Compound for synthesizing non-steroidal FXR regulator

Abstract

The invention discloses a compound for synthesizing a non-steroidal FXR regulator, and provides a phenylisoxazole derivative as shown in a formula I or a non-steroidal FXR regulator intermediate as shown in a formula II, and the non-steroidal FXR regulator synthesized by taking the intermediate or the phenylisoxazole derivative as a substrate has good affinity. The expression of an FXR downstream target gene can be induced at a cellular level.

Description

Technical Field

[0001] This application is a divisional application of the invention patent application with the application date of July 18, 2023, the application number of 202310876729.4, and the invention title of "Five-membered and Six-membered Compounds, Their Intermediates, Preparation Methods, Compositions and Applications".

[0002] The present invention relates to a compound for synthesizing a non-steroidal FXR regulator. Background Art

[0003] Farnesoid X receptor (FXR) belongs to the nuclear receptor family and is a ligand-activated transcription factor (D.J. Mangelsdorf, et al., Cell, 1995, 83(6), 841-850). There are four subtypes in total, which are widely distributed in tissues and organs such as the liver, intestine, and kidney. FXR can be activated by the endogenous ligand bile acid (Makishima M, et al. Identification of a Nuclear Receptor for Bile Acids. Science 1999, 284(5418), 1362-1365; Wang H, et al. Endogenous bile acids are ligands for the nuclear receptor FXR / BAR. Molecular cell 1999, 3(5), 543-53.), and directly or indirectly participates in the transcriptional regulation of more than forty downstream target genes. FXR is crucial for regulating metabolism and maintaining the in vivo homeostasis of bile acids, lipids, and glucose. Due to the multiple important roles of FXR in the body, it is considered an important target for treating diseases such as hepatitis, liver fibrosis, diabetes, and obesity.

[0004] The reported FXR agonists can be mainly divided into two categories. One is steroidal, represented by obeticholic acid (OCA) of Intercept Company; the other is non-steroidal molecules, which are mostly designed and synthesized with reference to early developed compounds such as GW4604 (WO2000037077). Some FXR agonists, including OCA, EDP-305, cilofexor, tropifexor, WAY-450, and EYP001, etc., have been or are in the clinical research stage. Steroidal FXR agonists (such as OCA) have shown pruritus and effects on cholesterol metabolism (increasing serum total cholesterol and low-density lipoprotein cholesterol levels and decreasing high-density lipoprotein) in clinical practice. Non-steroidal FXR agonists are considered likely to reduce and avoid drug-related side effects. Therefore, they are the focus of current development. Summary of the Invention

[0005] The present invention provides a compound for synthesizing a non-steroidal FXR regulator to solve the problems in the prior art.

[0006] The compound for synthesizing a non-steroidal FXR regulator includes a phenylisoxazole derivative represented by Formula I, or an intermediate of a non-steroidal FXR regulator represented by Formula II.

[0007] A phenylisoxazole derivative represented by Formula I

[0008]

[0009] wherein L1 is any one of;

[0010] wherein R1 is -NR a R b wherein R a and R b are each independently selected from H, an amino protecting group, -CH2(CO)NR aa R ba , and a C1 to C6 branched alkyl group;

[0011] wherein R aa and R ba are each independently selected from a cycloalkyl group, H.

[0012] An intermediate of a non-steroidal FXR regulator represented by Formula II, or a salt thereof;

[0013]

[0014] wherein L2 is

[0015] X is unsubstituted -CH2-;

[0016] Y is -N(R 4 )-;

[0017] R 4 is hydrogen, cyclopentyl, propenyl, unsubstituted C1-C5 alkyl or C1-C2 alkyl substituted by one R 4-1 ;

[0018] R 4-1 is carboxyl, a 6-membered aryl group, -C(=O)-R 4-1-1 ;

[0019] wherein R 4-1-1 is methyl, tetrahydropyrrolyl, a 6-membered aryl group, methoxy;

[0020] or, R 4-1-1-NR a R b ; wherein said R a and R b one of which is hydrogen and the other is an unsubstituted or R-substituted C1-C3 alkyl group, C5 cycloalkyl group, quinolinyl group, pyridyl group, unsubstituted 6-membered or 10-membered aryl group or 6-membered aryl group substituted by one R a-1 ; a-2 or, R

[0021] is -NR 4-1-1 R a ; wherein said R b and R a one of which is an unsubstituted C1-C3 alkyl group and the other is a 6-membered aryl group, C1-C2 alkyl group unsubstituted or substituted by a six-membered aryl group; b

[0022] or, R 4-1-1 is -NR a R b ; wherein said R a and R b one of which is an ethyl group substituted by a methoxy group and the other is an unsubstituted aryl group; 4-1-1

[0023] or, R 4-1-1 is -OR a ; wherein said R a is methyl;

[0024] R a-1 is C1-C6 alkyl group, methoxy group or 6-membered aryl group, chlorine;

[0025] R a-2 is chlorine, methyl or methoxy group.

[0026] A phenylisoxazole derivative, any one of the following compounds:

[0027]

[0028]

[0029] A non-steroidal FXR regulator intermediate, any one of the following compounds:

[0030]

[0031]

[0032]

[0033] A compound for synthesizing a non-steroidal FXR regulator, such as The regulator synthesized by the present invention has the following structure:

[0034]

[0035]

[0036]

[0037]

[0038] If a linking group is represented as "absent", the structures on both sides of the linking group are directly connected by a single bond. For example, for -A-B-C-, when B is absent, -A-B-C- becomes -A-C-.

[0039] The term "group B which is unsubstituted or substituted by multiple groups A" means that one or more hydrogen atoms in group B are independently replaced by group A or B is unsubstituted. When multiple A groups appear simultaneously, unless otherwise specified, their definitions are independent of each other and do not affect each other. For example, "C6-C 10 aryl" means C6-C 10 The aryl group is substituted by 3 halogen atoms, and the definitions of the 3 halogen atoms are independent of each other and do not affect each other, including but not limited to: etc.

[0040] The term "multiple" means 2 or more, such as 2, 3, 4, 5.

[0041] The term "halogen" means fluorine, chlorine, bromine or iodine.

[0042] The term "alkyl" means a straight-chain or branched-chain alkyl group having a specified number of carbon atoms (such as C1-C6). Alkyl groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, etc.

[0043] The term "heterocycloalkyl" means a cyclic group having a specified number of ring atoms (such as 3-8 membered), a specified number of heteroatoms (such as 1, 2 or 3), and a specified type of heteroatoms (one or more of N, O and S), where the heteroatoms can be used as linking groups to connect with others or not connect with other groups (for example, piperidinyl can be etc.), the ring in the heterocycloalkyl is a monocyclic ring, and each ring is saturated. Heterocycloalkyl groups include but are not limited to azetidinyl.

[0044] The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5 to 9 membered), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one or more of N, O, and S), which is monocyclic or polycyclic and at least one ring is aromatic (complies with Hückel's rule). The heteroaryl is linked to other fragments in the molecule through an aromatic ring or a non-aromatic ring. Heteroaryl includes, but is not limited to, imidazolyl, etc.

[0045] The term "heteroaromatic ring" refers to a cyclic group having a specified number of ring atoms (e.g., 5 to 9 membered), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one or more of N, O, and S), which is monocyclic or polycyclic and at least one ring is aromatic (complies with Hückel's rule). The heteroaromatic ring is linked to other fragments in the molecule through an aromatic ring or a non-aromatic ring.

[0046] The "-" at the end of a group means that the group is linked to other fragments in the molecule through this site. For example, CH3-C(=O)- means acetyl.

[0047] In the structural fragment it means that the structural fragment is linked to other fragments in the molecule through this site. For example, means acetyl.

[0048] When any variable (e.g., group R 1-1 ) appears multiple times in the definition of a compound, their definitions are independent of each other and do not affect each other. For example, a C6-C 1-1 aryl substituted by 3 R 10 where aryl refers to C6-C 10 aryl will be substituted by 3 R 1-1 and the definitions of the 3 R 1-1 are independent of each other and do not affect each other.

[0049] The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use in patients.

[0050] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use in patients) acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, etc. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride salts, maleate salts, acetate salts, trifluoroacetate salts, sulfate salts, methanesulfonate salts, etc. See specifically Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002).

[0051] The term "pharmaceutical excipient" refers to excipients and additives used in the production of drugs and the formulation of prescriptions, and includes all substances contained in pharmaceutical preparations except the active ingredient. See specifically the Pharmacopoeia of the People's Republic of China (2020 Edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).

[0052] The term "treatment" refers to any of the following situations: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that triggers the disease; (3) slowing the development of one or more biological manifestations of the disease.

[0053] The term "prevention" refers to reducing the risk of developing a disease.

[0054] The term "patient" refers to any animal that has received or is about to receive treatment, preferably a mammal, and most preferably a human. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0055] The term "alkylene" refers to a divalent group of a straight-chain or branched-chain saturated aliphatic hydrocarbon group having a specified number of carbon atoms. The two valences can be concentrated on the same atom, such as methylene (-CH2-), ethylene The two valences can also be attached to two atoms respectively, such as 1,2-ethylene (-CH2CH2-).

[0056] On the basis of not violating the common knowledge in the art, the above preferred conditions can be arbitrarily combined to obtain various preferred examples of the present invention.

[0057] The reagents and raw materials used in the present invention are all commercially available.

[0058] The positive and progressive effects of the present invention are as follows: The compounds of the present invention have good affinity for the FXR receptor and can induce the expression of FXR downstream target genes at the cellular level. Detailed implementation manners

[0059] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0060] Example 1

[0061]

[0062] Synthesis of Compound 1-B

[0063] Step 1: Compound 1-1

[0064] Intermediate A (500 mg, 1.0 eq.), N-Boc-ethanolamine (250 mg, 1.0 eq.), and 18-crown-6 (580 mg, 1.4 eq.) were dissolved in THF (20 mL). The temperature was lowered to 0 °C in an ice-salt bath, and a solution of potassium tert-butoxide in THF (1 M, 2.2 mL, 1.4 eq.) was added dropwise over 35 min. After the addition, the mixture was stirred at room temperature for 1 h. After the reaction was completed, the solvent was evaporated under reduced pressure. The residue was dissolved and diluted with ethyl acetate, washed with saturated brine, and the aqueous phase was extracted twice with EA. The combined organic phases were evaporated under reduced pressure, and the crude product (705 mg, pale yellow liquid) was purified by silica gel column chromatography with a purity of 83.8% and a yield > 100%. m / z: [M + 1] + 443;

[0065] Step 2: Compound 1-2

[0066] 418 mg of Compound 1-1 (418 mg, 1.0 eq.) was dissolved in 3 mL of a self-prepared dioxane hydrochloride solution (4 N, 3 mL, 12 eq.). The mixture was stirred at room temperature for 10 min until the raw materials reacted completely. The solvent was evaporated under reduced pressure to obtain a yellow oil, which was directly used in the next step. m / z: [M + 1] + 343;

[0067] Step 3: Compound 1-A

[0068] Compound 1-2 (323 mg, 1.0 eq.) was dissolved in N,N-dimethylacetamide (5 mL). After adding Compound B (274 mg, 1.0 eq.), the mixture was stirred until dissolved. Diisopropylethylamine (468 μL, 3.0 eq.) was added, and the reaction was stirred at 65 °C for 4 h. TLC was used to monitor the reaction, and a trace amount of the raw material remained. After the reaction was completed, the system was quenched by adding 30 mL of saturated ammonium chloride solution. The aqueous phase was extracted with EA (20 mL * 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The product was purified by silica gel column chromatography (PE:EA = 10:1) and recrystallized from ether / n-hexane to obtain 97 mg of a yellow solid with a purity of 99.2%. The yield was 18.6%. m / z: [M+1] + 552;

[0069] 1 H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 1.1 Hz, 1H), 7.71 (dd, J = 11.2, 1.2 Hz, 1H), 7.56 - 7.49 (m, 2H), 7.41 - 7.35 (m, 2H), 5.86 (s, 1H), 4.42 (s, 2H), 3.92 (s, 3H), 3.60 - 3.56 (m, 4H), 2.13 - 2.06 (m, 1H), 1.24 - 1.20 (m, 2H), 1.13 - 1.07 (m, 2H).

[0070] Step 4: Compound 1-B

[0071] Compound 1-A (50 mg, 1.0 eq.) was dissolved in a mixed solution of acetonitrile / water (10V / 2V). LiOH·H2O (10 mg, 3.0 eq.) was added, and the mixture was stirred at room temperature until completely dissolved. The reaction was stirred at 45 °C for 5 h until completion. The reaction was quenched with saturated ammonium chloride solution (5 mL). The aqueous phase was extracted three times with EA (5 mL * 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 35 mg of a white solid powder with a purity of 98% and a yield of 71.9%. m / z: [M+1] + 538;

[0072] 1 H NMR (400 MHz, DMSO-d6): δ 12.92 (s, 1H), 8.67 - 8.61 (m, 1H), 8.13 (d, J = 1.3 Hz, 1H), 7.65 - 7.59 (m, 2H), 7.58 - 7.50 (m, 2H), 7.49 - 7.43 (m, 1H), 4.35 (s, 2H), 3.57 - 3.48 (m, 4H), 2.35 - 2.30 (m, 1H), 1.10 - 1.04 (m, 4H).

[0073] Example 2

[0074]

[0075] Synthesis of Compound 2-B

[0076] Step 1: Compound 2-A

[0077] Compound 1-A (20 mg, 1.0 eq.) was dissolved in acetonitrile (1 mL). Cesium carbonate (35 mg, 3.0 eq.) was added, and methyl iodide (9 μL, 4.0 eq.) was added under stirring. The reaction mixture was sealed with a lid and stirred at room temperature for 6 hours. The raw material reacted completely. The reaction was quenched with 20 mL of saturated ammonium chloride solution, and the organic phase was extracted with ethyl acetate. The combined organic phases were washed with pure water and then with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. Purification by column chromatography (PE:EA = 15:1) gave 19 mg of a white oily substance with a purity of 99.0% and a yield of 92.7%. m / z: [M+1] + 566;

[0078] 1 H NMR (400 MHz, CDCl3): δ8.09 (d, J = 1.3 Hz, 1H), 7.71 (dd, J = 11.4, 1.4 Hz, 1H), 7.54 - 7.44 (m, 2H), 7.37 - 7.29 (m, 2H), 4.39 (s, 2H), 3.92 (s, 3H), 3.77 - 3.69 (m, 2H), 3.66 (t, J = 4.8 Hz, 2H), 3.08 (s, 3H), 2.11 - 2.03 (m, 1H), 1.21 - 1.17 (m, 2H), 1.07 - 1.02 (m, 2H).

[0079] Step 2: Compound 2-B

[0080] Compound 2-B was prepared by referring to Example 1, using Compound 2-A instead of Compound 1-A. m / z: [M+1] + 552;

[0081] 1 H NMR (400 MHz, CDCl3): δ8.15 (s, 1H), 7.77 (d, J = 10.9 Hz, 1H), 7.54 - 7.44 (m, 2H), 7.38 - 7.29 (m, 2H), 4.39 (s, 2H), 3.79 - 3.70 (m, 2H), 3.66 (t, J = 4.8 Hz, 2H), 3.08 (s, 3H), 2.08 (td, J = 8.4, 4.2 Hz, 1H), 1.23 - 1.17 (m, 2H), 1.09 - 1.02 (m, 2H).

