Novel ferroptosis inhibitor as well as preparation method and application thereof

Abstract

The invention provides a novel ferroptosis inhibitor as well as a preparation method and application thereof, and belongs to the technical field of chemical synthesis medicines. The invention synthesizes a compound shown in the formula I and having a good inhibition effect on ferroptosis, and the compound can be used for preparing a ferroptosis inhibitor. The compound can also be used for preparing medicines for treating diseases such as ischemia-reperfusion injury, drug-induced liver injury, acute kidney injury, renal failure, hepatic pulmonary fibrosis, neurodegenerative diseases, cerebral apoplexy, myocarditis, myocardial infarction, heart failure, arthritis, chronic atrophic gastritis and the like related to ferroptosis, and has a wide market prospect.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis drug technology, specifically to a novel ferroptosis inhibitor, its preparation method, and its uses. Background Technology

[0002] Ferroptosis is a novel type of regulated cell death proposed and named by the Dixon team in 2012. This cell death mechanism is characterized by iron-dependent lipid peroxidation, and its morphological, biochemical, and genetic characteristics differ significantly from apoptosis, necroptosis, autophagy, and pyroptosis. Cells undergoing ferroptosis exhibit unique morphological features, including marked mitochondrial condensation, reduced or absent mitochondrial cristae, increased mitochondrial membrane density, and loss of plasma membrane integrity. These characteristic morphological changes are used as biomarkers of ferroptosis. Intracellular glutathione (GSH) depletion, insufficient glutathione peroxidase 4 (GPX4), lipid peroxide accumulation, and iron-dependent fenton reactions promote the generation of reactive oxygen species (ROS), leading to oxidative damage to the phospholipid membrane and thus triggering ferroptosis. Lipid peroxidation can be regulated through non-enzymatic reactions and enzymatic reactions induced by arachidonic acid lipid oxygenases (ALOXs) and cytochrome P450 oxidoreductases (PORs), producing lipid hydroperoxides (LOOHs) and their derivatives such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). Glutathione peroxidase 4 (GPX4), a selenoprotein phospholipid hydroperoxidase, can reduce lipid hydroperoxides to their corresponding alcohols, playing an important role in protecting against ferroptosis.

[0003] Recent studies have shown that ferroptosis is closely related to the onset and progression of various diseases, including ischemia-reperfusion injury, drug-induced liver injury, acute kidney injury, renal failure, hepatic and pulmonary fibrosis, neurodegenerative diseases, stroke, myocarditis, myocardial infarction, heart failure, arthritis, and chronic atrophic gastritis. Inhibiting ferroptosis is considered an effective strategy for treating these diseases. Although several ferroptosis inhibitors have been developed, many suffer from poor activity or pharmacokinetic properties, limiting their clinical application. Therefore, developing novel ferroptosis inhibitors for the treatment of ferroptosis-related diseases remains of significant value. Summary of the Invention

[0004] In order to address the problems existing in the prior art, the purpose of this invention is to provide a novel ferroptosis inhibitor, its preparation method, and its uses.

[0005] This invention provides a compound of formula I, or a salt thereof, wherein the structural formula of the compound is:

[0006]

[0007] in,

[0008] In the diagram, when there is no dashed line, it represents a single bond; when there is a dashed line, it represents a double bond.

[0009] A is selected from O, S, and NH;

[0010] R 1 Selected from hydrogen, halogens, C 1～5 Alkyl, L 2 L 2 'R';L 2 Selected from none, C 1～5 Alkylene, phenyl; L 2 R′ is selected from none, -C(O)-; R′ is selected from unsubstituted or substituted by 1 to 3 Rs. A Substituted groups include: 3-6 membered saturated cycloalkyl groups, 3-6 membered saturated heterocyclic groups, 5-10 membered aromatic rings, and 5-10 membered heteroaromatic rings; R A Each is independently selected from halogens, C 1～5 Alkyl, C 1～5 Alkoxy, -NR C R D ;

[0011] L is selected from none, C 1～5 Alkylene, phenyl, -C(O)-;

[0012] The B ring is selected from 5-10 member aromatic rings, 5-10 member heteroaromatic rings, and 3-6 member saturated heterocycles;

[0013] R 2 Each is independently selected from hydrogen and C. 1～5 Alkyl, C 1～5 Alkoxy, halogen, L 3 R″;L 3 Selected from none, -C(O)-; R″ selected from unsubstituted or substituted by 1 to 3 Rs B Substituted groups include: 3-6 membered saturated heterocycles, 5-10 membered aromatic rings, and 5-10 membered heteroaromatic rings; R B Each is independently selected from C 1～5 Alkyl, C 1～5 Alkoxy, -NR C R D ;R C R D Each is independently selected from hydrogen and C. 1～5 alkyl;

[0014] n is selected from 1, 2, or 3;

[0015] The C ring is selected from 5-10 quinary aromatic rings and 5-10 heterocyclic aromatic rings;

[0016] R 3 Selected from hydrogen, halogens, C1～5 Alkoxy, C 1～5 Alkyl, halogen-substituted C 1～5 Alkyl, -SO2NHR 5 L 4 R E , cyano; R 5 Selected from C 1～5 Alkyl; L 4 Selected from phenyl or phenyl; R E Selected from those that have not been replaced or have 1 to 3 Rs F Substituted phenyl groups, 3- to 6-membered saturated heterocycles; R F Each is independently selected from C 1～5 Alkyl groups, 3- to 6-membered saturated heterocycles;

[0017] D is selected from CH and N.

