, weigh the mice on days 0, 3, 5, and 7, and observe the abnormal behaviors and deaths of the mice.

[0309] 2. Experimental Results

[0310] As Figure 3 shown, compared with the control group, there were no obvious weight changes in the mice of the drug administration group, nor any acute toxicity phenomena such as mouse death, abnormal behavior, and reduced appetite.

[0311] Based on the test data of the inhibitory effect of cyclamide-tetrahydroisoquinoline compounds on pancreatic cancer cells, the influence on the intracellular iron ion level, and the acute toxicity, it is sufficient to show that the cyclamide-tetrahydroisoquinoline compounds prepared through Examples 1-104 have a significant inhibitory effect on pancreatic cancer cells and low toxicity to organisms. This not only expands the types of drugs for clinical treatment of pancreatic cancer but is also suitable for large-scale production.

[0312] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. Use of a cyclic amide-tetrahydroisoquinoline compound in the preparation of an anti-pancreatic cancer drug, characterized in that, The cyclic amide-tetrahydroisoquinoline compound has the following structure of 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, where R2 is an H atom, an alkyl group of C 1～12 , an alkamino group of C 1～12 , an alkoxy group of C 1～12 , an alkanoyl group of C 1～12 , an alkanamido group of C 1～12 , an alkoxycarbonyl group of C 1～12 , any one of them; Y is a C or N atom; R1 is wherein A1 is any one of C, O, S atoms or -NH, A2, A3, A4, A5 and A6 are the same or different and are C or N atoms, and R 11 is mono-substituted or multi-substituted and is selected from one or more of an H atom, a C 1～12 alkyl group, a halogen atom, a C 1～12 alkoxy group, a C 1～12 alkylamino group, a C 1～12 alkanoyl group, a C 1～12 alkanoylamino group of, a C 1～12 alkanoate group of, an amino group, a hydroxyl group, an unsubstituted or substituted aromatic ring, and an unsubstituted or substituted aliphatic ring.

2. The application according to claim 1, wherein Ring A is an aliphatic or aromatic cyclic amide; Z is an O or N atom; X is -N-R2, where R2 is a hydrogen atom or an alkyl group of C 1～3 ; Y is a C or N atom; R1 is wherein A1 is any one of O, S atoms or -NH, A2, A3, A4, A5 and A6 are the same or different and are C or N atoms, and R 11 is mono-substituted or multi-substituted and is selected from H atom, C 1～3 alkyl, halogen atom, C 1～3 alkoxy, C 1～3 alkylamino, amino, hydroxyl, unsubstituted or substituted piperazine, indole, morpholine, or any one or more of them.

3. The application according to claim 2, wherein Ring A is a 4- to 7-membered aliphatic cyclic amide; Z is an O atom; X is -N-R2, where R2 is a hydrogen atom or an alkyl group of C 1～3 ; Y is a C or N atom; R1 is wherein A1 is an S atom or -NH, A2, A3, A4, A5 and A6 are the same or different and are C or N atoms, and R 11 is mono-substituted or multi-substituted and is selected from an H atom, C 1～3 alkyl, a halogen atom, C 1～3 alkoxy, C 1～3 alkylamino, amino, hydroxyl, unsubstituted or substituted piperazine, indole, morpholine, and one or more of them. Among them, the substituent of the said substituted piperazine is C 1～6 alkyl, halogen, C 1～6 alkoxy, hydroxyl or amino.

4. The application according to claim 3, wherein Ring A is a 4- to 6-membered aliphatic cyclic amide; Z is an O atom; X is -N-R2, where R2 is a hydrogen atom or an alkyl group of C 1～3 ; Y is a C atom; R1 is wherein A1 is -NH; A2, A3, A4, A5 and A6 are the same or different and are C or N atoms, and R 11 is mono-substituted or multi-substituted and is selected from one or more of an H atom, a C 1～3 alkyl group, a halogen atom, an unsubstituted or substituted piperazine, and a morpholine, wherein the substituent of the substituted piperazine is a C 1～3 alkyl group, a C 1～3 alkoxy group, a hydroxyl group or an amino group.

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

6. The application according to claim 1, wherein The cyclic amide-tetrahydroisoquinoline compound can be applied in any one of its pharmaceutically acceptable salts, solvates or chiral isomers.

7. The application according to claim 6, characterized in that, The pharmaceutically acceptable salt is obtained by reacting the cyclic amide-tetrahydroisoquinoline compound with an inorganic acid or an organic acid.

8. The application according to claim 7, wherein The organic acid is any one of citric acid, acetic acid, oxalic acid, isonicotinic acid, lactic acid, salicylic acid, acid citrate, tartaric acid, oleic acid, tannic acid, pantothenic acid, tartaric acid, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or pamoic acid.

9. The application according to claim 7, wherein The inorganic acid is any one of hydrochloric acid, phosphoric acid, sulfuric acid or nitric acid.

10. The application according to claim 1, wherein The drug is any one of an oral preparation, an injection, a topical preparation or an inhalation preparation.

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