[0082] Example 3

[0083]

[0084] Synthesis of Compound 3-B

[0085] Step 1: Compound 3-A

[0086] Compound 1-A (46 mg, 1.0 eq.) was dissolved in N,N-dimethylformamide (1 mL). Benzyl bromide (30 μL, 3.0 eq.) was added. After purging with nitrogen, cesium carbonate (84 mg, 3.0 eq.) was added, and the reaction was stirred at room temperature for 1 hour. The reaction was quenched with 10 mL of pure water, and the organic phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain 87 mg of a crude product. Purification by silica gel column chromatography (PE:EA = 10:1) gave 44 mg of an oily substance with a purity of 97.2% and a yield of 82.2%. m / z: [M+1] + 642;

[0087] 1 H NMR (400 MHz, CDCl3): δ 8.07 (d, J = 1.3 Hz, 1H), 7.72 (dd, J = 11.3, 1.3 Hz, 1H), 7.51 (dd, J = 7.6, 1.6 Hz, 1H), 7.48 - 7.43 (m, 1H), 7.36 - 7.27 (m, 5H), 7.22 - 7.17 (m, 2H), 4.65 (s, 2H), 4.37 (s, 2H), 3.92 (s, 3H), 3.72 - 3.61 (m, 4H), 2.10 - 2.03 (m, 1H), 1.22 - 1.17 (m, 2H), 1.07 - 1.01 (m, 2H).

[0088] Step 2: Compound 3-B

[0089] Compound 3-B was prepared by referring to Example 1 using Compound 3-A instead of Compound 1-A. m / z: [M+1] + 628;

[0090] 1 H NMR (400 MHz, DMSO-d6): δ 12.97 (s, 1H), 8.21 (d, J = 1.3 Hz, 1H), 7.63 - 7.55 (m, 3H), 7.52 - 7.48 (m, 1H), 7.44 - 7.39 (m, 1H), 7.35 - 7.22 (m, 5H), 4.70 (s, 2H), 4.35 (s, 2H), 3.74 - 3.63 (m, 2H), 3.63 - 3.58 (m, 2H), 2.32 - 2.24 (m, 1H), 1.03 (d, J = 6.7 Hz, 4H).

[0091] Example 4

[0092]

[0093] Synthesis of Compound 4-B

[0094] Step 1: Compound 4-A

[0095] Compound 1-A (40 mg, 1.0 eq.) was dissolved in acetonitrile (1 mL). 2-Bromo-N-(pyrrolidin-1-yl)acetamide (30 μL, 3.0 eq.) was added. After purging with nitrogen, potassium carbonate (23 mg, 2.0 eq.) was added. The reaction was stirred at room temperature overnight. After filtration, the solvent was removed by rotary evaporation to obtain 87 mg of crude product. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain 50 mg of a white oily substance with a purity of 98.4% and a yield of 100%. m / z: [M+1] + 663;

[0096] 1 H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 1.3 Hz, 1H), 7.71 (dd, J = 11.3, 1.3 Hz, 1H), 7.55 - 7.45 (m, 2H), 7.38 - 7.29 (m, 2H), 4.41 (s, 2H), 4.29 (s, 2H), 3.94 (s, 3H), 3.82 - 3.71 (m, 2H), 3.69 (t, J = 4.9 Hz, 2H), 3.48 (t, J = 6.8 Hz, 4H), 2.14 - 2.09 (m, 1H), 2.06 - 2.00 (m, 2H), 1.92 - 1.86 (m, 2H), 1.24 - 1.20 (m, 2H), 1.12 - 1.06 (m, 2H).

[0097] Step 2: Compound 4-B

[0098] Compound 4-B was prepared by referring to Example 1 with Compound 4-A replacing Compound 1-A. m / z: [M+1] + 671;

[0099] 11H NMR (400 MHz, DMSO-d6): δ 7.84 (s, 1H), 7.63 (d, J = 11.5 Hz, 1H), 7.53 - 7.49 (m, 1H), 7.48 - 7.43 (m, 1H), 7.36 - 7.30 (m, 2H), 4.39 (s, 2H), 4.31 (s, 2H), 3.75 - 3.65 (m, 4H), 3.54 - 3.45 (m, 4H), 2.12 - 2.08 (m, 1H), 2.05 - 2.01 (m, 2H), 1.92 - 1.87 (m, 2H), 1.22 - 1.18 (m, 2H), 1.10 - 1.06 (m, 2H).

[0100] Example 5

[0101]

[0102] Synthesis of Compound 5-B

[0103] Step 1: Compound 5-A

[0104] Compound 5-A was prepared by referring to Example 4 and using 2-bromoacetophenone instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M + 1] + 670;

[0105] 1 1H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 1.2 Hz, 1H), 7.96 - 7.89 (m, 2H), 7.74 - 7.64 (m, 2H), 7.57 - 7.51 (m, 2H), 7.51 - 7.47 (m, 1H), 7.47 - 7.41 (m, 1H), 7.35 - 7.31 (m, 1H), 7.30 - 7.25 (m, 1H), 5.01 (s, 2H), 4.38 (s, 2H), 3.93 (s, 3H), 3.68 (d, J = 3.4 Hz, 5H), 2.08 - 2.00 (m, 1H), 1.20 - 1.15 (m, 2H), 1.07 - 1.01 (m, 2H).

[0106] Step 2: Compound 5-B

[0107] Compound 5-B was prepared by referring to Example 1 and using Compound 4-A instead of Compound 1-A. m / z: [M + 1] + 656;

[0108] 11H NMR (400 MHz, DMSO-d6): δ 8.22 (s, 1H), 8.00 (d, J = 7.2 Hz, 2H), 7.73 (t, J = 7.4 Hz, 1H), 7.59 (t, J = 7.9 Hz, 5H), 7.45 (dd, J = 17.5, 7.5 Hz, 2H), 5.17 (s, 2H), 4.36 (s, 2H), 3.63 (s, 4H), 2.32 - 2.25 (m, 1H), 1.03 - 1.01 (m, 4H).

[0109] Example 6

[0110]

[0111] Synthesis of Compound 6-B

[0112] Step 1: Compound 6-A

[0113] Compound 6-A was prepared by referring to Example 4 and using 2-bromoacetanilide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 685;

[0114] 1 1H NMR (400 MHz, DMSO-d6): δ 10.17 (s, 1H), 8.29 (d, J = 1.3 Hz, 1H), 7.65 (s, 1H), 7.57 (t, J = 8.0 Hz, 4H), 7.49 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 7.4 Hz, 1H), 7.31 (t, J = 7.9 Hz, 2H), 7.06 (t, J = 7.3 Hz, 1H), 4.44 - 4.32 (m, 4H), 3.85 (s, 3H), 3.80 - 3.56 (m, 4H), 2.30 (dt, J = 13.5, 6.8 Hz, 1H), 1.24 - 1.22 (m, 2H), 1.03 - 1.00 (m, 2H).

[0115] Step 2: Compound 6-B

[0116] Compound 6-B was prepared by referring to Example 1 and using Compound 6-A instead of Compound 1-A. m / z: [M+1]+671;

[0117] 11H NMR (400 MHz, CDCl3): δ 9.26 (s, 1H), 8.16 (s, 1H), 7.82 (d, J = 11.1 Hz, 1H), 7.56 - 7.35 (m, 4H), 7.33 - 7.26 (m, 4H), 7.13 - 7.04 (m, 1H), 4.47 (s, 2H), 4.23 (s, 2H), 3.78 (s, 4H), 1.97 (s, 1H), 1.13 - 1.04 (m, 2H), 0.93 - 0.87 (m, 2H).

[0118] Example 7

[0119]

[0120] Synthesis of Compound 7-B

[0121] Step 1: Compound 7-1

[0122] Compound 7-1 was prepared by referring to Example 1 and using N-Boc-propanolamine instead of N-Boc-ethanolamine. m / z: [M+1] + 457;

[0123] Step 2: Compound 7-2

[0124] Compound 7-2 was prepared by referring to Example 1 and using Compound 7-1 instead of Compound 1-1. m / z: [M+1] + 357;

[0125] Step 3: Compound 7-A

[0126] Compound 7-A was prepared by referring to Example 1 and using Compound 7-2 instead of Compound 1-2. m / z: [M+1] + 566;

[0127] 1 1H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 1.3 Hz, 1H), 7.71 (dd, J = 11.2, 1.4 Hz, 1H), 7.56 (dd, J = 7.5, 1.7 Hz, 1H), 7.52 - 7.46 (m, 1H), 7.41 - 7.33 (m, 2H), 6.05 (s, 1H), 4.39 (s, 2H), 3.92 (s, 3H), 3.49 (t, J = 5.6 Hz, 2H), 3.43 - 3.37 (m, 2H), 2.16 - 2.09 (m, 1H), 1.88 - 1.82 (m, 2H), 1.26 - 1.22 (m, 2H), 1.15 - 1.09 (m, 2H).

[0128] Step 4: Compound 7-B

[0129] Compound 7-B was prepared by using compound 7-A to replace compound 1-A with reference to Example 1. m / z: [M+1] + 552;

[0130] 1 H NMR(400 MHz, DMSO-d6): δ 8.57 (t, J = 4.4 Hz, 1H), 8.13 (d, J = 1.0 Hz, 1H), 7.66 - 7.61 (m, 2H), 7.58 - 7.49 (m, 3H), 4.31 (s, 2H), 3.43 - 3.37 (m, 4H), 2.37 - 2.29 (m, 1H), 1.77 - 1.69 (m, 2H), 1.15 - 1.04 (m, 4H).

[0131] Example 8

[0132]

[0133] Synthesis of Compound 8-B

[0134] Step 1: Compound 8-A

[0135] Compound 8-A was prepared by using compound 7-A to replace compound 1-A with reference to Example 2. m / z: [M+1] + 580;

[0136] 1 H NMR(400 MHz, CDCl3): δ 8.07 (d, J = 1.2 Hz, 1H), 7.70 (dd, J = 11.4, 1.3 Hz, 1H), 7.58 - 7.46 (m, 2H), 7.40 - 7.34 (m, 2H), 4.35 (s, 2H), 3.92 (s, 3H), 3.57 - 3.45 (m, 2H), 3.45 - 3.37 (m, 2H), 3.13 (s, 3H), 2.16 - 2.12 (m, 1H), 1.90 - 1.84 (m, 2H), 1.24 - 1.21 (m, 2H), 1.12 - 1.08 (m, 2H).

[0137] Step 2: Compound 8-B

[0138] Compound 8-B was prepared by using compound 8-A to replace compound 1-A with reference to Example 1. m / z: [M+1] + 566;

[0139] 11H NMR (400 MHz, CDCl3): δ 8.13 (d, J = 1.3 Hz, 1H), 7.76 (dd, J = 11.2, 1.4 Hz, 1H), 7.56 (dd, J = 7.8, 1.7 Hz, 1H), 7.53 - 7.47 (m, 1H), 7.42 - 7.35 (m, 2H), 4.36 (s, 2H), 3.55 - 3.46 (m, 2H), 3.42 (t, J = 5.8 Hz, 2H), 3.14 (s, 3H) 2.16 - 2.11 (m, 1H), 1.91 - 1.84 (m, 2H), 1.25 - 1.21 (m, 2H), 1.10 (dt, J = 7.4, 4.4 Hz, 2H).

[0140] Example 9

[0141]

[0142] Synthesis of Compound 9-B

[0143] Step 1: Compound 9-A

[0144] Compound 9-A was prepared by referring to Example 8 and using bromoethane instead of iodomethane. m / z: [M+1] + 594;

[0145] 1 1H NMR (400 MHz, CDCl3): δ 8.23 (d, J = 1.2 Hz, 1H), 7.68 - 7.58 (m, 3H), 7.57 - 7.49 (m, 2H), 4.34 (s, 2H), 3.85 (s, 3H), 3.54 - 3.45 (m, 2H), 3.41 - 3.35 (m, 4H), 2.38 - 2.30 (m, 1H), 1.83 - 1.75 (m, 2H), 1.16 (t, J = 6.8 Hz, 3H), 1.13 - 1.06 (m, 4H).

[0146] Step 2: Compound 9-B

[0147] Compound 9-B was prepared by referring to Example 1 and using Compound 9-A instead of Compound 1-A. m / z: [M+1] + 580;

[0148] 11H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 1.2 Hz, 1H), 7.71 - 7.61 (m, 2H), 7.60 - 7.48 (m, 3H), 4.34 (s, 2H), 3.48 (q, J = 6.8 Hz, 2H), 3.42 - 3.35 (m, 4H), 2.37 - 2.30 (m, 1H), 1.84 - 1.75 (m, 1H), 1.15 (t, J = 6.8 Hz, 3H), 1.14 - 1.06 (m, 4H).

[0149] Example 10

[0150]

[0151] Synthesis of Compound 10 - B

[0152] Step 1: Compound 10 - A

[0153] Dissolve Compound 7 - A (42 mg, 1 eq.) in acetonitrile (2 mL), add cesium carbonate (49 mg, 2 eq.) and 2 - bromopropane (45 mg, 5 eq.) to the reaction solution, microwave heat at 120 °C for 0.5 h. Filter the reaction solution and concentrate it under reduced pressure to obtain the crude product, which is purified by column chromatography to give 22 mg of a white solid with a purity of 99.0% and a yield of 49%. m / z: [M + 1] + 608;

[0154] 1 1H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 1.4 Hz, 1H), 7.71 (dd, J = 11.4, 1.4 Hz, 1H), 7.61 (dd, J = 7.6, 1.6 Hz, 1H), 7.53 - 7.49 (m, 1H), 7.39 (t, J = 7.4 Hz, 2H), 4.45 - 4.30 (m, 3H), 3.93 (s, 3H), 3.47 (t, J = 5.8 Hz, 2H), 3.39 - 3.33 (m, 2H), 2.16 - 2.21 (m, 1H), 1.96 - 1.90 (m, 2H), 1.26 (d, J = 6.7 Hz, 8H), 1.15 - 1.11 (m, 2H).

[0155] Step 2: Compound 10 - B

[0156] Refer to Example 1, use Compound 10 - A instead of Compound 1 - A to prepare Compound 10 - B. m / z: [M + 1] + 594;

[0157] 11H NMR (400 MHz, CDCl3): δ 8.15 (d, J = 1.4 Hz, 1H), 7.77 (dd, J = 11.2, 1.4 Hz, 1H), 7.61 (dd, J = 7.7, 1.6 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.39 (t, J = 7.4 Hz, 2H), 4.45 - 4.30 (m, 3H), 3.48 (t, J = 5.6 Hz, 2H), 3.36 - 3.39 (m, 2H), 2.22 - 2.16 (m, 1H), 1.92 - 1.96 (m, 2H), 1.28 - 1.26 (m, 8H), 1.16 - 1.12 (m, 2H).