[0018] Furthermore, A is selected from O, S, and NH;

[0019] R 1 Selected from hydrogen, halogens, C 1～3 Alkyl, L 2 L 2 'R';L 2 Selected from none, C 1～3 Alkylene, phenyl; L 2 R′ is selected from none, -C(O)-; R′ is selected from unsubstituted or substituted by 1 to 3 Rs. A The following groups are substituted: 3-6 membered saturated cycloalkyl groups, 3-6 membered saturated heterocyclic groups, 5-10 membered aromatic rings, 5-10 membered heteroaromatic rings, preferably: phenyl, R A Each is independently selected from halogens, C 1～3 Alkyl, C 1～3 Alkoxy, -NR C R D ;

[0020] L is selected from none, C 1～3 Alkylene, phenyl, -C(O)-;

[0021] Ring B is selected from 5-10 membered aromatic rings, 5-10 membered heteroaromatic rings, and 3-6 membered saturated heterocycles, preferably phenyl rings.

[0022] R 2 Each is independently selected from hydrogen and C. 1～3 Alkyl, C 1～3 Alkoxy, halogen, L 3 R″;L 3 Selected from none, -C(O)-; R″ selected from unsubstituted or substituted by 1 to 3 Rs BThe following groups are substituted: 3-6 membered saturated heterocycles, 5-10 membered aromatic rings, 5-10 membered heteroaromatic rings, preferably phenyl. R B Each is independently selected from C 1～3 Alkyl, C 1～3 Alkoxy, -NR C R D ;R C R D Each is independently selected from hydrogen and C. 1～3 alkyl;

[0023] n is selected from 1, 2, or 3;

[0024] The C ring is selected from phenyl,

[0025] R 3 Selected from hydrogen, halogens, C 1～3 Alkoxy, C 1～3 Alkyl, halogen-substituted C 1～3 Alkyl, -SO2NHR 5 L 4 R E , cyano; R 5 Selected from C 1～3 Alkyl; L 4 Selected from phenyl or phenyl; R E Selected from those that have not been replaced or have 1 to 3 Rs F Substituted phenyl groups, 3- to 6-membered saturated heterocycles; R F Each is independently selected from C 1～3 Alkyl groups, 3- to 6-membered saturated heterocycles;

[0026] D is selected from CH and N.

[0027] Furthermore, the compound is as shown in Formula II:

[0028]

[0029] in,

[0030] In the diagram, when there is no dashed line, it represents a single bond; when there is a dashed line, it represents a double bond.

[0031] A, B, L, R 1 R 2 R 3 As mentioned above, n...

[0032] Furthermore, the compound is as shown in Formula III:

[0033]

[0034] in,

[0035] In the diagram, when there is no dashed line, it represents a single bond; when there is a dashed line, it represents a double bond; A, L, R 1 R 2 R 3 As mentioned above, n...

[0036] Furthermore, the compound is shown in Formula IV:

[0037]

[0038] in,

[0039] In the diagram, when there is no dashed line, it represents a single bond; when there is a dashed line, it represents a double bond; A, B, L, R 1 R 2 R 3 As mentioned above, n...

[0040] Furthermore, the compound is as shown in Formula V:

[0041]

[0042] in,

[0043] In the diagram, when there is no dashed line, it represents a single bond; when there is a dashed line, it represents a double bond; A, L, R 1 R 2 R 3 As mentioned above, n...

[0044] Furthermore, the compound is selected from one of the following compounds:

[0045]

[0046]

[0047]

[0048]

[0049] The present invention also provides the use of the above-described compounds, or salts thereof, in the preparation of ferroptosis inhibitors, medicaments for the prevention and / or treatment of ferroptosis-related diseases.

[0050] Furthermore, the iron-related diseases mentioned are ischemia-reperfusion injury, drug-induced liver injury, acute kidney injury, kidney failure, hepatopulmonary fibrosis, neurodegenerative diseases, stroke, myocarditis, myocardial infarction, heart failure, arthritis, or chronic atrophic gastritis.

[0051] The present invention also provides a pharmaceutical composition, which is a formulation prepared by using the above-mentioned compound or its salt as the active ingredient and adding pharmaceutically acceptable excipients.

[0052] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0053] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0054] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.

[0055] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a- C b Alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, "C 1～5 "Alkyl" refers to an alkyl group containing 1 to 5 carbon atoms.

[0056] "Alkyl" refers to a saturated hydrocarbon chain with a specified number of member atoms. For example, C 1～5 Alkyl groups are alkyl groups having 1 to 5 member atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups may optionally be substituted by one or more substituents as defined herein. C 1～5 Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), and pentyl (n-pentyl, isopentyl and neopentyl).

[0057] "Alkoxy" refers to a group in which an alkyl group is connected to a linking site through an oxygen atom. Its alkane chain can be a saturated alkane chain. For example, methoxy refers to -OCH3.

[0058] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0059] "Aromatic ring" refers to a monocyclic ring consisting entirely of carbon atoms (including fused rings, spiro rings, or bridged rings) with a conjugated π-electron system, such as, but not limited to, phenyl, naphthyl, phenanthryl, anthraceneyl, fluorenyl, and indene. The aromatic ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as O, N, or S. Furthermore, the point of attachment to the parent group must be on a carbon atom of a ring with a conjugated π-electron system, such as, but not limited to, [other types of rings].

[0060] "Heteroaromatic ring" refers to an aromatic ring in which at least one carbon atom in the conjugated π-electron system is replaced by a heteroatom, which is O, N, or S, including but not limited to:

[0061]

[0062] "3- to 6-membered saturated cycloalkyl groups" refers to saturated cycloalkyl groups with 3, 4, 5, or 6 ring atoms.

[0063] "3- to 6-membered saturated heterocycles" refer to saturated heterocyclic groups containing one or more heteroatoms, with the number of ring atoms being 3, 4, 5, or 6, and the heteroatoms being O, N, or S.

[0064] The term "salt" refers to the above-mentioned compounds, acidic and / or basic salts formed with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts), and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compounds. Alternatively, they can be obtained by mixing the above-mentioned compounds, or their stereoisomers, with a suitable (e.g., equimolar) amount of acid or base. These salts may be obtained by precipitating in solution and collecting by filtration, or by recovery after solvent evaporation, or by freeze-drying after reaction in an aqueous medium. The salts described in this invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluoric acids, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compounds.

[0065] The present invention has achieved the following beneficial effects:

[0066] This invention synthesizes a class of compounds with good inhibitory effects on ferroptosis, which can be used to prepare ferroptosis inhibitors. They can also be used to prepare drugs for treating ferroptosis-related ischemia-reperfusion injury, drug-induced liver injury, acute kidney injury, kidney failure, liver and lung fibrosis, neurodegenerative diseases, stroke, myocarditis, myocardial infarction, heart failure, arthritis, chronic atrophic gastritis, and other diseases, and have broad market prospects.

[0067] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0068] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0069] Figure 1 The results of this study show that compound 59 protects cells from ferroptosis in ES-2 (ovarian cancer cells), AC16 (human cardiomyocytes), HT1080 (human fibrosarcoma cell line), and PANC-1 (human pancreatic cancer cell line). Detailed Implementation

[0070] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0071] Example 1: Synthesis of Compound 1

[0072] The synthetic route for compound 1 is as follows:

[0073]

[0074] Phenyzine hydrochloride (1.00 g, 6.92 mmol, 1.00 eq) and ethyl acetoacetate (0.87 mL, 6.92 mmol, 1.00 eq) were dissolved in anhydrous ethanol (30 mL), heated to 80 °C and stirred for 7 hours. The anhydrous ethanol was removed under reduced pressure to give intermediate a pale yellow solid (638 mg, 3.67 mmol, 53%).

[0075] Phosphorus oxychloride (2.28 mL, 25 mmol, 7.00 eq) was slowly added dropwise to N,N-dimethylformamide (0.77 mL, 10 mmol, 3.00 eq) under ice bath conditions and reacted for 30 minutes. Then, intermediate a (638 mg, 3.67 mmol, 1.00 eq) was added to the reaction mixture, and the resulting mixture was heated to 100 °C and reacted for 2 hours. The reaction mixture was then slowly poured into ice water (200 mL), and a large amount of yellow solid gradually precipitated. The mixture was filtered, washed with water, and dried under vacuum to obtain intermediate b (339 mg, 1.54 mmol, 42%).

[0076] Intermediate b (339 mg, 1.54 mmol, 1.00 eq), o-nitroaniline (212 mg, 1.54 mmol, 1.00 eq), and piperidine (0.02 mL, 0.2 mmol, 0.12 eq) were dissolved in anhydrous ethanol and the mixture was heated to 80 °C and stirred for 7 hours. After the reaction was completed by TLC, the solvent was removed under reduced pressure, and intermediate c (245 mg, 0.76 mmol, 50%) was obtained by column chromatography.

[0077] Intermediate C (245 mg, 0.76 mmol, 1.00 eq) was dissolved in anhydrous ethanol (16 ml) and water (8 ml). Iron powder (128 mg, 2.28 mmol, 3.00 eq) and ammonium chloride solid (61 mg, 1.14 mmol, 1.50 eq) were added. The mixture was heated to 80 °C and reacted for 2 hours. The reaction was monitored by TLC until it was complete. The mixture was filtered while hot, and the solvent was removed under reduced pressure. Compound 1 (90 mg, 0.34 mmol, 44%) was obtained by separation with silica gel plates.

[0078] Compound 1 1 The H NMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.59 (s, 1H), 7.53 (t, J = 7.4Hz, 2H), 7.41 (dd, J = 20.3, 7.2Hz, 4H),6.89(d,J=7.5Hz,1H),6.80(m,2H),6.55(d,J=7.7Hz,1H),2.08(s,3H).HRMS m / z(ESI)calcd for C 17 H 14 N4[M+H] + 275.1292 found: 275.1285.

[0079] Example 2, Synthesis of Compound 2

[0080]

[0081] Using a synthesis method similar to that in Example 1, intermediate e (380 mg, 1.54 mmol, 42%) was obtained.

[0082] Intermediate e (380 mg, 1.54 mmol, 1.00 eq), o-aminophenol (168 mg, 1.54 mmol, 1.00 eq), and piperidine (0.02 mL, 0.2 mmol, 0.12 eq) were dissolved in anhydrous ethanol and the mixture was heated to 80 °C and stirred for 7 hours. After the reaction was completed by TLC, the solvent was removed under reduced pressure, and intermediate f (230 mg, 0.76 mmol, 50%) was obtained by column chromatography.

[0083] Intermediate f (230 mg, 0.76 mmol, 1.00 eq) was dissolved in anhydrous ethanol, cooled to 0 °C, and treated in batches with NaBH4 (72 mg, 1.9 mmol, 2.5 eq). After dissolution, the mixture was heated to 80 °C and refluxed for 1 hour. The solvent was removed under reduced pressure, and the mixture was then extracted with water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The organic layer was separated by column chromatography to give compound 2 (185 mg, 0.61 mmol, 80%).