[0158] Example 11

[0159]

[0160] Synthesis of Compound 11

[0161] Step 1: Compound 11-A

[0162] Dissolve Compound 7-A (50 mg, 1 eq) in acetonitrile (2 mL), add potassium carbonate (25 mg, 2 eq) and 1-bromopropane (43 mg, 4 eq) to the reaction solution, microwave heat at 80 °C for 3 hours. Filter the reaction solution and concentrate it under reduced pressure to obtain the crude product, which is purified by column chromatography to obtain 35 mg of a white solid with a purity of 94.5% and a yield of 65.0%. m / z: [M + 1] + 608;

[0163] Step 2: Compound 11

[0164] Dissolve Compound 11-A (35 mg, 1 eq.) in tetrahydrofuran (1.4 mL), then dissolve LiOH·H2O (5 mg, 2 eq.) in water (350 μL), mix the organic phase and the aqueous phase, and react at 40 °C overnight. Acidify to pH = about 6 with 0.1 M hydrochloric acid, extract three times with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and evaporate to obtain 28 mg of the product with a purity of 95.6% and a yield of 74.77%. m / z: [M + 1] + 594;

[0165] 11H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 1.5 Hz, 1H), 7.77 (dd, J = 11.2, 1.6 Hz, 1H), 7.59 (dd, J = 7.8, 1.8 Hz, 1H), 7.57 - 7.48 (m, 1H), 7.43 - 7.35 (m, 2H), 4.39 (s, 2H), 3.51 (s, 2H), 3.47 - 3.37 (m, 4H), 2.21 - 2.13 (m, 1H), 1.96 - 1.87 (m, 2H), 1.70 (q, J = 7.5 Hz, 2H), 1.26 (dd, J = 5.1, 2.3 Hz, 2H), 1.13 (dt, J = 8.5, 3.4 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H).

[0166] Example 12

[0167]

[0168] Synthesis of Compound 12

[0169] Step 1: Compound 12-A

[0170] Dissolve Compound 7-A (50 mg, 1 eq) in acetonitrile (2 mL), add potassium carbonate (25 mg, 2 eq) and 1-bromobutane (48 mg, 4 eq) to the reaction solution, microwave heat at 80 °C for 2 hours. Concentrate the reaction solution under reduced pressure to obtain the crude product, and purify it by column chromatography to obtain 42 mg of an oily substance with a purity of 95.7% and a yield of 72.7%. m / z: [M + 1] + 622;

[0171] Step 2: Compound 12

[0172] Refer to Example 11, use Compound 12-A instead of Compound 11-A to prepare Compound 12-B. m / z: [M + 1] + 608;

[0173] 11H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 1.5 Hz, 1H), 7.77 (dd, J = 11.1, 1.6 Hz, 1H), 7.59 (dd, J = 7.9, 1.8 Hz, 1H), 7.52 (td, J = 7.9, 1.9 Hz, 1H), 7.43 - 7.35 (m, 2H), 4.39 (s, 2H), 3.51 (q, J = 7.0 Hz, 2H), 3.49 - 3.41 (m, 4H), 2.20 - 2.13 (m, 1H), 1.97 - 1.86 (m, 2H), 1.68 - 1.59 (m, 2H), 1.47 - 1.38 (m, 2H), 1.27 - 1.21 (m, 2H), 1.13 (dt, J = 8.5, 3.4 Hz, 2H), 0.98 (t, J = 7.3 Hz, 3H).

[0174] Example 13

[0175]

[0176] Synthesis of Compound 13

[0177] Step 1: Compound 13-A

[0178] Dissolve Compound A (100 mg, 1 eq.) in acetonitrile (1 mL), then add Cs2CO3 (116 mg, 2 eq.) and 1-bromo-2-methylpropane (96 mg, 2.0 eq.) to the reaction solution. Heat the reaction under microwave at 80 °C for 2 h until the raw materials react completely. Quench the system with saturated ammonium chloride, extract with ethyl acetate. Combine the organic phases, wash with pure water, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and remove the solvent by rotary evaporation to obtain the crude product. Purify by silica gel column chromatography to obtain 82 mg of pale yellow oil, with a purity of 90% and a yield of 74.6%. m / z: [M + 1] + 622;

[0179] Step 2: Compound 13

[0180] Refer to Example 11, use Compound 13-A instead of Compound 11-A to prepare Compound 13. m / z: [M + 1] + 608;

[0181] 11H NMR (400 MHz, DMSO-d6): δ 8.18 (d, J = 1.6 Hz, 1H), 7.65 (q, J = 1.7 Hz, 1H), 7.63 (q, J = 1.8 Hz, 1H), 7.58 (dd, J = 11.6, 1.6 Hz, 1H), 7.56 - 7.49 (m, 2H), 4.34 (s, 2H), 3.40 (brs, 2H), 3.37 (t, J = 8.0 Hz, 2H), 3.27 (brs, 2H), 2.36 - 2.31 (m, 1H), 2.09 - 2.02 (m, 1H), 1.83 - 1.76 (m, 2H), 1.13 - 1.07 (m, 4H), 0.88 (d, J = 6.6 Hz, 6H).

[0182] Example 14

[0183]

[0184] Synthesis of Compound 14-B

[0185] Step 1: Compound 14-1

[0186] Dissolve compound 7-2 (120 mg, 1 eq.) and pivalaldehyde (52 mg, 2 eq.) in methanol (2 mL). After stirring at room temperature for 8 hours, cool the reaction apparatus to 0 °C, and add sodium borohydride (51 mg, 4.0 eq.) to the reaction solution in three portions. After addition, restore to room temperature and react overnight. Quench the reaction with 0.1 M dilute hydrochloric acid solution, extract with ethyl acetate. After combining the organic phases, wash with pure water and saturated sodium chloride aqueous solution respectively, dry over anhydrous sodium sulfate, and evaporate the solvent by rotary evaporation. Purify by silica gel column chromatography to obtain 65 mg of a colorless oil, with a yield of 51% and a purity of 99.0%. m / z: [M+1] + 427;

[0187] Step 2: Compound 14-A

[0188] Dissolve compound 14-1 (65 mg, 1 eq.), compound B (31 mg, 1.1 eq.) and potassium iodide (5 mg, 0.2 eq.) in acetonitrile (2 mL), add potassium carbonate (25 mg, 1.2 eq.) and react overnight at 85 °C. After the reaction, concentrate under reduced pressure to obtain a crude product, and purify by silica gel column chromatography to obtain 47 mg of a colorless oil, with a yield of 37% and a purity of 99.0%. m / z: [M+1] + 636;

[0189] 11H NMR (600 MHz, CDCl3): δ 8.05 (d, J = 1.2 Hz, 1H), 7.68 (d, J = 11.3 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 7.2 Hz, 1H), 7.36 (t, J = 7.6 Hz, 2H), 4.35 (d, J = 6.8 Hz, 2H), 3.91 (s, 3H), 3.56 (d, J = 6.9 Hz, 2H), 3.38 - 3.43 (m, 2H), 3.29 (s, 2H), 2.16 - 2.12 (m, 1H), 1.90 (dd, J = 14.3, 5.9 Hz, 2H), 1.23 (dd, J = 4.8, 2.2 Hz, 2H), 1.10 (dd, J = 8.3, 2.6 Hz, 2H), 0.98 (s, 9H).

[0190] Step 3: Compound 14-B

[0191] Compound 14-B was prepared by using Compound 14-A instead of Compound 1-A according to Reference Example 1. m / z: [M+1] + 622;

[0192] 1 1H NMR (600 MHz, CDCl3): δ 8.12 (s, 1H), 7.74 (d, J = 11.1 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 7.2 Hz, 1H), 7.37 (t, J = 7.6 Hz, 2H), 4.36 (d, J = 6.7 Hz, 2H), 3.54 (d, J = 45.1 Hz, 2H), 3.41 (dd, J = 11.8, 5.8 Hz, 2H), 3.31 (s, 2H), 2.16 - 2.13 (m, 1H), 1.93 - 1.88 (m, 2H), 1.25 - 1.23 (m, 2H), 1.12 - 1.09 (m, 2H), 1.01 - 0.95 (m, 9H).

[0193] Example 15

[0194]

[0195] Synthesis of Compound 15-B

[0196] Step 1: Compound 15-A

[0197] Compound 15-A was prepared by using bromocyclopentane instead of 2-bromopropane according to Reference Example 10. m / z: [M+1] + 634;

[0199] 11H NMR (400 MHz, CDCl3): δ 8.05 (d, J = 1.6 Hz, 1H), 7.72 - 7.64 (m, 3H), 7.60 - 7.52 (m, 2H), 5.34 - 5.26 (m, 1H), 4.36 (s, 2H), 3.91 (s, 3H), 3.46 (t, J = 6.0 Hz, 2H), 3.05 (t, J = 6.4 Hz, 2H), 2.40 - 2.34 (m, 1H), 2.20 - 1.58 (m, 8H), 1.83 - 1.77 (m, 2H), 1.18 - 1.10 (m, 4H)

[0200] Step 2: Compound 15 - B

[0201] Compound 15 - B was prepared by using compound 15 - A instead of compound 1 - A according to Reference Example 1. m / z: [M + 1] + 620;

[0202] 1 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 1.2 Hz, 1H), 7.68 - 7.62 (m, 2H), 7.58 - 7.49 (m, 3H), 4.37 (s, 2H), 4.26 (s, 1H), 3.39 (t, J = 6.0 Hz, 2H), 3.28 (t, J = 7.6 Hz, 2H), 2.38 - 2.32 (m, 1H), 1.94 - 1.52 (m, 10H), 1.15 - 1.07 (m, 4H).

[0203] Example 16

[0204]

[0205] Synthesis of Compound 16 - B

[0206] Step 1: 16 - A Compound 7 - A (55 mg, 1.0 eq.) was dissolved in N,N - dimethylformamide (2 mL). Under ice - bath cooling, cesium carbonate (99 mg, 3.0 eq.) and benzyl bromide (35 μL, 3.0 eq.) were added. The mixture was stirred for 1 hour until the raw materials reacted completely. It was quenched with 0.1 M dilute hydrochloric acid, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. Purification by silica gel column chromatography gave 57 mg of a pale yellow oil, with a yield of 89%, m / z: [M + 1] + 656;

[0207] 11H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 1.1 Hz, 1H), 7.73 (dd, J = 11.3, 1.2 Hz, 1H), 7.56 - 7.49 (m, 1H), 7.48 - 7.41 (m, 1H), 7.38 - 7.32 (m, 4H), 7.30 - 7.25 (m, 3H), 4.76 (s, 2H), 4.35 (s, 2H), 3.94 (s, 3H), 3.54 - 3.44 (m, 2H), 3.41 (t, J = 5.8 Hz, 2H), 2.15 - 2.07 (m, 1H), 1.93 - 1.83 (m, 2H), 1.25 - 1.20 (m, 2H), 1.11 - 1.05 (m, 2H).

[0208] Step 2: 16 - B

[0209] Compound 16 - B was prepared by using compound 16 - A instead of compound 1 - A according to Reference Example 1. m / z: [M + 1] + 642;

[0210] 1 1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.77 (d, J = 12.0 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.45 - 7.40 (m, 1H), 7.36 - 7.30 (m, 4H), 7.28 (d, J = 7.5 Hz, 1H), 7.26 - 7.22 (m, 2H), 4.74 (s, 2H), 4.34 (s, 2H), 3.46 (s, 2H), 3.39 (t, J = 5.8 Hz, 2H), 2.12 - 2.07 (m, 1H), 1.90 - 1.84 (m, 2H), 1.22 - 1.19 (m, 2H), 1.08 - 1.03 (m, 2H).

[0211] Example 17

[0212]

[0213] Preparation of Compound 17

[0214] Step 1: Compound 17 - A

[0215] Compound 17 - A was prepared by using (1 - bromoethyl)benzene instead of 1 - bromopropane according to Reference Example 11. m / z: [M + 1] + 670;

[0216] Step 2: Compound 17

[0217] Compound 17-B was prepared by replacing compound 11-A with compound 17-A according to Example 11. m / z: [M+1] + 656;

[0218] 1 H NMR(400MHz,CDCl3):δ8.17(d,J = 1.5Hz,1H),7.80(dd,J = 11.1,1.5Hz,1H),7.54(dd,J = 7.6,1.8Hz,1H),7.45(td,J = 7.9,1.8Hz,1H),7.35(s,5H),7.34(d,J = 2.8Hz,1H),7.31(d,J = 7.9Hz,1H),5.72(s,1H),4.32(s,2H),3.38 - 3.15(m,4H),2.16 - 2.06(m,1H),1.87 - 1.72(m,2H),1.68(d,J = 7.0Hz,3H),1.26 - 1.19(m,2H),1.11 - 1.03(m,2H).

[0219] Example 18

[0220]

[0221] Synthesis of Compound 18

[0222] Step 1: Compound 18-A

[0223] Compound 16-A was prepared by replacing 2-bromo-N-(pyrrolidin-1-yl)acetamide with 3-bromopropene according to Example 4. m / z: [M+1] + 606;

[0224] Step 2: Compound 18

[0225] Compound 18 was prepared by replacing compound 11-A with compound 18-A according to Example 11. m / z: [M+1] + 592;

[0226] 1 H NMR(400MHz,DMSO-d6):δ12.87(s,1H),8.20(d,J = 1.5Hz,1H),7.65 - 7.50(m,5H),5.88 - 5.80(m,1H),5.23 - 5.17(m,2H),4.33(s,2H),4.11(s,2H),3.42(s,2H),3.38(d,J = 5.9Hz,2H),2.35 - 2.31(m,1H),1.83 - 1.77(m,2H),1.12 - 1.06(m,4H).

[0227] Example 19

[0228]

[0229] Synthesis of Compound 19-B

[0230] Step 1: Compound 19-A

[0231] Compound 19-A was prepared with 2-bromoacetophenone instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide according to Reference Example 4. m / z: [M+1] + 684;

[0232] 1 H NMR (400 MHz, CDCl3): δ8.09 (d, J = 1.2 Hz, 1H), 7.99 (d, J = 7.4 Hz, 2H), 7.72 - 7.64 (m, 2H), 7.58 - 7.52 (m, 3H), 7.51 - 7.46 (m, 1H), 7.40 - 7.32 (m, 2H), 5.09 (s, 2H), 4.38 (s, 2H), 3.93 (s, 3H), 3.55 - 3.45 (m, 4H), 2.16 - 2.09 (m, 1H), 1.96 - 1.88 (m, 2H), 1.24 - 1.20 (m, 2H), 1.12 - 1.06 (m, 2H).

[0233] Step 2: Compound 19-B

[0234] Compound 19-B was prepared with Compound 19-A instead of Compound 1-A according to Reference Example 1. m / z: [M+1] + 670;

[0235] 1 H NMR (400 MHz, CDCl3): δ8.12 (d, J = 1.2 Hz, 1H), 7.97 (d, J = 7.4 Hz, 2H), 7.72 (dd, J = 11.1, 1.2 Hz, 1H), 7.65 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.7 Hz, 3H), 7.49 - 7.44 (m, 1H), 7.34 (t, J = 7.6 Hz, 2H), 5.08 (s, 2H), 4.36 (s, 2H), 3.53 - 3.43 (m, 4H), 2.14 - 2.06 (m, 1H), 1.94 - 1.87 (m, 2H), 1.22 - 1.18 (m, 2H), 1.10 - 1.04 (m, 2H).

[0236] Example 20

[0237]

[0238] Synthesis of Compound 20-B

[0239] Step 1: Compound 20-A

[0240] Compound 20-A was prepared by referring to Example 2 and using bromoacetone instead of methyl iodide. m / z: [M+1] + 622;

[0241] 1 H NMR(400MHz, DMSO-d6): δ8.25(d, J = 1.2Hz, 1H), 7.68 - 7.60(m, 3H), 7.57 - 7.50(m, 2H), 4.49(s, 2H), 4.32(s, 2H), 3.85(s, 3H), 3.41 - 3.35(m, 4H), 2.36 - 2.31(m, 1H), 2.15(s, 3H), 1.80 - 1.72(m, 2H), 1.14 - 1.06(m, 4H).

[0242] Step 2: Compound 20-B

[0243] Compound 20-B was prepared by referring to Example 1 and using Compound 20-A instead of Compound 1-A. m / z: [M+1] + 608;

[0244] 1 H NMR(400MHz, DMSO-d6): δ12.98(s, 1H), 8.25(d, J = 1.6Hz, 1H), 7.70 - 7.62(m, 3H), 7.63 - 7.55(m, 2H), 4.53(s, 2H), 4.37(s, 2H), 3.46 - 3.40(m, 4H), 2.41 - 2.36(m, 1H), 2.20(s, 3H), 1.84 - 1.78(m, 2H), 1.18 - 1.11(m, 4H).

[0245] Example 21

[0246]

[0247] Synthesis of Compound 21

[0248] Dissolve Compound 7-B (35 mg, 1 eq.) in acetonitrile (2 mL), add methyl bromoacetate (14 mg, 1.5 eq.), stir to dissolve, add potassium carbonate (25 mg, 3 eq.) to the system, and then react under microwave heating at 60 °C for 4 hours. After the reaction, concentrate under reduced pressure to obtain the crude product, and purify it by silica gel column chromatography to obtain 25 mg of white solid, with a purity of 99.9% and a yield of 67%. m / z: [M+1] + 624;

[0249] 1 1H NMR (400 MHz, DMSO-d6): δ 8.63 (s, 1H), 8.24 (d, J = 1.4 Hz, 1H), 7.60 - 7.65 (m, 3H), 7.56 - 7.51 (m, 2H), 4.92 (s, 2H), 4.32 (s, 2H), 3.71 (s, 3H), 3.70 - 3.64 (m, 2H), 3.40 (t, J = 6.1 Hz, 2H), 2.36 - 2.31 (m, 1H), 1.77 - 1.72 (m, 2H), 1.13 - 1.07 (m, 4H).

[0250] Example 22

[0251]

[0252] Synthesis of Compound 22

[0253] Compound 22 was prepared by using Compound 7-A instead of Compound 7-B with reference to Example 21. m / z: [M + 1] + 637;

[0254] 1 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 1.4 Hz, 1H), 7.72 (dd, J = 11.3, 1.5 Hz, 1H), 7.58 (dd, J = 7.8, 1.7 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.42 - 7.38 (m, 2H), 4.38 (s, 2H), 4.34 (s, 2H), 3.94 (s, 3H), 3.78 (s, 3H), 3.50 (t, J = 7.1 Hz, 2H), 3.45 (t, J = 5.7 Hz, 2H), 2.10 - 2.18 (m, 1H), 1.93 - 1.86 (m, 2H), 1.27 - 1.24 (m, 2H), 1.16 - 1.10 (m, 2H).

[0255] Example 23

[0256]

[0257] Synthesis of Compound 23

[0258] Step 1: Compound 23-A

[0259] Compound 23 was prepared by using tert-butyl bromoacetate instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide with reference to Example 4. m / z: [M + 1] + 680;

[0260] Step 2: Compound 23

[0261] Compound 23-A (105 mg, 1.0 eq.) was placed in a reaction flask, and dioxane hydrochloride solution (4 M, 6 mL) was added under the protection of a nitrogen balloon. The system was reacted in an oil bath at 40 °C for 2 h. Dioxane and excess hydrochloric acid were removed by rotary evaporation. m / z: [M+1] + 624;

[0262] 1 1H NMR (400 MHz, DMSO-d6): δ 8.37 - 8.18 (s, 1H), 7.74 - 7.46 (m, 5H), 4.48 - 4.18 (m, 4H), 3.86 (s, 3H), 3.60 - 3.40 (m, 4H), 2.39 - 2.29 (s, 1H), 1.88 - 1.74 (m, 2H), 1.16 - 1.05 (m, 4H).

[0263] Example 24

[0264]

[0265] Synthesis of Compound 24

[0266] Compound 24 was prepared by referring to Example 1 and using Compound 22 instead of Compound 1-A. m / z: [M+1] + 610; Example 25

[0267]

[0268] Synthesis of Compound 25-B

[0269] Step 1: Compound 25-A

[0270] Compound 25-A was prepared by referring to Example 2 and using 2-bromo-1-(pyrrolidin-1-yl)ethanone instead of methyl iodide. m / z: [M+1] + 677;

[0271] 1H NMR (400 MHz, CDCl3): δ 8.07 (d, J = 1.1 Hz, 1H), 7.70 (d, J = 11.3 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.55 - 7.49 (m, 1H), 7.43 - 7.37 (m, 2H), 4.37 (s, 2H), 4.33 (s, 2H), 3.94 (s, 3H), 3.57 (t, J = 6.9 Hz, 4H), 3.52 - 3.44 (m, 4H), 2.19 - 2.13 (m, 1H), 2.07 - 2.02 (m, 2H), 1.95 - 1.88 (m, 4H), 1.26 - 1.23 (m, 2H), 1.15 - 1.10 (m, 2H).

[0272] Step 2

[0273] Compound 25-B was prepared by using Compound 25-A to replace Compound 1-A with reference to Example 1. m / z: [M+1] + 663;

[0274] 1 H NMR(400MHz, CDCl3): δ 7.86(s, 1H), 7.65 - 7.56(m, 2H), 7.56 - 7.50(m, 1H), 7.44 - 7.38(m, 2H), 4.38(s, 2H), 4.37(s, 2H), 3.62 - 3.52(m, 6H), 3.47(t, J = 5.7Hz, 2H), 2.19 - 2.14(m, 1H), 2.08 - 2.04(m, 2H), 1.97 - 1.88(m, 4H), 1.27 - 1.23(m, 2H), 1.16 - 1.11(m, 2H).

[0275] Example 26

[0276]

[0277] Synthesis of Compound 26-B

[0278] Step 1: Compound 26-A

[0279] Compound 26-A was prepared by using 2-bromo-N-methylacetamide to replace 2-bromo-N-(pyrrolidin-1-yl)acetamide with reference to Example 4. m / z: [M+1] + 637;

[0280] 1 H NMR(400MHz, DMSO-d6): δ 8.27(d, J = 1.6Hz, 1H), 8.05 - 7.99(m, 1H), 7.68 - 7.61(m, 3H), 7.56 - 7.50(m, 2H), 4.31(s, 2H), 4.15(s, 2H), 3.86(s, 3H), 3.38(t, J = 5.6Hz, 2H), 3.33 - 3.30(m, 2H), 2.61(d, J = 4.8Hz, 3H), 2.35 - 2.30(m, 1H), 1.84 - 1.77(m, 2H), 1.13 - 1.06(m, 4H).

[0281] Step 2: Compound 26-B

[0282] Compound 26-B was prepared by using Compound 26-A to replace Compound 1-A with reference to Example 1. m / z: [M+1] + 623;

[0283] 1 1H NMR (400 MHz, DMSO-d6): δ 13.0 (brs, 1H), 8.27 (d, J = 1.6 Hz, 1H), 8.13 - 8.01 (m, 1H), 7.74 - 7.63 (m, 3H), 7.62 - 7.55 (m, 2H), 4.37 (s, 2H), 4.20 (s, 2H), 3.59 - 3.49 (m, 2H), 3.44 (t, J = 6.0 Hz, 2H), 2.67 (d, J = 4.4 Hz, 3H), 2.42 - 2.35 (m, 1H), 1.91 - 1.82 (m, 2H), 1.20 - 1.12 (m, 4H).

[0284] Example 27

[0285]

[0286] Synthesis of Compound 27-B

[0287] Step 1: Compound 27-A

[0288] Compound 27-A was prepared by referring to Example 2 and replacing methyl iodide with N,N-dimethyl-bromoacetamide. m / z: [M+1] + 651;

[0289] 1 1H NMR (400 MHz, DMSO-d6): δ 8.24 (d, J = 1.2 Hz, 1H), 7.68 - 7.60 (m, 3H), 7.57 - 7.49 (m, 2H), 4.46 (s, 2H), 4.32 (s, 2H), 3.85 (s, 3H), 3.39 (t, J = 6.0 Hz, 2H), 3.33 - 3.30 (m, 2H), 3.01 (s, 3H), 2.85 (s, 3H), 2.38 - 2.30 (m, 1H), 1.85 - 1.77 (m, 2H), 1.14 - 1.05 (m, 4H).

[0290] Step 2: Compound 27-B

[0291] The target compound 27-B was prepared by referring to Example 1 and replacing compound 1-A with compound 27-A. m / z: [M+1] + 637;

[0292] 11H NMR (400 MHz, DMSO-d6): δ 13.05 (brs, 1H), 8.25 (s, 1H), 7.74 - 7.69 (m, 2H), 7.67 - 7.56 (m, 3H), 4.51 (s, 2H), 4.39 (s, 2H), 3.47 - 3.43 (m, 4H), 3.07 (s, 3H), 2.91 (s, 3H), 2.44 - 2.37 (m, 1H), 1.91 - 1.83 (m, 2H), 1.20 - 1.12 (m, 4H).

[0293] Example 28

[0294]

[0295] Synthesis of Compound 28 - B

[0296] Step 1: Compound 28 - A

[0297] Compound 28 - A was prepared by referring to Example 2 and replacing methyl iodide with N,N - diethyl - bromoacetamide. m / z: [M + 1] + 679;

[0298] 1 1H NMR (400 MHz, DMSO-d6): δ 8.25 (d, J = 1.6 Hz, 1H), 7.68 - 7.60 (m, 3H), 7.56 - 7.49 (m, 2H), 4.43 (s, 2H), 4.32 (s, 2H), 3.85 (s, 1H), 3.42 - 3.35 (m, 4H), 3.33 - 3.23 (m, 4H), 2.37 - 2.31 (m, 1H), 1.84 - 1.78 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H), 1.13 - 1.06 (m, 4H), 1.02 (t, J = 7.2 Hz, 3H).

[0299] Step 2: Compound 28 - B

[0300] Compound 28 - B was prepared by referring to Example 1 and replacing Compound 1 - A with Compound 28 - A. m / z: [M + 1] + 665;

[0301] 11H NMR (400 MHz, DMSO-d6): δ 8.07 (s, 1H), 7.68 - 7.62 (m, 2H), 7.57 - 7.50 (m, 3H), 4.40 (s, 2H), 4.32 (s, 2H), 3.41 - 3.38 (m, 4H), 3.29 - 3.26 (m, 4H), 2.37 - 2.32 (m, 1H), 1.85 - 1.77 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H), 1.14 - 1.06 (m, 4H), 1.02 (t, J = 7.2 Hz, 3H).

[0302] Example 29

[0303]

[0304] Preparation of Compound 29-B

[0305] Step 1: Compound 29-1

[0306] Dissolve compound 7-2 (107 mg, 1 eq.) in acetonitrile (2 mL). After adding 2-bromo-N-cyclohexylacetamide (66 mg, 1 eq.) and stirring until dissolved, add potassium carbonate (83 mg, 2 eq.). React at room temperature for 2 hours. Remove the solvent under reduced pressure and purify by silica gel column chromatography to obtain 15 mg of a colorless oil, with a yield of 10%. m / z: [M + 1] + 496;

[0307] Step 2: Compound 29-A

[0308] Dissolve compound 29-1 (15 mg, 1 eq.) in acetonitrile (1 mL). After adding compound B (13 mg, 1.5 eq.) and stirring until dissolved, add diisopropylethylamine (8 mg, 2 eq.). React by microwave heating at 80 °C for 4 hours. After the reaction, concentrate under reduced pressure to obtain a crude product, and purify by silica gel column chromatography to obtain 13 mg of a colorless oil, with a purity of 91% and a yield of 63%. m / z: [M + 1] + 704;

[0309] 11H NMR (600 MHz, CDCl3): δ 8.01 (d, J = 1.2 Hz, 1H), 7.66 (dd, J = 11.1, 1.2 Hz, 1H), 7.49 (dd, J = 7.9, 1.6 Hz, 1H), 7.42 (dd, J = 11.8, 4.0 Hz, 1H), 7.32 - 7.29 (m, 2H), 4.27 (s, 2H), 4.06 (s, 2H), 3.86 (s, 3H), 3.70 - 3.65 (m, 1H), 3.44 (t, J = 7.2 Hz, 2H), 3.34 (t, J = 5.6 Hz, 2H), 2.04 (td, J = 8.4, 4.2 Hz, 1H), 1.86 - 1.82 (m, 2H), 1.74 (dd, J = 12.4, 3.6 Hz, 2H), 1.29 - 1.21 (m, 4H), 1.17 - 1.15 (m, 2H), 1.09 - 1.00 (m, 6H).

[0310] Step 3: Compound 29-B

[0311] Compound 29-B was prepared by using Compound 29-A instead of Compound 1-A according to Reference Example 1. m / z: [M+1] + 691;

[0312] 1 1H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 1.4 Hz, 1H), 7.79 (dd, J = 11.0, 1.4 Hz, 1H), 7.59 (dd, J = 7.8, 1.7 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.42 - 7.38 (m, 2H), 4.37 (s, 2H), 4.18 (s, 2H), 3.81 - 3.75 (m, 1H), 3.54 (t, J = 7.2 Hz, 2H), 3.44 (t, J = 5.6 Hz, 2H), 2.16 - 2.11 (m, 1H), 1.97 - 1.91 (m, 2H), 1.85 (dd, J = 12.4, 3.7 Hz, 2H), 1.67 - 1.61 (m, 2H), 1.27 - 1.22 (m, 4H), 1.19 - 1.09 (m, 6H).