[0084] Compound 2 1 The H NMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.49(d,J=8.1Hz,2H),7.30(t,J=6.9Hz,2H),7.11(t,J=7.3Hz,1H),6.88(d,J=7.2Hz, 2H),6.82(t,J=7.4Hz,1H),6.67(t,J=7.5Hz,1H),5.40(s,1H),3.87(s,2H),1.56(m,1H),0.61(m,4H).HRMS m / z(ESI)calcd for C 19 H 17 N3O[M+H] + 304.3725 found 304.3721.

[0085] Example 3, Synthesis of Compound 3

[0086]

[0087] Compound 3 was prepared using a synthetic method similar to that in Example 2, with a yield of 23%. Compound 3... 1 The H NMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.54(s,2H),7.40(t,J=7.0Hz,1H),7.10(m,4H),6.89(t,J=7.5Hz,1H),5.59(s,1H),3.99(s,2H),2.40(s,3H),2.12(s,3H).HRMS m / z(ESI)calcd for C 18 H 17 N3O[M+H] + 304.3725 found 304.3721.

[0088] Example 4, Synthesis of Compound 4

[0089]

[0090] Compound 4 was prepared using a synthetic method similar to that in Example 2, with a yield of 27%. Compound 4... 1 The H NMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ7.39(dd,J=14.5,7.1Hz,1H),7.05(m,6H),6.87(t,J=7.6Hz,1H),5.48(s,1H),5.24(s,2H),3.91(s,2H),2.03(s,3H).HRMS m / z(ESI)calcd for C 18 H 16 FN3O[M+H] + 310.3519 found 310.3517.

[0091] Example 5: Synthesis of Compound 5

[0092]

[0093] Compound 5 was prepared using a synthetic method similar to that in Example 2, with a yield of 26%. Compound 5... 1 The H NMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.85(d,J=6.4Hz,2H),7.65(d,J=6.2Hz,2H),7.59(t,J=6.3Hz,2H),7.48(t ,J=6.3Hz,2H),7.42(m,2H),7.11(m,3H),6.94(t,J=6.8Hz,1H),5.64(s,1H),4.24(s,2H).HRMS m / z(ESI)calcd for C 22 H 17 N3O[M+H] + 340.4055 found 340.4059.

[0094] Example 6: Synthesis of Compound 6

[0095]

[0096] Compound 6 was prepared using a synthetic method similar to that in Example 2, with a yield of 21%. Compound 6... 1 The H NMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ8.67(d,J=3.3Hz,2H),7.86(d,J=6.9Hz,2H),7.63(dd,J=16.0,5.9Hz,4 H),7.46(t,J=7.3Hz,1H),7.12(m,3H),6.95(t,J=7.4Hz,1H),5.68(s,1H),4.31(s,2H).HRMS m / z(ESI)calcd for C 21 H 16 N4O[M+H] + 341.3935found341.3932.

[0097] Example 7, Synthesis of Compound 7

[0098]

[0099] Compound 7 was prepared using a synthetic method similar to that in Example 2, with a yield of 32%. Compound 7... 1 The H NMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.53(m,3H),7.38(t,J=7.5Hz,1H),7.11(d,J=7.8Hz,1H),7.03(t, J=7.3Hz,1H),6.88(dt,J=14.8,7.5Hz,2H),5.57(s,1H),3.99(s,2H),2.12(s,3H).HRMS m / z(ESI)calcd for C 17 H 14 FN3O[M+H] + 296.3249 found 296.3244.

[0100] Example 8, Synthesis of Compound 8

[0101]

[0102] Compound 8 was prepared using a synthetic method similar to that in Example 2, with a yield of 29%. Compound 8... 1 The H NMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ7.77 (dd, J=8.3, 4.2Hz, 2H), 7.36 (td, J=8.9, 3.3Hz, 2H), 7 .07(m,3H),6.89(t,J=6.7Hz,1H),5.60(s,1H),3.98(s,2H),2.12(s,3H).HRMS m / z(ESI)calcd for C 17 H 14 FN3O[M+H] + 296.3249 found 296.3253.

[0103] Example 9, Synthesis of Compound 9

[0104]

[0105] Compound 9 was prepared using a synthetic method similar to that in Example 2, with a yield of 24%. Compound 9... 1 The H NMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.58(m,1H),7.39(dd,J=5.6,3.5Hz,2H),7.27(t,J=8.5Hz,1H),7.12(m ,2H),6.88(m,1H),6.68(dd,J=10.1,4.5Hz,1H),5.91(s,1H),4.28(s,2H),2.18(s,3H).HRMS m / z(ESI)calcd for C 17 H 14 FN3S[M+H] + 312.3859 found 312.3863.

[0106] Example 10: Synthesis of Compound 10

[0107]

[0108] Compound 10 was prepared using a synthetic method similar to that in Example 2, with a yield of 20%. Compound 10... 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ7.74(d,J=8.3Hz,2H),7.52(t,J=7.9Hz,2H),7.33(t,J=7.4Hz,1H),7.10(d,J=8.0Hz ,2H),7.04(t,J=7.3Hz,1H),6.89(t,J=6.8Hz,1H),5.60(s,1H),3.98(d,J=2.3Hz,2H),2.12(s,3H).HRMS m / z(ESI)calcd forC 17 H 15 N3O[M+H] + 278.1288 found 278.1284.