[0313] Example 30

[0314]

[0315] Preparation of Compound 30-B

[0316] Step 1: Compound 30-A

[0317] Compound 30-A was prepared using 2-bromo-N-phenylacetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide with reference to Example 4. m / z: [M+1] + 699;

[0318] 1 H NMR (400 MHz, CDCl3): 9.59 (s, 1H), 8.12 (s, 1H), 7.80 (d, J = 10.3 Hz, 1H), 7.60 - 7.54 (m, 1H), 7.55 - 7.45 (m, 3H), 7.41 - 7.35 (m, 2H), 7.34 - 7.28 (m, 2H), 7.11 (t, J = 7.5 Hz, 1H), 4.37 (s, 2H), 4.34 (s, 2H), 3.97 (s, 3H), 3.53 (t, J = 7.1 Hz, 2H), 3.44 (t, J = 5.4 Hz, 2H), 2.12 - 2.08 (m, 1H), 2.00 - 1.94 (m, 2H), 1.23 - 1.21 (m, 2H), 1.11 - 1.09 (m, 2H).

[0319] Step 2: Compound 30-B

[0320] The target compound 30-B was prepared using Compound 30-A instead of Compound 1-A with reference to Example 1. m / z: [M+1] + 685;

[0321] 1 H NMR (400 MHz, CDCl3): δ 9.53 (s, 1H), 8.15 (s, 1H), 7.83 (d, J = 11.2 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.48 (dd, J = 12.3, 7.5 Hz, 3H), 7.37 (d, J = 7.7 Hz, 2H), 7.31 (dd, J = 15.5, 7.8 Hz, 2H), 7.09 (t, J = 7.5 Hz, 1H), 4.35 (s, 2H), 4.34 (s, 2H), 3.53 (t, J = 7.2 Hz, 2H), 3.42 (t, J = 5.5 Hz, 2H), 2.11 - 2.06 (m, 1H), 1.99 - 1.92 (m, 2H), 1.24 - 1.21 (m, 2H), 1.11 - 1.05 (m, 2H).

[0322] Example 31

[0323]

[0324] Synthesis of Compound 31

[0325] Step 1: Compound 31-A

[0326] Compound 31-A was prepared by replacing 2-bromo-N-(pyrrolidin-1-yl)acetamide with 2-bromo-N-methyl-N-acetylaniline according to Example 4. m / z: [M+1] + 713;

[0327] Step 2: Compound 31

[0328] Compound 31 was prepared by replacing Compound 11-A with Compound 31-A according to Example 11. m / z: [M+1] + 698;

[0329] 1 H NMR (400 MHz, DMSO-d6): δ 12.97 (s, 1H), 8.20 (d, J = 1.5 Hz, 1H), 7.68 - 7.44 (m, 10H), 4.28 (s, 2H), 4.06 (s, 2H), 3.44 (s, 2H), 3.34 (s, 2H), 3.19 (s, 3H), 2.33 - 2.27 (m, 1H), 1.80 - 1.72 (m, 2H), 1.14 - 1.01 (m, 4H).

[0330] Example 32

[0331]

[0332] Synthesis of Compound 32

[0333] Step 1: Compound 32-A

[0334] Compound 32-A was prepared by replacing 2-bromo-N-(pyrrolidin-1-yl)acetamide with 2-bromo-N-ethyl-N-acetylaniline according to Example 4. m / z: [M+1] + 727;

[0335] Step 2: Compound 32

[0336] Compound 32 was prepared by replacing Compound 11-A with Compound 32-A according to Example 11. m / z: [M+1] + 713;

[0337] 11H NMR (400 MHz, DMSO-d6): δ 8.25 (d, J = 1.5 Hz, 1H), 7.70 - 7.63 (m, 3H), 7.62 - 7.54 (m, 4H), 7.54 - 7.46 (m, 3H), 4.34 (s, 2H), 4.04 (s, 2H), 3.72 (q, J = 8.0 Hz, 2H), 3.48 (s, 2H), 3.40 (s, 2H), 2.39 - 2.33 (m, 1H), 1.84 - 1.76 (m, 2H), 1.16 - 1.11 (m, 4H), 1.10 - 1.04 (m, 3H).

[0338] Example 33

[0339]

[0340] Synthesis of Compound 33

[0341] Step 1: Compound 33-A

[0342] Compound 33-A was prepared by referring to Example 4 and using N-benzyl-2-bromoacetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 713;

[0343] Step 2: Compound 33

[0344] Compound 33 was prepared by referring to Example 11 and using Compound 33-A instead of Compound 11-A. m / z: [M+1] + 699;

[0345] 1 1H NMR (400 MHz, DMSO-d6): δ 13.00 (s, 1H), 8.63 (t, J = 6.4 Hz, 1H), 8.23 (d, J = 1.5 Hz, 1H), 7.66 - 7.61 (m, 3H), 7.56 - 7.51 (m, 2H), 7.30 - 7.27 (m, 4H), 7.25 - 7.21 (m, 1H), 4.34 - 4.31 (m, 4H), 4.25 (s, 2H), 3.49 (s, 2H), 3.41 - 3.39 (m, 2H), 2.36 - 2.31 (m, 1H), 1.86 - 1.80 (m, 2H), 1.12 - 1.07 (m, 4H).

[0346] Example 34

[0347]

[0348] Synthesis of Compound 34

[0349] Step 1: Compound 34-A

[0350] Compound 34-A was prepared by replacing 2-bromo-N-(pyrrolidin-1-yl)acetamide with N-(1-naphthyl)-2-bromo-acetamide according to Example 4. m / z: [M+1] + 749;

[0351] Step 2: Compound 34

[0352] Compound 34 was prepared by replacing Compound 11-A with Compound 34-A according to Example 11. m / z: [M+1] + 735;

[0353] 1 H NMR(400MHz, DMSO-d6): δ 12.91(s, 1H), 10.20(s, 1H), 8.25(d, J = 1.5Hz, 1H), 8.18(d, J = 8.0Hz, 1H), 7.94(d, J = 8.0Hz, 1H), 7.79(d, J = 8.2Hz, 1H), 7.67 - 7.59(m, 4H), 7.57 - 7.47(m, 5H), 4.57(s, 2H), 4.34(s, 2H), 3.56(s, 2H), 3.44(t, J = 5.9Hz, 2H), 2.37 - 2.29(m, 1H), 1.94 - 1.83(m, 2H), 1.12 - 1.04(m, 4H).

[0354] Example 35

[0355]

[0356] Synthesis of Compound 35

[0357] Step 1: Compound 35-A

[0358] Compound 35-A was prepared by replacing 2-bromo-N-(pyrrolidin-1-yl)acetamide with 2-bromo-N-(3-methoxyphenyl)acetamide according to Example 4. m / z: [M+1] + 729;

[0359] Step 2: Compound 35

[0360] Compound 35 was prepared by replacing Compound 11-A with Compound 35-A according to Example 11. m / z: [M+1] + 715;

[0361] 11H NMR (400 MHz, DMSO-d6): δ 13.00 (s, 1H), 10.22 (s, 1H), 8.23 (s, 1H), 7.67 - 7.56 (m, 3H), 7.52 (q, J = 7.3 Hz, 2H), 7.31 (s, 1H), 7.22 (t, J = 8.2 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 4.40 (s, 2H), 4.33 (s, 2H), 3.72 (s, 3H), 3.51 (s, 2H), 3.41 (s, 2H), 2.35 - 2.31 (m, 1H), 1.87 - 1.83 (m, 2H), 1.13 - 1.06 (m, 4H).

[0362] Example 36

[0363]

[0364] Step 1: Compound 36-A

[0365] Compound 36-A was prepared by referring to Example 4 and using 2-bromo-N-(4-methoxyphenyl)acetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 729;

[0366] Step 2: Compound 36

[0367] Compound 36 was prepared by referring to Example 11 and using Compound 36-A instead of Compound 11-A. m / z: [M+1] + 715;

[0368] 1 1H NMR (400 MHz, DMSO-d6): δ 13.00 (s, 1H), 10.08 (s, 1H), 8.23 (s, 1H), 7.67 - 7.46 (m, 7H), 6.89 (d, J = 8.6 Hz, 2H), 4.37 (s, 2H), 4.33 (s, 2H), 3.72 (s, 2H), 3.51 (m, 2H), 3.42 (m, 3H), 2.33 (s, 1H), 1.95 - 1.78 (m, 2H), 1.13 - 1.06 (m, 4H).

[0369] Example 37

[0370]

[0371] Synthesis of Compound 37

[0372] Step 1: Compound 37-A

[0373] Compound 37-A was prepared by replacing 2-bromo-N-(pyrrolidin-1-yl)acetamide with 2-bromo-N-(3-chlorophenyl)acetamide according to Example 4. m / z: [M+1] + 733;

[0374] Step 2: Compound 37

[0375] Compound 37 was prepared by replacing Compound 11-A with Compound 37-A according to Example 11. m / z: [M+1] + 719;

[0376] 1 H NMR (400 MHz, DMSO-d6): δ 13.04 (s, 1H), 10.47 (s, 1H), 8.22 (s, 1H), 7.81 (s, 1H), 7.70 - 7.62 (m, 2H), 7.59 - 7.49 (m, 3H), 7.47 - 7.43 (d, J = 8.2 Hz, 1H), 7.38 - 7.33 (t, J = 8.1 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 4.43 (s, 2H), 4.33 (s, 2H), 3.51 (s, 2H), 3.41 (t, J = 5.9 Hz, 2H), 2.37 - 2.30 (m, 1H), 1.88 - 1.81 (m, 2H), 1.12 - 1.07 (m, 4H).

[0377] Example 38

[0378]

[0379] Synthesis of Compound 38

[0380] Step 1: Compound 38-A

[0381] Compound 38-A was prepared by replacing 2-bromo-N-(pyrrolidin-1-yl)acetamide with 2-bromo-N-(4-chlorophenyl)acetamide according to Example 4. m / z: [M+1] + 733;

[0382] Step 2: Compound 38

[0383] Compound 38 was prepared by replacing Compound 11-A with Compound 38-A according to Example 11. m / z: [M+1] + 719;

[0384] 11H NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 8.21 (d, J = 1.5 Hz, 1H), 7.66 - 7.61 (m, 4H), 7.58 - 7.48 (m, 3H), 7.38 (d, J = 8.9 Hz, 2H), 4.42 (s, 2H), 4.33 (s, 2H), 3.51 (s, 2H), 3.41 (t, J = 6.0 Hz, 2H), 2.36 - 2.30 (m, 1H), 1.89 - 1.81 (m, 2H), 1.12 - 1.06 (m, 4H).

[0385] Example 39

[0386]

[0387] Step 1: Compound 39-A

[0388] Compound 39-A was prepared by referring to Example 4 and using 2-bromo-N-(3-methylphenyl)acetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 733;

[0389] Step 2: Compound 39

[0390] Compound 39 was prepared by referring to Example 11 and using Compound 39-A instead of Compound 11-A. m / z: [M+1] + 719;

[0391] 1 1H NMR (400 MHz, DMSO-d6): δ 12.90 (s, 1H), 10.15 (s, 1H), 8.26 (s, 1H), 7.67 - 7.57 (m, 3H), 7.55 - 7.48 (m, 2H), 7.45 (s, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 6.88 (d, J = 7.3 Hz, 1H), 4.45 (s, 2H), 4.33 (s, 2H), 3.52 (s, 2H), 3.41 (t, J = 6.0 Hz, 2H), 2.36 - 2.31 (m, 1H), 2.27 (s, 3H), 1.90 - 1.81 (m, 2H), 1.13 - 1.05 (m, 4H).

[0392] Example 40

[0393]

[0394] Synthesis of Compound 40

[0395] Step 1: Compound 40-A

[0396] Compound 40-A was prepared by replacing 2-bromo-N-(pyrrolidin-1-yl)acetamide with 2-bromo-N-(4-methylphenyl)acetamide according to Example 4. m / z: [M+1] + 713;

[0397] Step 2: Compound 40

[0398] Compound 40 was prepared by replacing Compound 11-A with Compound 40-A according to Example 11. m / z: [M+1] + 699;

[0399] 1 H NMR (400 MHz, DMSO-d6): δ 12.98 (s, 1H), 10.13 (s, 1H), 8.23 (d, J = 1.6 Hz, 1H), 7.66 - 7.57 (m, 3H), 7.56 - 7.50 (m, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 4.42 (s, 2H), 4.33 (s, 2H), 3.52 (s, 2H), 3.41 (t, J = 5.9 Hz, 2H), 2.36 - 2.30 (m, 1H), 2.25 (s, 3H), 1.90 - 1.81 (m, 2H), 1.12 - 1.04 (m, 4H).

[0400] Example 41

[0401]

[0402] Synthesis of Compound 41

[0403] Step 1: Compound 41-A

[0404] Compound 41-A was prepared by replacing 2-bromo-N-(pyrrolidin-1-yl)acetamide with 2-bromo-N-(2-methylphenyl)acetamide according to Example 4. m / z: [M+1] + 713;

[0405] Step 2: Compound 41

[0406] Compound 41 was prepared by replacing Compound 11-A with Compound 41-A according to Example 11. m / z: [M+1] + 699;

[0407] 11H NMR (400 MHz, DMSO-d6): δ 13.06 (s, 1H), 9.59 (s, 1H), 8.23 (d, J = 1.6 Hz, 1H), 7.67 - 7.60 (m, 3H), 7.56 - 7.50 (m, 2H), 7.37 (d, J = 6.4 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.11 - 7.07 (m, 1H), 4.43 (s, 2H), 4.33 (s, 2H), 3.53 (s, 2H), 3.42 (t, J = 5.9 Hz, 2H), 2.36 - 2.31 (m, 1H), 2.21 (s, 3H), 1.89 - 1.82 (m, 2H), 1.12 - 1.07 (m, 4H).

[0408] Example 42

[0409]

[0410] Synthesis of Compound 42

[0411] Step 1: Compound 42-A

[0412] Compound 42-A was prepared by referring to Example 4 and using 2-bromo-N-(2-chlorophenyl)acetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 733;

[0413] Step 2: Compound 42

[0414] Compound 42 was prepared by referring to Example 11 and using Compound 42-A instead of Compound 11-A. m / z: [M+1] + 719;

[0415] 1 1H NMR (600 MHz, CDCl3): δ 9.16 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 8.15 (d, J = 1.5 Hz, 1H), 7.79 (dd, J = 10.8, 1.5 Hz, 1H), 7.56 (dd, J = 7.5, 1.8 Hz, 1H), 7.48 - 7.44 (m, 1H), 7.39 - 7.29 (m, 4H), 7.04 (td, J = 7.7, 1.5 Hz, 1H), 4.45 (s, 2H), 4.36 (s, 2H), 3.52 (t, J = 7.4 Hz, 2H), 3.41 (t, J = 5.6 Hz, 2H), 2.11 - 2.08 (m, 1H), 1.96 - 1.92 (m, 2H), 1.23 - 1.21 (m, 2H), 1.11 - 1.07 (m, 2H).

[0416] Example 43

[0417]

[0418] Synthesis of Compound 43

[0419] Step 1: Compound 43-A

[0420] Compound 43-A was prepared with reference to Example 4 by using 2-bromo-N-(2-methoxyphenyl)acetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 729;

[0421] Step 2: Compound 43

[0422] Compound 43 was prepared with reference to Example 11 by using Compound 43-A instead of Compound 11-A. m / z: [M+1] + 715;

[0423] 1 H NMR (600 MHz, DMSO-d6): δ 13.00 (s, 1H), 9.47 (s, 1H), 8.23 (d, J = 1.5 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.66 - 7.58 (m, 3H), 7.55 - 7.48 (m, 2H), 7.11 - 7.03 (m, 2H), 6.90 (t, J = 7.5 Hz, 1H), 4.49 (s, 2H), 4.32 (s, 2H), 3.82 (s, 3H), 3.50 (brs, 2H), 3.40 (t, J = 6.0 Hz, 2H), 2.36 - 2.30 (m, 1H), 1.87 - 1.81 (m, 2H), 1.13 - 1.04 (m, 4H).

[0424] Example 44

[0425]

[0426] Synthesis of Compound 57-B

[0427] Step 1: Compound 57-A

[0428] Compound 57-A was prepared with reference to Example 4 by using 2-bromo-N-propyl-N-acetylaniline instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 741;

[0429] 11H NMR (400 MHz, DMSO-d6): δ 8.25 (d, J = 1.5 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.56 - 7.44 (m, 7H), 4.28 (s, 2H), 4.00 (s, 2H), 3.86 (s, 3H), 3.60 (t, J = 7.2 Hz, 2H), 3.43 (s, 2H), 3.33 (s, 2H), 2.31 (td, J = 8.0, 3.9 Hz, 1H), 1.76 (d, J = 7.0 Hz, 2H), 1.42 (q, J = 7.2 Hz, 2H), 1.07 (ddt, J = 10.8, 5.1, 2.7 Hz, 4H), 0.82 (t, J = 7.3 Hz, 3H).

[0430] Step 2: Compound 57-B

[0431] Compound 57-B was prepared by using compound 57-A instead of compound 11-A with reference to Example 11. m / z: [M + 1] + 727;

[0432] 1 1H NMR (400 MHz, DMSO-d6): δ 8.20 (d, J = 1.4 Hz, 1H), 7.64 - 7.59 (m, 3H), 7.56 - 7.42 (m, 7H), 4.28 (s, 2H), 4.07 - 3.94 (m, 2H), 3.60 (t, J = 7.2 Hz, 2H), 3.52 - 3.32 (m, 4H), 2.35 - 2.27 (m, 1H), 1.80 - 1.72 (m, 2H), 1.42 (q, J = 7.4 Hz, 2H), 1.11 - 1.04 (m, 4H), 0.82 (t, J = 7.4 Hz, 3H).

[0433] Example 45

[0434]

[0435] Synthesis of Compound 58-B

[0436] Step 1: Compound 58-A

[0437] Compound 58-A was prepared by using 2-bromo-N-isopropyl-N-acetylaniline instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide with reference to Example 4. m / z: [M + 1] + 741;

[0438] 11H NMR (400 MHz, DMSO-d6): δ 8.25 (d, J = 1.5 Hz, 1H), 7.67 - 7.59 (m, 3H), 7.57 - 7.46 (m, 5H), 7.39 (d, J = 7.4 Hz, 2H), 4.84 - 4.74 (m, 1H), 4.27 (s, 2H), 3.86 (s, 3H), 3.84 (s, 2H), 3.52 - 3.33 (m, 4H), 2.33 - 2.26 (m, 1H), 1.80 - 1.65 (m, 2H), 1.09 (d, J = 8.7 Hz, 4H), 1.00 (d, J = 6.8 Hz, 6H).

[0439] Step 2: Compound 58-B

[0440] Compound 58-B was prepared by using Compound 58-A instead of Compound 11-A according to Reference Example 11. m / z: [M+1] + 727;

[0441] 1 1H NMR (600 MHz, DMSO-d6): δ 12.96 (s, 1H), 8.20 (s, 1H), 7.64 - 7.58 (m, 3H), 7.53 (t, J = 7.5 Hz, 3H), 7.49 (t, J = 7.2 Hz, 2H), 7.40 (d, J = 7.5 Hz, 2H), 4.83 - 4.76 (m, 1H), 4.27 (s, 2H), 3.84 (s, 2H), 3.50 - 3.36 (m, 2H), 3.32 (d, J = 6.0 Hz, 2H), 2.33 - 2.26 (m, 1H), 1.73 (t, J = 6.8 Hz, 2H), 1.11 - 1.07 (m, 2H), 1.07 - 1.04 (m, 2H), 1.00 (d, J = 6.8 Hz, 6H).

[0442] Example 46

[0443]

[0444] Synthesis of Compound 59-B

[0445] Step 1: Compound 59-A

[0446] Compound 59-A was prepared by using 2-bromo-N-(methoxyethyl)-N-acetylaniline instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide according to Reference Example 4. m / z: [M+1] + 757;

[0447] Step 2: Compound 59-B

[0448] Compound 59-B was prepared by using compound 59-A to replace compound 11-A with reference to Example 11. m / z: [M+1] + 743;

[0449] Example 47

[0450]

[0451] Synthesis of Compound 60-B

[0452] Step 1: Compound 60-A

[0453] Compound 60-A was prepared by using N-benzyl-2-bromo-N-ethylacetamide to replace 2-bromo-N-(pyrrolidin-1-yl)acetamide with reference to Example 4. m / z: [M+1] + 741;

[0454] 1 H NMR (400 MHz, DMSO-d6): δ8.27 (t, J = 1.9 Hz, 1H), 7.68 - 7.62 (m, 3H), 7.57 - 7.48 (m, 2H), 7.44 - 7.26 (m, 5H), 4.61 - 4.53 (m, 4H), 4.32 (d, J = 12.4 Hz, 2H), 3.86 (s, 3H), 3.55 - 3.37 (m, 4H), 3.29 - 3.15 (m, 2H), 2.37 - 2.30 (m, 1H), 1.90 - 1.77 (m, 2H), 1.12 - 0.94 (m, 7H).

[0455] Step 2: Compound 60-B

[0456] Compound 60-B was prepared by using compound 60-A to replace compound 11-A with reference to Example 11. m / z: [M+1] + 727;

[0457] 1 H NMR (400 MHz, DMSO-d6): δ12.95 (s, 1H), 8.22 (d, J = 1.8 Hz, 1H), 7.67 - 7.60 (m, 3H), 7.57 - 7.49 (m, 2H), 7.43 - 7.39 (m, 1H), 7.32 - 7.29 (m, 1H), 7.28 - 7.23 (m, 3H), 4.63 - 4.53 (m, 4H), 4.32 (d, J = 12.3 Hz, 2H), 3.50 - 3.36 (m, 4H), 3.30 - 3.14 (m, 2H), 2.37 - 2.30 (m, 1H), 1.87 - 1.77 (m, 2H), 1.12 - 0.97 (m, 7H).

[0458] Example 48

[0459]

[0460] Synthesis of Compound 61-B

[0461] Step 1: Compound 61-A

[0462] Compound 61-A was prepared with reference to Example 4 by using 2-bromo-N-(1-phenylethyl)acetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 727;

[0463] 1 H NMR (400 MHz, DMSO-d6): δ 8.59 (d, J = 7.9 Hz, 1H), 8.26 (d, J = 1.5 Hz, 1H), 7.68 - 7.61 (m, 3H), 7.55 - 7.48 (m, 2H), 7.34 (d, J = 7.2 Hz, 2H), 7.28 (t, J = 7.5 Hz, 2H), 7.20 (t, J = 7.2 Hz, 1H), 4.93 (t, J = 7.3 Hz, 1H), 4.31 (s, 2H), 4.29 - 4.15 (m, 2H), 3.86 (s, 3H), 3.46 (s, 2H), 3.38 (t, J = 5.9 Hz, 2H), 2.36 - 2.29 (m, 1H), 1.85 - 1.77 (m, 2H), 1.38 (d, J = 7.0 Hz, 3H), 1.12 - 1.06 (m, 4H).

[0464] Step 2: Compound 61-B

[0465] Compound 61-B was prepared with reference to Example 11 by using Compound 61-B instead of Compound 11-A. m / z: [M+1] + 713;

[0466] 11H NMR (400 MHz, DMSO-d6): δ 12.92 (s, 1H), 8.59 (d, J = 7.9 Hz, 1H), 8.21 (d, J = 1.5 Hz, 1H), 7.65 - 7.60 (m, 3H), 7.54 - 7.48 (m, 2H), 7.35 (d, J = 7.1 Hz, 2H), 7.29 (t, J = 7.4 Hz, 2H), 7.23 - 7.18 (m, 1H), 4.93 (t, J = 7.3 Hz, 1H), 4.31 (s, 2H), 4.27 - 4.13 (m, 2H), 3.46 (s, 2H), 3.39 (d, J = 5.9 Hz, 2H), 2.36 - 2.29 (m, 1H), 1.85 - 1.78 (m, 2H), 1.38 (d, J = 7.0 Hz, 3H), 1.12 - 1.06 (m, 4H).

[0467] Example 49

[0468]

[0469] Synthesis of Compound 62-B

[0470] Step 1: Compound 62-A

[0471] Compound 62-A was prepared with reference to Example 4 using 2-bromo-N-(1-phenylpropyl)acetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 741;

[0472] 1 1H NMR (400 MHz, DMSO-d6): δ 8.52 (d, J = 8.3 Hz, 1H), 8.25 (d, J = 1.6 Hz, 1H), 7.70 - 7.58 (m, 3H), 7.54 - 7.47 (m, 2H), 7.34 - 7.26 (m, 4H), 7.20 (t, J = 6.9 Hz, 1H), 4.76 - 4.65 (m, 1H), 4.30 (s, 2H), 4.24 (s, 2H), 3.86 (s, 3H), 3.46 (s, 2H), 3.37 (t, J = 5.9 Hz, 2H), 2.36 - 2.26 (m, 1H), 1.86 - 1.76 (m, 2H), 1.75 - 1.66 (m, 2H), 1.13 - 1.05 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H).

[0473] Step 2: Compound 62-B (BE048-133-P1)

[0474] Compound 62-B was prepared by replacing compound 11-A with compound 62-A according to Example 11. m / z: [M+1] + 727;

[0475] 1 H NMR (400 MHz, DMSO-d6): δ 12.83 (s, 1H), 8.52 (d, J = 8.4 Hz, 1H), 8.21 (d, J = 1.5 Hz, 1H), 7.65 - 7.59 (m, 3H), 7.54 - 7.47 (m, 2H), 7.34 - 7.27 (m, 4H), 7.23 - 7.18 (m, 1H), 4.74 - 4.68 (m, 1H), 4.30 (s, 2H), 4.23 (s, 2H), 3.46 (s, 2H), 3.37 (t, J = 5.8 Hz, 2H), 2.35 - 2.29 (m, 1H), 1.84 - 1.77 (m, 2H), 1.74 - 1.66 (m, 2H), 1.11 - 1.05 (m, 4H), 0.87 (t, J = 7.3 Hz, 3H).

[0476] Example 50

[0477]

[0478] Synthesis of Compound 64-B

[0479] Step 1: Compound 64-A (BE048-124-P1)

[0480] Compound 64-A was prepared by replacing 2-bromo-N-(pyrrolidin-1-yl)acetamide with N-benzyl-2-bromo-N-methylacetamide according to Example 4. m / z: [M+1] + 727;

[0481] Compound 64-A showed as a mixture of isomers on NMR, and the ratio of a:b was about 2:1;

[0482] Isomer a 1 H NMR (400 MHz, DMSO-d6): δ 8.26 (d, J = 1.5 Hz, 1H), 7.68 - 7.61 (m, 3H), 7.57 - 7.49 (m, 2H), 7.43 - 7.23 (m, 5H), 4.63 - 4.50 (m, 4H), 4.33 (s, 2H), 3.86 (s, 3H), 3.52 - 3.35 (m, 4H), 2.98 (s, 3H), 2.38 - 2.29 (m, 1H), 1.88 - 1.74 (m, 2H), 1.13 - 1.05 (m, 4H).

[0483] Isomer b 11H NMR (400 MHz, DMSO-d6): δ 8.26 (d, J = 1.5 Hz, 1H), 7.68 - 7.61 (m, 3H), 7.57 - 7.49 (m, 2H), 7.43 - 7.23 (m, 5H), 4.63 - 4.50 (m, 4H), 4.31 (s, 2H), 3.86 (s, 3H), 3.52 - 3.35 (m, 4H), 2.80 (s, 3H), 2.38 - 2.29 (m, 1H), 1.88 - 1.74 (m, 2H), 1.13 - 1.05 (m, 4H).

[0484] Step 2: Compound 64-B

[0485] Compound 64-B was prepared by using Compound 64-A instead of Compound 11-A with reference to Example 11. m / z: [M+1] + 713;

[0486] Compound 64-B showed as a mixture of isomers in NMR, and the ratio of a:b was about 2:1;

[0487] Isomer a 1 1H NMR (400 MHz, DMSO-d6): δ 12.93 (s, 1H), 8.22 (d, J = 1.5 Hz, 1H), 7.66 - 7.60 (m, 3H), 7.56 - 7.49 (m, 2H), 7.42 (d, J = 4.3 Hz, 1H), 7.32 (dd, J = 9.1, 5.7 Hz, 2H), 7.28 - 7.22 (m, 2H), 4.62 - 4.52 (m, 4H), 4.33 (s, 2H), 3.50 - 3.37 (m, 4H), 2.98 (s, 3H), 2.37 - 2.30 (m, 1H), 1.87 - 1.78 (m, 2H), 1.12 - 1.06 (m, 4H).

[0488] Isomer b 1 1H NMR (400 MHz, DMSO-d6): δ 12.93 (s, 1H), 8.22 (d, J = 1.5 Hz, 1H), 7.66 - 7.60 (m, 3H), 7.56 - 7.49 (m, 2H), 7.42 (d, J = 4.3 Hz, 1H), 7.32 (dd, J = 9.1, 5.7 Hz, 2H), 7.28 - 7.22 (m, 2H), 4.62 - 4.52 (m, 4H), 4.31 (s, 2H), 3.50 - 3.37 (m, 4H), 2.80 (s, 3H), 2.37 - 2.30 (m, 1H), 1.87 - 1.78 (m, 2H), 1.12 - 1.06 (m, 4H). Example 51

[0489]

[0490] Synthesis of Compound 44-B

[0491] Step 1: Compound 44-A

[0492] Dissolve Compound 23 (70 mg, 1.0 eq.) in dichloromethane (2.5 mL). Under nitrogen protection and in an ice bath at 0 °C, add 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (51 mg, 1.4 eq.) and diisopropylethylamine (30 μL, 1.5 eq.). After stirring the reaction for 30 minutes, add 2-aminopyridine (13 mg, 1.2 eq.), and transfer the reaction to room temperature for 16 hours. Adjust the system to weakly acidic with 0.1 mol / L dilute hydrochloric acid, dilute with water, and extract the aqueous phase with ethyl acetate 3 times. Combine the organic phases, wash the product with saturated sodium chloride aqueous solution, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. Purify by silica gel column chromatography to obtain 34 mg of white solid, with a purity of 95.0% and a yield of 43%. m / z: [M+1] + 700;

[0493] 1 1H NMR (400 MHz, DMSO-d6): δ 10.79 (s, 1H), 8.35 (dd, J = 5.3, 1.9 Hz, 1H), 8.27 (d, J = 1.5 Hz, 1H), 8.07 - 7.93 (m, 1H), 7.83 - 7.73 (m, 1H), 7.67 - 7.59 (m, 3H), 7.55 - 7.48 (m, 2H), 7.12 (dd, J = 7.5, 5.0 Hz, 1H), 4.50 (s, 2H), 4.33 (s, 2H), 3.85 (s, 3H), 3.50 (s, 2H), 3.40 (t, J = 5.9 Hz, 2H), 2.37 - 2.30 (m, 1H), 1.88 - 1.80 (m, 2H), 1.12 - 1.04 (m, 4H).