[0109] Example 11, Synthesis of Compound 11

[0110]

[0111] Compound 11 was prepared using a synthetic method similar to that in Example 2, with a yield of 26%. Compound 11... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.26(s,1H),8.08(d,J=8.8Hz,2H),7.97(d,J=8.5Hz,2H),7.57(t,J=7.5Hz,2H),7.1 5(dd,J=16.0,7.1Hz,2H),7.06(m,1H),6.91(t,J=7.0Hz,1H),5.64(s,1H),4.03(s,2H),2.18(s,3H).HRMS m / z(ESI)calcd for C 21 H 17 N3O[M+H] + 328.3945 found 328.3948.

[0112] Example 12, Synthesis of Compound 12

[0113]

[0114] Compound 12 was prepared using a similar synthetic method as in Example 2, with a yield of 23%.

[0115] Compound 12 1 The H NMR and HRMS data are as follows:

[0116] 1H NMR (400MHz, DMSO) δ8.99(s,1H),8.54(d,J=4.4Hz,1H),8.17(d,J=7.0Hz,1H),7.62–7.55(m,1H),7.13 (d,J=6.9Hz,2H),7.06(t,J=7.5Hz,1H),6.90(t,J=7.6Hz,1H),5.63(s,1H),4.00(s,2H),2.15(s,3H).

[0117] HRMS m / z(ESI)calcd for C 16 H 14 N4O[M+H] + 279.3225 found 279.3227.

[0118] Example 13, Synthesis of Compound 13

[0119]

[0120] Compound 13 was prepared using a synthetic method similar to that in Example 2, with a yield of 19%. Compound 13... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.93(d,J=1.5Hz,1H),7.84(d,J=7.5Hz,1H),7.51(t,J=8.0Hz,2H),7.08(dt ,J=22.5,7.6Hz,3H),6.91(t,J=7.5Hz,1H),5.63(s,1H),3.98(s,2H),2.13(d,J=1.3Hz,3H).HRMS m / z(ESI)calcd for C 17 H 14 BrN3O[M+H] + 357.2305 found 357.2301.

[0121] Example 14, Synthesis of Compound 14

[0122]

[0123] Compound 14 was prepared using a synthetic method similar to that in Example 2, with a yield of 25%. Compound 14... 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ7.79(d,J=1.6Hz,2H),7.54(t,J=7.5Hz,1H),7.37(d,J=7.9Hz,1H),7.10(d,J=6.1Hz,2H ),7.04(dd,J=10.4,4.5Hz,1H),6.90(t,J=7.5Hz,1H),5.62(s,1H),3.98(s,2H),2.12(d,J=1.6Hz,3H).HRMS m / z(ESI)calcd forC 17 H 14 ClN3O[M+H] + 312.7765 found 312.7766.

[0124] Example 15, Synthesis of Compound 15

[0125]

[0126] Compound 15 was prepared using a synthetic method similar to that in Example 2, with a yield of 20%. Compound 15... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.71 (t, J=8.6Hz, 2H), 7.55 (dd, J=14.7, 6.3Hz, 1H), 7.17 (t, J= 8.5Hz,1H),7.07(dt,J=5.7,3.6Hz,3H),5.89(s,1H),4.01(s,2H),2.14(s,3H).HRMS m / z(ESI)calcd for C 17 H 13 ClFN3O[M+H] + 330.7669 found 330.7666.

[0127] Example 16, Synthesis of Compound 16

[0128]

[0129] Compound 16 was prepared using a synthetic method similar to that in Example 2, with a yield of 18%. Compound 16... 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ7.69 (d, J=8.2Hz, 1H), 7.61 (dd, J=12.1, 9.2Hz, 2H), 7.21 (dd, J= 10.6,8.2Hz,3H),6.95(d,J=8.7Hz,1H),5.94(s,1H),4.06(s,2H),2.18(s,3H).HRMS m / z(ESI)calcd for C 17 H 13 ClFN3O[M+H] + 330.7669 found 330.7671.

[0130] Example 17, Synthesis of Compound 17

[0131]

[0132] Compound 17 was prepared using a synthetic method similar to that in Example 2, with a yield of 24%. Compound 17... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.69(t,J=10.1Hz,2H),7.55(dd,J=15.6,7.8Hz,1H),7.16(t,J=8.4Hz,1H ),7.02(dd,J=14.9,7.1Hz,1H),6.93–6.81(m,2H),5.95(s,1H),4.03(s,2H),2.15(s,3H).HRMS m / z(ESI)calcd for C 17 H 13 F2N3O[M+H] + 314.3153 found 314.3156.

[0133] Example 18, Synthesis of Compound 18

[0134]

[0135] Compound 18 was prepared using a synthetic method similar to that in Example 2, with a yield of 21%. Compound 18... 1 The HNMR and HRMS data are as follows: 1H NMR(400MHz,DMSO)δ7.71(d,J=8.0Hz,1H),7.62(dd,J=14.6,7.9Hz,2H),7.40(s,1H), 7.29–7.18(m,2H),7.10(d,J=8.5Hz,1H),5.88(s,1H),4.03(s,2H),2.18(s,3H).HRMS m / z(ESI)calcd for C 17 H 13 BrFN3O[M+H] + 375.2209 found 375.2206.

[0136] Example 19, Synthesis of Compound 19

[0137]

[0138] Compound 19 was prepared using a synthetic method similar to that in Example 2, with a yield of 17%. 1 The HNMR and HRMS data are as follows: 1 H NMR(400MHz,DMSO)δ7.65(d,J=7.8Hz,1H),7.61–7.52(m,2H),7.47(s,1H),7.31(d ,J=8.4Hz,1H),7.18(t,J=8.6Hz,2H),6.12(s,1H),4.05(s,2H),2.14(s,3H).HRMS m / z(ESI)calcd for C 18 H 13 F4N3O[M+H] + 364.3231 found.