[0494] Step 2: Compound 44-B

[0495] Refer to Example 11, and use Compound 44-A instead of Compound 11-A to prepare Compound 44-B. m / z: [M+1] + 686;

[0496] 11H NMR (400 MHz, DMSO-d6): δ 12.99 (s, 1H), 10.78 (s, 1H), 8.35 (dd, J = 5.0, 1.8 Hz, 1H), 8.22 (d, J = 1.7 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.81 - 7.75 (m, 1H), 7.65 - 7.60 (m, 3H), 7.54 - 7.50 (m, 2H), 7.17 - 7.08 (m, 1H), 4.50 (s, 2H), 4.33 (s, 2H), 3.50 (s, 2H), 3.41 - 3.39 (m, 2H), 2.35 - 2.31 (m, 1H), 1.86 - 1.81 (m, 2H), 1.12 - 1.08 (m, 4H).

[0497] Example 52

[0498]

[0499] Synthesis of Compound 45-B

[0500] Step 1: Compound 45-A

[0501] Compound 45-A was prepared by referring to Example 44 and using 3-aminopyridine instead of 2-aminopyridine. m / z: [M + 1] + 700;

[0502] 1 1H NMR (400 MHz, DMSO-d6): δ 10.47 (s, 1H), 8.74 (d, J = 2.5 Hz, 1H), 8.28 (dd, J = 4.5, 1.5 Hz, 2H), 8.07 - 7.97 (m, 1H), 7.68 - 7.58 (m, 3H), 7.55 - 7.45 (m, 2H), 7.36 (dd, J = 8.3, 4.7 Hz, 1H), 4.46 (s, 2H), 4.33 (s, 2H), 3.85 (s, 3H), 3.52 (s, 2H), 3.42 (t, J = 5.9 Hz, 2H), 2.37 - 2.30 (m, 1H), 1.91 - 1.81 (m, 2H), 1.14 - 1.04 (m, 4H).

[0503] Step 2: Compound 45-B

[0504] Compound 45-B was prepared by referring to Example 11 and using Compound 45-A instead of Compound 11-A. m / z: [M + 1] + 686;

[0505] 11H NMR (400 MHz, CDCl3): δ 10.37 (s, 1H), 8.60 (s, 1H), 8.32 (dd, J = 18.2, 6.5 Hz, 2H), 8.10 (s, 1H), 7.80 (d, J = 11.0 Hz, 1H), 7.58 - 7.53 (m, 1H), 7.50 - 7.45 (m, 1H), 7.39 - 7.32 (m, 3H), 4.35 (s, 4H), 3.53 - 3.48 (m, 2H), 3.41 (t, J = 5.6 Hz, 2H), 2.12 - 2.06 (m, 1H), 1.97 - 1.89 (m, 2H), 1.23 - 1.18 (m, 2H), 1.11 - 1.05 (m, 2H).

[0506] Example 53

[0507]

[0508] Synthesis of Compound 46 - B

[0509] Step 1: Compound 46 - A

[0510] Compound 46 - A was prepared by using 4 - aminopyridine instead of 2 - aminopyridine with reference to Example 44. m / z: [M + 1] + 700;

[0511] 1 1H NMR (400 MHz, DMSO - d6): δ 10.63 (s, 1H), 8.44 (d, J = 5.4 Hz, 2H), 8.28 (d, J = 1.6 Hz, 1H), 7.68 - 7.58 (m, 3H), 7.59 - 7.47 (m, 4H), 4.46 (s, 2H), 4.33 (s, 2H), 3.85 (s, 3H), 3.50 (s, 2H), 3.41 (t, J = 5.9 Hz, 2H), 2.37 - 2.29 (m, 1H), 1.89 - 1.81 (m, 2H), 1.13 - 1.04 (m, 4H).

[0512] Step 2: Compound 46 - B

[0513] Compound 46 - B was prepared by using Compound 46 - A instead of Compound 11 - A with reference to Example 11. m / z: [M + 1] + 686;

[0514] 11H NMR (400 MHz, DMSO-d6): δ 12.97 (s, 1H), 10.68 (s, 1H), 8.48 - 8.41 (m, 2H), 8.23 (d, J = 1.6 Hz, 1H), 7.64 (dd, J = 7.8, 2.0 Hz, 2H), 7.62 - 7.59 (m, 1H), 7.58 - 7.56 (m, 2H), 7.54 - 7.52 (m, 1H), 7.41 - 7.36 (m, 1H), 4.46 (s, 2H), 4.33 (d, J = 2.8 Hz, 2H), 3.50 (s, 2H), 3.41 (t, J = 5.8 Hz, 2H), 2.35 - 2.32 (m, 1H), 1.86 - 1.82 (m, 2H), 1.11 - 1.07 (m, 4H).

[0515] Example 54

[0516]

[0517] Synthesis of Compound 47

[0518] Step 1: Compound 47-A

[0519] Compound 47-A was prepared by referring to Example 44 and using 3-aminoquinoline instead of 2-aminopyridine. m / z: [M + 1] + 750;

[0520] 1 1H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.93 (d, J = 2.6 Hz, 1H), 8.71 (d, J = 2.5 Hz, 1H), 8.29 (d, J = 1.6 Hz, 1H), 8.00 - 7.87 (m, 2H), 7.69 - 7.48 (m, 7H), 4.53 (s, 2H), 4.34 (s, 2H), 3.85 (s, 3H), 3.55 (s, 2H), 3.44 (t, J = 5.9 Hz, 2H), 2.38 - 2.30 (m, 1H), 1.93 - 1.84 (m, 2H), 1.14 - 1.04 (m, 4H).

[0521] Step 2: Compound 47-B

[0522] Compound 47-B was prepared by referring to Example 11 and using Compound 47-A instead of Compound 11-A. m / z: [M + 1] + 736;

[0523] 11H NMR (400 MHz, CDCl3): δ 10.88 (s, 1H), 8.91 (s, 1H), 8.74 (s, 1H), 8.26 - 8.09 (m, 2H), 7.91 (d, J = 11.0 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.60 - 7.51 (m, 2H), 7.49 - 7.43 (m, 1H), 7.39 - 7.31 (m, 2H), 4.42 (s, 2H), 4.36 (s, 2H), 3.53 (t, J = 7.3 Hz, 2H), 3.42 (t, J = 5.5 Hz, 2H), 2.13 - 2.07 (m, 1H), 2.00 - 1.92 (m, 2H), 1.24 - 1.18 (m, 2H), 1.12 - 1.04 (m, 2H).

[0524] Example 55

[0525]

[0526] Synthesis of Compound 48

[0527] Step 1: Compound 48-1

[0528] Compound 48-1 was prepared by referring to Example 1 and using tert-butyl (3-hydroxy-2,2-dimethylpropyl)carbamate instead of N-Boc-ethanolamine. m / z: [M+1] + 485;

[0529] Step 2: Compound 48-2

[0530] Compound 48-2 was prepared by referring to Example 1 and using Compound 48-1 instead of Compound 1-1. m / z: [M+1] + 385;

[0531] Step 3: Compound 48-A

[0532] Compound 48-A was prepared by referring to Example 1 and using Compound 48-2 instead of Compound 1-2. m / z: [M+1] + 594;

[0533] Step 4: Compound 48-B

[0534] Compound 48-B was prepared by referring to Example 11 and using Compound 48-A instead of Compound 11-A. m / z: [M+1] + 580;

[0535] 11H NMR (400 MHz, DMSO-d6): δ 12.88 (brs, 1H), 8.37 (s, 1H), 8.12 (d, J = 1.5 Hz, 1H), 7.65 - 7.60 (m, 2H), 7.57 - 7.46 (m, 3H), 4.35 - 4.29 (m, 4H), 4.33 (s, 2H), 3.22 (d, J = 5.5 Hz, 2H), 3.10 (s, 2H), 2.33 - 2.26 (m, 1H), 1.10 - 1.04 (m, 4H), 0.78 (s, 6H).

[0536] Example 56

[0537]

[0538] Synthesis of Compound 49

[0539] Step 1: Compound 49-A

[0540] Compound 49-A was prepared by referring to Example 11 and using bromoethane instead of 1-bromopropane. m / z: [M+1] + 622;

[0541] Step 2: Compound 49

[0542] Compound 49-B was prepared by referring to Example 11 and using Compound 49-A instead of Compound 11-A. m / z: [M+1] + 608;

[0543] 1 1H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 1.5 Hz, 1H), 7.76 (dd, J = 11.1, 1.5 Hz, 1H), 7.62 - 7.56 (m, 1H), 7.55 - 7.49 (m, 1H), 7.43 - 7.35 (m, 2H), 4.36 (s, 2H), 3.61 - 3.53 (m, 2H), 3.38 (s, 2H), 3.12 (s, 2H), 2.17 - 2.09 (m, 1H), 1.25 (t, J = 3.7 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H), 1.16 - 1.08 (m, 2H), 0.90 (s, 6H).

[0544] Example 57

[0545]

[0546] Synthesis of Compound 55-B

[0547] Step 1: Compound 55-A

[0548] Compound 55-A was prepared by using methyl iodide instead of 1-bromopropane with reference to Example 11. m / z: [M+1] + 608;

[0549] 1 H NMR (400 MHz, DMSO-d6): δ 7.98 (d, J = 1.6 Hz, 1H), 7.68 - 7.58 (m, 3H), 7.55 - 7.45 (m, 2H), 4.30 (s, 2H), 3.84 (s, 3H), 3.54 (d, J = 3.3 Hz, 3H), 3.12 (s, 2H), 2.75 (s, 2H), 2.33 - 2.26 (m, 1H), 1.11 - 1.02 (m, 4H), 0.78 (s, 6H).

[0550] Step 2: Compound 55-B

[0551] Compound 55-B was prepared by using compound 55-A instead of compound 11-A with reference to Example 11. m / z: [M+1] + 594;

[0552] 1 H NMR (400 MHz, CDCl3): δ 8.11 (s, 1H), 7.74 (d, J = 11.1 Hz, 1H), 7.56 (dd, J = 7.8, 1.8 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.39 - 7.34 (m, 2H), 4.34 (s, 2H), 3.38 (s, 2H), 3.15 (s, 3H), 3.10 (s, 2H), 2.12 - 2.08 (m, 1H), 1.24 - 1.21 (m, 2H), 1.11 - 1.07 (m, 2H), 0.88 (s, 6H).

[0553] Example 58

[0554]

[0555] Synthesis of Compound 56-B

[0556] Step 1: Compound 56-A

[0557] Compound 56-A was prepared by using 2-bromo-N-ethyl-N-acetylaniline instead of 1-bromopropane with reference to Example 11. m / z: [M+1] + 755;

[0558] Step 2: Compound 56-B

[0559] Compound 56-B was prepared by using compound 56-A instead of compound 11-A with reference to Example 11. m / z: [M+1]+ 741;

[0560] 1 H NMR(400 MHz, DMSO-d6) δ 12.96 (s, 1H), 8.18 (d, J = 1.5 Hz, 1H), 7.65 - 7.57 (m, 3H), 7.55 - 7.40 (m, 7H), 4.28 (s, 2H), 3.94 (s, 2H), 3.63 (d, J = 7.3 Hz, 2H), 3.02 (s, 2H), 2.24 (d, J = 13.2 Hz, 1H), 1.10 - 1.03 (m, 4H), 0.99 (t, J = 6.7 Hz, 3H), 0.72 (s, 6H).

[0561] Example 59

[0562]

[0563] Synthesis of Compound 63-B

[0564] Step 1: Compound 63-A

[0565] Compound 63-A was prepared by referring to Example 11 and using N-benzyl-2-bromoacetamide instead of 1-bromopropane. m / z: [M+1] + 622;

[0566] Step 2: Compound 63-B

[0567] Compound 63-B was prepared by referring to Example 11 and using Compound 63-A instead of Compound 11-A. m / z: [M+1] + 608;

[0568] 1 H NMR(400 MHz, DMSO-d6): δ 13.03 (s, 1H), 8.66 (t, J = 6.0 Hz, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.66 - 7.47 (m, 5H), 7.31 - 7.26 (m, 2H), 7.22 (d, J = 6.9 Hz, 2H), 4.78 (s, 2H), 4.29 (d, J = 5.9 Hz, 2H), 4.25 (s, 2H), 3.07 (s, 2H), 2.77 (s, 2H), 2.26 (s, 1H), 1.10 - 1.00 (m, 4H), 0.74 (s, 6H).

[0569] Example 60

[0570]

[0571] Preparation of Compound 50-B

[0572] Step 1: Compound 50-1

[0573] Dissolve tert-butyl 2-(methylamino)ethylcarbamate (522 mg, 2 eq.) and Compound B (433 mg, 1 eq.) in tetrahydrofuran (5 mL), add triethylamine (150 mg, 3 eq.), and stir at room temperature for 2 hours. Quench with saturated NH4Cl aqueous solution, extract with ethyl acetate, wash the combined organic phases with pure water and saturated NaCl aqueous solution respectively, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and triturate with ether to obtain 525 mg of white solid product with a purity of 99% and a yield of 91%. m / z: [M+1] + 384;

[0574] Step 2: Compound 50-2

[0575] Dissolve Compound 50-1 (334 mg, 1 eq.) in dichloromethane (5 mL), add trifluoroacetic acid (4 mL, 40 eq.), stir at room temperature for 1 hour, then remove the solvent under reduced pressure to obtain 170 mg of pale yellow oil with a purity of 98.0% and a yield of 69%. m / z: [M+1] + 284;

[0576] Step 3: Compound 50-A

[0577] Dissolve Compound A (48 mg, 1 eq.) and Compound 50-2 (82 mg, 2 eq.) in N,N-dimethylformamide (2 mL), add cesium carbonate (98 mg, 2 eq.), and react overnight at room temperature. Quench with saturated ammonium chloride aqueous solution, extract with ethyl acetate, wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, and rotary evaporate to remove the solvent to obtain a crude product. Purify by silica gel column chromatography to obtain 24 mg of white solid with a purity of 96% and a yield of 28%. m / z: [M+1] + 565;

[0578] 1 H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 1.4 Hz, 1H), 7.73 (dd, J = 11.4, 1.4 Hz, 1H), 7.53 (dd, J = 7.5, 1.6 Hz, 1H), 7.50 - 7.45 (m, 1H), 7.35 (dd, J = 7.9, 3.2 Hz, 2H), 3.94 (s, 3H), 3.70 - 3.64 (m, 4H), 3.14 (s, 3H), 2.88 (t, J = 6.1 Hz, 2H), 2.15 (td, J = 8.4, 4.2 Hz, 1H), 1.16 - 1.20 (m, 2H), 1.04 - 1.00 (m, 2H).

[0579] Step 4: Compound 50-B

[0580] Compound 50-B was prepared by replacing compound 1-A with compound 50-A according to Reference Example 1. m / z: [M+1] + 565;

[0581] 1 H NMR(600MHz,DMSO-d6):δ8.20(s,1H),7.67(dd,J=7.6,1.4Hz,1H),7.62-7.57(m,2H),7.47(dd,J=19.5,7.9Hz,2H),3.59-3.53(m,4H),3.07(s,3H),2.74(t,J=6.0Hz,2H),2.34-2.30(m,1H),1.00(dd,J=9.3,5.9Hz,4H).

[0582] Example 61

[0583]

[0584] Synthesis of Compound 51-B

[0585] Step 1: Compound 51-1

[0586] Compound 51-1 was prepared by replacing 2-(methylamino)ethyl carbamate with tert-butyl (2-(methylamino)ethyl)carbamate according to Reference Example 50. m / z: [M+1] + 398;

[0587] Step 2: Compound 51-2

[0588] Compound 51-2 was prepared by replacing compound 50-1 with compound 51-1 according to Reference Example 50. m / z: [M+1] + 298;

[0589] Step 3: Compound 51-A

[0590] Compound 51-A was prepared by replacing compound 50-2 with compound 51-2 according to Reference Example 50. m / z: [M+1] + 579;

[0591] 11H NMR (400 MHz, CDCl3): δ 7.60 - 7.46 (m, 4H), 7.41 - 7.34 (m, 2H), 4.00 (s, 2H), 3.88 (s, 3H), 3.43 - 3.36 (m, 2H), 3.36 - 3.27 (m, 2H), 2.62 (s, 6H), 2.18 - 2.10 (m, 1H), 1.19 - 1.14 (m, 2H), 1.02 - 1.07 (m, 2H).

[0592] Step 4: Compound 51-B

[0593] Compound 51-B was prepared by using Compound 51-A instead of Compound 50-A according to Reference Example 1. m / z: [M+1] + 565;

[0594] 1 1H NMR (400 MHz, CDCl3): δ 7.63 (s, 1H), 7.58 - 7.53 (m, 2H), 7.53 - 7.48 (m, 1H), 7.40 - 7.36 (m, 2H), 4.01 (s, 2H), 3.42 - 3.39 (m, 2H), 3.38 - 3.33 (m, 2H), 2.64 (s, 6H), 2.18 - 2.13 (m, 1H), 1.20 - 1.16 (m, 2H), 1.09 - 1.04 (m, 2H).

[0595] Example 62

[0596]

[0597] Synthesis of Compound 52

[0598] Step 1: Compound 52-1

[0599] Compound 52-1 was prepared by using tert-butyl 2-(methylamino)propylcarbamate instead of tert-butyl 2-(methylamino)ethylcarbamate according to Reference Example 50. m / z: [M+1] + 398;

[0600] Step 2: Compound 52-2

[0601] Compound 52-2 was prepared by using Compound 52-1 instead of Compound 50-1 according to Reference Example 50. m / z: [M+1] + 298;

[0602] Step 3: Compound 52-A

[0603] Compound 52-A was prepared by using Compound 52-2 instead of Compound 50-2 according to Reference Example 50. m / z: [M+1]+ 579;

[0604] Step 4: Compound 51-B

[0605] Compound 52-B was prepared by using Compound 52-A to replace Compound 50-A with reference to Example 1. m / z: [M+1] + 565;

[0606] 1 H NMR(600MHz, DMSO-d6): δ8.2(s, 1H), 7.72 - 7.68(m, 1H), 7.65 - 7.61(m, 1H), 7.59(d, J = 11.5Hz, 1H), 7.51(dd, J = 13.8, 6.7Hz, 2H), 3.61(s, 2H), 3.51(s, 2H), 3.28 - 3.20(s, 2H), 3.09(s, 3H), 2.41 - 2.36(m, 1H), 1.76 - 1.67(m, 2H), 1.10 - 1.05(m, 4H).

[0607] Example 63

[0608]

[0609] Synthesis of Compound 53-B

[0610] Step 1: Compound 53-A

[0611] Compound 52-A (38 mg, 1 eq.) and methyl iodide (9 mg, 1 eq.) were dissolved in acetonitrile (2 mL), and potassium carbonate (9 mg, 1 eq.) was added to the system and reacted overnight. After concentration under reduced pressure to obtain the crude product, it was purified by silica gel column chromatography to obtain 20 mg of a colorless oil, with a purity of 99% and a yield of 50%. m / z: [M+1] + 592;

[0612] 11H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 1.5 Hz, 1H), 7.72 (dd, J = 11.3, 1.5 Hz, 1H), 7.59 (dd, J = 7.6, 1.6 Hz, 1H), 7.50 - 7.46 (m, 1H), 7.36 (dd, J = 11.6, 4.2 Hz, 2H), 3.93 (s, 3H), 3.36 (s, 2H), 3.34 - 3.28 (m, 2H), 3.13 (s, 3H), 2.31 (t, J = 6.5 Hz, 2H), 2.21 - 2.16 (m, 1H), 2.09 (s, 3H), 1.75 - 1.71 (m, 2H), 1.23 (dd, J = 5.0, 2.4 Hz, 2H), 1.12 - 1.08 (m, 2H).

[0613] Step 2: Compound 53-B

[0614] Compound 53-B was prepared by using compound 53-A instead of compound 1-A with reference to Example 1. m / z: [M+1] + 579;

[0615] 1 1H NMR (400 MHz, CDCl3): δ 7.90 (s, 1H), 7.66 (dd, J = 11.4, 1.2 Hz, 1H), 7.58 (dd, J = 7.5, 1.6 Hz, 1H), 7.50 (dd, J = 8.5, 1.6 Hz, 1H), 7.42 - 7.38 (m, 2H), 3.68 (s, 2H), 3.39 (s, 2H), 3.15 (s, 3H), 2.54 (s, 2H), 2.17 (s, 3H), 2.10 - 1.95 (m, 1H), 1.91 - 1.84 (m, 2H), 1.26 (dd, J = 4.9, 2.3 Hz, 2H), 1.15 - 1.10 (m, 2H).

[0616] Example 64

[0617]

[0618] Synthesis of Compound 54-B

[0619] Step 1: Compound 54-1

[0620] Compound 48-1 was prepared by using 4-(N-tert-butoxycarbonylamino)-1-butanol instead of N-Boc-ethanolamine with reference to Example 1. m / z: [M+1] + 471;

[0621] Step 2: Compound 54-2

[0622] Compound 54-2 was prepared by replacing compound 1-1 with compound 54-1 according to Example 1. m / z: [M+1] + 371;

[0623] Step 3: Compound 54-3

[0624] Compound 54-3 was prepared by replacing compound 1-2 with compound 54-2 according to Example 1. m / z: [M+1] + 580;

[0625] Step 4: Compound 54-A

[0626] Compound 54-A was prepared by replacing compound 1-A with compound 54-3 according to Example 2. m / z: [M+1] + 594;

[0627] 1 H NMR (400 MHz, DMSO-d6): δ8.26 (d, J = 1.6 Hz, 1H), 7.64 - 7.56 (m, 3H), 7.51 - 7.43 (m, 2H), 4.30 (s, 2H), 3.85 (s, 3H), 3.48 (brs, 2H), 3.32 - 3.29 (m, 2H), 3.12 (s, 3H), 2.33 - 2.26 (m, 1H), 1.54 - 1.46 (m, 2H), 1.44 - 1.37 (m, 2H), 1.11 - 1.03 (m, 4H).

[0628] Compound 54-B was prepared by replacing compound 11-A with compound 54-A according to Example 11. m / z: [M+1] + 580;

[0629] 1 H NMR (400 MHz, DMSO-d6): δ8.16 (d, J = 1.2 Hz, 1H), 7.63 - 7.55 (m, 3H), 7.53 - 7.44 (m, 2H), 4.30 (s, 2H), 3.49 - 3.45 (m, 2H), 3.33 (t, J = 6.0 Hz, 2H), 3.11 (s, 3H), 2.34 - 2.26 (m, 1H), 1.53 - 1.46 (m, 2H), 1.45 - 1.38 (m, 4H), 1.12 - 1.04 (m, 4H).

[0630] Determination of compound receptor affinity

[0631] Experimental method: The labeled human FXR (GST-FXR) (Cat. No.: PV4834) protein (Invitroren) and biotinylated SRC-1 peptide (Biotin-Src-1) (Cat. No.: PV4586) were incubated with the test compound in the HTRF assay buffer to achieve a dose response. After incubating for 1 hour in the dark, the plate was read for HTRF on an Envision 2105 plate reader (Perkin Elmer). Each compound was tested in triplicate and the mean value was shown. The data was processed with GraphPad Prism 8.0 to calculate the EC50 value of receptor affinity.

[0632] The reported range of EC50 values for the FXR receptor affinity experiment is as follows: A represents <100 nM, B represents 100 nM - 500 nM, C represents 500 nM - 1 μM, and D represents 1 μM - 10 μM.

[0633] Table 1. Results of FXR receptor affinity assay

[0634]

[0635] Determination of compound cell-level activity

[0636] The restriction enzymes, KOD PLUS high-fidelity DNA polymerase (Pfu DNA polymerase), LA-Taq DNA polymerase, T4 DNA polymerase, T4 DNA ligase, and dNTP used in this example were all purchased from TaKaRa. Other conventional reagents were imported in bulk or of domestic analytical purity.

[0637] TE Buffer: 10 mM Tris·HCl, 1 mM EDTA (pH 8.0);

[0638] Ampicillin: Prepared as a stock solution of 100 mg / mL with sterile water and stored at -20 °C;

[0639] The sequence from 500 bp upstream to 100 bp downstream of BSEP with GenBank accession number AC008177 was amplified by PCR and ligated into the pGL3-Basic expression vector at the double restriction enzyme sites KpnI and HindIII to construct the recombinant plasmid pGL3-Basic-BSEP.

[0640] The sequence of FXR (NR1H4) with GenBank accession number NM_001206977.1 was amplified by PCR and ligated into the pLV CS2.0 expression vector at the double restriction enzyme sites BamHI and SmaI to construct the recombinant plasmid pLV-FXR.

[0641] The sequence of RXRa with GenBank accession number NM_002957 was amplified by PCR and ligated into the pLV CS2.0 expression vector at the double restriction enzyme sites XbaI and MluI to construct the recombinant plasmid pLV-RXRa.

[0642] The above recombinant plasmid was transformed into competent Escherichia coli (E. coli) cells, spread on LB medium containing 30 μg / mL ampicillin, cultured overnight at 37 °C, the bacteria were harvested, and colony PCR verification was performed.

[0643] Plasmid construction and sequencing verification were carried out by Wuhan Kingcare Bioengineering Co., Ltd.

[0644] The gene amplification system is shown in Table 2 below:

[0645] Table 2

[0646]

[0647] The PCR amplification reaction conditions are shown in Table 3 below:

[0648] Table 3

[0649]

[0650] The restriction enzyme digestion system of the vector and the target fragment is shown in Table 4 below:

[0651] Table 4

[0652]

[0653] Experimental method: Lipofectamin 2000 reagent and plasmids: 10 ng pLV-hRXR, 10.4 ng pLV-hFXR, 10.4 ng pGL3-pBSEP-Luc, and 40 ng pRL-TK were transfected into 5 × 10 5 cells per well in a 96-well plate. After 24 h, the cells were replaced with medium and various compounds at specific concentrations were added. After 24 h, the cells were lysed, the substrate was added, and the activities of firefly luciferase and Renilla luciferase were detected by a microplate reader. The ratio of the two represented the transcriptional activity of the compound. The data were processed with GraphPad 8.0 to obtain a dose-response curve and calculate the EC50. The results are shown in Table 5.

[0654] The reported range of EC50 values in the FXR cell activity dual-luciferase reporter gene assay is as follows: A represents <200 nM, B represents 200 nM - 500 nM, C represents 500 nM - 1 μM, and D represents 1 μM - 10 μM.

[0655] Table 5. Results of FXR cell level activity

[0656] Compound number FXR cell activity (EC50) Compound number FXR cell activity (EC50) 1-B D 18 C 2-B C 19-B D 3-B D 20-B D 7-B C 28-B D 8-B A 30-B D 9-B A 31 B 11 A 32 A 12 A 33 B 13 D 48 A 16-B C 49 B 15-B B 54-B D 17 C

Claims

1. A phenylisoxazole derivative represented by Formula I, The L1 is any one; The R1 is -NR a R b , and the R a and R b are each independently selected from H, an amino protecting group, -CH2(CO)NR aa R ba , and C1 to C6 branched alkyl; Said R aa and R ba are each independently selected from cycloalkyl, H.

2. The phenylisoxazole derivative represented by Formula I according to claim 1, characterized in that, The cycloalkyl group is selected from cyclohexyl.

3. A non-steroidal FXR regulator intermediate represented by Formula II, or a salt thereof; L2 is X is unsubstituted -CH2-; Y is -N(R 4 )-; R 4 is hydrogen, a cyclopentyl group, an allyl group, an unsubstituted C1-C5 alkyl group or a C1-C2 alkyl group substituted with one R 4-1 substituent; R 4-1 is carboxyl, 6-membered aryl, -C(=O)-R 4-1-1 ; Among them, R 4-1-1 is methyl, pyrrolidinyl, 6-membered aryl, or methoxy; Or, R 4-1-1 is -NR a R b ; said R a and R b One of them is hydrogen, and the other is unsubstituted or substituted by one R a-1 substituted C1-C3 alkyl, C5 cycloalkyl, quinolinyl, pyridyl, unsubstituted 6-membered or 10-membered aryl or 6-membered aryl substituted by one R a-2 ; Or, R 4-1-1 is -NR a R b , where the R a and R b one of which is an unsubstituted C1-C3 alkyl group and the other is a 6-membered aryl group, a C1-C2 alkyl group which is unsubstituted or substituted by a 6-membered aryl group; Or, R 4-1-1 is -NR a R b , where the R a and R b one of them is ethyl substituted by a methoxy group, and the other is an unsubstituted aryl group; Or, R 4-1-1 is -OR a , said R a is methyl; R a-1 is a C1-C6 alkyl group, a methoxy group, a 6-membered aryl group, or chlorine; R a-2 is chlorine, methyl or methoxy.

4. A phenylisoxazole derivative is as follows:

5. A non-steroidal FXR regulator intermediate, any of the following compounds:

6. A substrate for synthesizing an intermediate of a non-steroidal FXR regulator, as shown in the formula

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