[0139] Example 20, Synthesis of Compound 20

[0140]

[0141] Compound 20 was prepared using a synthetic method similar to that in Example 2, with a yield of 27%. Compound 20... 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ7.71 (d, J = 8.1Hz, 1H), 7.65–7.55 (m, 2H), 7.33–7.24 (m, 4H), 7.20 (t, J = 7.7Hz, 2H), 7. 12(d,J=8.0Hz,1H),7.08–7.00(m,2H),6.89(t,J=7.3Hz,1H),5.53(s,1H),3.91(s,2H),3.80(s,2H).HRMS m / z(ESI)calcd forC 23 H 18 FN3O[M+H] + 372.4229 found 372.4224.

[0142] Example 21, Synthesis of Compound 21

[0143]

[0144] Compound 21 was prepared using a synthetic method similar to that in Example 2, with a yield of 23%. Compound 21... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.66(d,J=8.1Hz,1H),7.57(t,J=10.4Hz,3H),7.41(d,J=4.9Hz,1H),7.33(d,J=8.4Hz,1H), 7.25(d,J=8.3Hz,1H),7.19(t,J=8.4Hz,1H),6.18(s,1H),4.05(s,2H),2.43(d,J=4.8Hz,3H),2.15(s,3H).HRMS m / z(ESI)calcd for C 18 H 17 FN4O3S[M+H] + 389.4249 found 389.4246.

[0145] Example 22, Synthesis of Compound 22

[0146]

[0147] Compound 22 was prepared using a synthetic method similar to that in Example 2, with a yield of 20%. Compound 22... 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ8.64(d,J=5.3Hz,2H),7.87(d,J=5.6Hz,2H),7.27(d,J=7.9Hz,1H) ,7.17–7.02(m,2H),6.92(t,J=7.4Hz,1H),5.65(s,1H),3.98(s,2H),2.14(s,3H).HRMS m / z(ESI)calcd for C 16 H 14 N4O[M+H] + 279.3225 found 279.3221.

[0148] Example 23, Synthesis of Compound 23

[0149]

[0150] Compound 23 was prepared using a synthetic method similar to that in Example 2, with a yield of 25%. Compound 23... 1 The HNMR and HRMS data are as follows: 1 H NMR(400MHz, DMSO)δ7.50(d,J=8.3Hz,2H),7.19(d,J=2.2Hz,1H),7.15–7.09(m,2H),7.09 –7.03(m,1H),6.92(d,J=6.7Hz,1H),5.64(s,1H),3.97(s,2H),2.12(d,J=3.1Hz,3H).HRMS m / z(ESI)calcd for C 17 H 13 F2N3O[M+H] + 314.3153 found 314.3152.

[0151] Example 24, Synthesis of Compound 24

[0152]

[0153] Compound 24 was prepared using a synthetic method similar to that in Example 2, with a yield of 19%. 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ8.92(d,J=1.7Hz,1H),8.55(d,J=8.2Hz,1H),8.34(s,1H),8.24(d,J=9.1Hz,1H),8.17(d,J=8.1Hz,1H),7.63–7.55(m,1H), HRMS m / z(ESI)calcd for C 20 H 16 N4O[M+H] + 329.3825 found 329.3822.

[0154] Example 25, Synthesis of Compound 25

[0155]

[0156] Compound 25 was prepared using a synthetic method similar to that in Example 2, with a yield of 29%. Compound 25... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.15(d,J=8.0Hz,1H),7.07(d,J=7.8Hz,1H),7.01(t,J=7.5Hz, 1H),6.89(t,J=7.6Hz,1H),5.46(s,1H),3.89(s,2H),3.64(s,3H),2.00(s,3H).HRMS m / z(ESI)calcd for C 12 H 13 N3O[M+H] + 216.2635 found 216.2633.

[0157] Example 26, Synthesis of Compound 26

[0158]

[0159] Compound 26 was prepared using a synthetic method similar to that in Example 2, with a yield of 21%. Compound 26... 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ7.82–7.69(m,3H),7.55(t,J=7.2Hz,1H),7.16(dd,J=14.5,7.6Hz,2H),7. 07(t,J=7.5Hz,1H),6.93(dd,J=10.8,4.3Hz,1H),5.64(s,1H),4.01(s,2H),2.15(s,3H).HRMS m / z(ESI)calcd for C 17 H 14 BrN3O[M+H] + 357.2305 found 357.2302.

[0160] Example 27, Synthesis of Compound 27

[0161]

[0162] Compound 27 was prepared using a synthetic method similar to that in Example 2, with a yield of 16%. Compound 27... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.70(d,J=8.2Hz,1H),7.60(d,J=7.7Hz,4H),7.45(dd,J=15.1,7.7Hz,3 H),7.36(t,J=7.2Hz,1H),7.21(t,J=7.9Hz,3H),5.75(s,1H),4.04(s,2H),2.15(s,3H).HRMS m / z(ESI)calcd for C 23 H 18 FN3O[M+H] + 372.4229 found 372.4224.

[0163] Example 28, Synthesis of Compound 28

[0164]

[0165] Compound 28 was prepared using a synthetic method similar to that in Example 2, with a yield of 18%. Compound 28... 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ7.63(d,J=8.8Hz,1H),7.60–7.57(m,1H),7.57–7.55(m,1H),7.53(dd,J=4.7,2.5Hz,1H),7.49(d HRMS m / z(ESI)calcd for C 18 H 13 FN4O[M+H] + 321.3349 found.

[0166] Example 29, Synthesis of Compound 29

[0167]

[0168] Compound 29 was prepared using a synthetic method similar to that in Example 2, with a yield of 18%. Compound 29... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.02(dd,J=4.6,1.3Hz,1H),7.75–7.69(m,1H),7.61(dd,J=17.6,7.7Hz,3H),7.24( td,J=8.6,2.4Hz,1H),6.92(dd,J=7.9,4.6Hz,1H),6.52(s,1H),4.15(d,J=2.7Hz,2H),2.21(s,3H).HRMS m / z(ESI)calcd for C 16 H 13 FN4O[M+H] + 297.3129 found 291.3131.

[0169] Example 30, Synthesis of Compound 30

[0170]

[0171] Compound 18 (100 mg, 0.27 mmol, 1.00 eq), 4-(4-methyl-1-piperazinyl)phenylboronic acid (58.7 mg, 0.27 mmol, 1.00 eq), Pd(dppf)Cl2 (9.76 mg, 0.01 mmol, 0.05 eq), and K2CO3 (110 mg, 0.80 mmol, 3.00 eq) were dissolved in 1,4-dioxane:water (4:1). The mixture was stirred at 100 °C under an argon atmosphere for 3 hours. The reaction was monitored by TLC until completion. The solvent was removed under reduced pressure, and compound 30 (69 mg, 0.15 mmol, 54%) was obtained by column chromatography.

[0172] Compound 30 1 The H NMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.72(d,J=8.2Hz,1H),7.60(d,J=8.5Hz,2H),7.48(d,J=7.2Hz,2H),7.29(s,2H),7.16(dd,J=19.4 ,8.5Hz,2H),6.97(d,J=7.3Hz,2H),5.66(s,1H),3.99(s,2H),3.16(m,4H),2.46(m,4H),2.23(s,3H),2.14(s,3H).HRMS m / z(ESI)calcd for C 28 H 28 FN5O[M+H] + 470.5719 found 470.5716.

[0173] Example 31, Synthesis of Compound 31

[0174]

[0175] Compound 31 was prepared using a synthetic method similar to that in Example 30, with a yield of 37%. Compound 31... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, CDCl3) 1H NMR (400MHz, DMSO) δ7.73(d,J=8.2Hz,1H),7.59(dd,J=15.3,8.3Hz,2H),7.50(d,J=7.8Hz,2H),7.30(d,J=5.9Hz,2H),7.16 HRMS m / z(ESI)calcd for C 27 H 25 FN4O2[M+H] + 470.5719 found 470.5716.

[0176] Example 32, Synthesis of Compound 32

[0177]

[0178] Compound 32 was prepared using a synthetic method similar to that in Example 2, with a yield of 16%. Compound 32... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, CDCl3) 1 H NMR (400MHz, DMSO) δ7.75 (d, J=8.2Hz, 1H), 7.71–7.60 (m, 3H), 7.37–7.25 (m, 2H), 7.19 (dd, J= 8.2,4.3Hz,3H),7.12(t,J=7.5Hz,1H),6.97(t,J=7.6Hz,1H),5.71(s,1H),4.28(s,2H).HRMS m / z(ESI)calcd for C 20 H 14 FN3OS[M+H] + 364.4179 found 364.4176.

[0179] Example 33, Synthesis of Compound 33

[0180]

[0181] Compound 33 was prepared using a synthetic method similar to that in Example 2, with a yield of 20%. Compound 33... 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ8.86(s,1H),8.62(s,1H),8.07(d,J=7.9Hz,1H),7.78(d,J=8.2Hz,1H),7.72(d,J=10.4Hz,1H),7.69–7. 61(m,1H),7.55–7.48(m,1H),7.28(t,J=8.4Hz,1H),7.21–7.05(m,3H),6.96(t,J=7.0Hz,1H),5.68(s,1H),4.25(s,2H).HRMS m / z(ESI)calcd for C 21 H 15 FN4O[M+H] + 358.3839 found 358.3842.

[0182] Example 34, Synthesis of Compound 34

[0183]

[0184] Compound 34 was prepared using a synthetic method similar to that in Example 2, with a yield of 24%. Compound 34... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.67(d,J=4.5Hz,2H),7.77(d,J=8.1Hz,1H),7.71(d,J=10.2Hz,1H),7.68–7.60(m,3H),7.29(t,J=8.4Hz ,1H),7.16(dd,J=6.6,5.0Hz,2H),7.10(t,J=7.5Hz,1H),6.96(t,J=7.6Hz,1H),5.69(s,1H),4.29(s,2H).HRMSm / z(ESI)calcd for C 21 H 15 FN4O[M+H] + 358.3839 found 358.3834.

[0185] Example 35, Synthesis of Compound 35

[0186]

[0187] Compound 35 was prepared using a synthetic method similar to that in Example 2, with a yield of 29%. Compound 35... 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ7.87(d,J=8.1Hz,2H),7.79–7.76(m,3H),7.74(d,J=7.8Hz,2H),7.60(t,J=6.9Hz,2H),7.50(t,J=6.8 HRMS m / z(ESI)calcd for C 28 H 20 FN3O[M+H] + 434.4939 found 434.4937.

[0188] Example 36, Synthesis of Compound 36

[0189]

[0190] Compound 36 was prepared using a synthetic method similar to that in Example 2, with a yield of 33%. Compound 36... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.65(t,J=6.9Hz,2H),7.52(dd,J=19.4,7.7Hz,3H),7.44(d,J=6.5Hz,1H),7.14(t,J=7.6Hz,2H),7 .09(d,J=2.4Hz,2H),7.03(t,J=7.2Hz,1H),6.91(d,J=8.0Hz,1H),6.85(t,J=7.4Hz,1H),5.70(s,1H),4.33(s,2H).HRMS m / z(ESI)calcd for C 21 H 16 N₂O[M+H] + 313.3795 found 313.3793.

[0191] Example 37, Synthesis of Compound 37

[0192]

[0193] Intermediate g was prepared using a synthesis method similar to that in Example 30.

[0194] Intermediate g (1.1 g, 3.52 mmol, 1.00 eq), o-nitroaniline (486 mg, 3.52 mmol, 1.00 eq), and cesium carbonate (3.44 g, 10.6 mmol, 3.00 eq) were dissolved in N,N-dimethylformamide (8 mL). The mixture was stirred at 100 °C for 4 hours and extracted with water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The organic layer was then separated by column chromatography to give intermediate h (340 mg, 0.79 mmol, 22%).

[0195] Intermediate h (340 mg, 0.79 mmol) was dissolved in anhydrous methanol, Pd (50 mg) was added, and the mixture was stirred overnight under H2 atmosphere. The resulting mixture was filtered and separated by column chromatography to obtain compound 37 (89 mg, 0.23 mmol, 29%).

[0196] Compound 37 1 The H NMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.37(s,1H),7.68(d,J=7.3Hz,2H),7.43(d,J=7.8Hz,3H),7.38(s,1H),6.98(d,J=8.0Hz,1H),6.88(d,J=7.9Hz HRMS m / z(ESI)calcd for C 24 H 23 N3O2[M+H] + 386.4745 found 386.4748.

[0197] Example 38, Synthesis of Compound 38

[0198]

[0199] Compound 38 was prepared using a synthetic method similar to that in Example 37, with a yield of 28%. Compound 38... 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ8.84(d,J=3.9Hz,1H),8.36(d,J=8.2Hz,1H),8.20(d,J=8.4 Hz,2H),8.09(d,J=8.9Hz,1H),8.03(d,J=8.8Hz,1H),7.59(d,J=8.3Hz,1H),7.52 (d,J=8.5Hz,2H),7.03(d,J=8.4Hz,1H),6.90(d,J=7.8Hz,1H),6.74(d,J=7.7Hz, 1H),6.66(t,J=7.3Hz,1H),6.56(t,J=7.4Hz,1H),5.74(s,1H),4.20(s,2H).HRMS m / z(ESI)calcd for C 22 H 17 N3[M+H] + 324.4065 found 324.4068.

[0200] Example 39, Synthesis of Compound 39

[0201]

[0202] Compound 39 was prepared using a synthetic method similar to that in Example 37, with a yield of 25%. Compound 39... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.23(s,1H),7.59(d,J=7.6Hz,2H),7.45(t,J=6.8Hz,2H),7.34(t,J=7.1Hz,1H),7.19(s,1H),7.04(d,J=7. 6Hz,1H),6.89–6.82(m,2H),6.69(d,J=7.8Hz,1H),6.63(t,J=7.5Hz,1H),6.53(t,J=7.3Hz,1H),5.63(s,1H),4.10(s,2H).HRMS m / z(ESI)calcd for C 19 H 16 N2[M+H] + 273.1387 found: 273.1382.

[0203] Example 40, Synthesis of Compound 40

[0204]

[0205] Compound 40 was prepared using a synthetic method similar to that in Example 37, with a yield of 21%. Compound 40...1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, CDCl3) 1 H NMR (400MHz, DMSO) δ8.36 (s, 1H), 7.67 (d, J = 6.6Hz, 2H), 7.43 (d, J = 11.8Hz, 2H), 7.38 (d, J = 6.9Hz, 2H), 6.98 (d, J = 8.2Hz, 1H), 6.88 (d, J = 7.9Hz, HRMS m / z(ESI)calcd forC 25 H 26 N4O[M+H] + 399.5175 found 399.5178.

[0206] Example 41, Synthesis of Compound 41

[0207]

[0208] Compound 41 was prepared using a synthetic method similar to that in Example 37, with a yield of 27%. Compound 41... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, CDCl3) 1 H NMR (400MHz, DMSO) δ8.16(s,1H),7.75(s,1H),6.99(s,1H),6.94(d,J=7.5Hz,1H),6.86(d,J=7.9Hz,1H),6.69(d,J =7.7Hz,1H),6.63(t,J=6.4Hz,2H),6.52(t,J=7.4Hz,1H),5.60(s,1H),4.08(s,2H),3.78(s,3H),2.31(s,3H).HRMS m / z(ESI)calcd for C 18 H 18 N4[M+H] + 291.3775 found 291.3773.

[0209] Example 42, Synthesis of Compound 42

[0210]

[0211] Compound 42 was prepared using a synthetic method similar to that in Example 37, with a yield of 27%. Compound 42... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.19(s,1H),7.71(d,J=2.3Hz,1H),7.10(d,J=8.2Hz,1H),7.03(s,1H),6.89(dd,J=17.6,6.5Hz ,2H),6.68(dd,J=28.0,6.3Hz,2H),6.53(d,J=5.5Hz,1H),5.98(s,1H),4.12(s,2H),3.75(s,3H),2.26(s,3H).HRMS m / z(ESI)calcd for C 18 H 18 N4[M+H] + 291.3775 found 291.3777.

[0212] Example 43, Synthesis of Compound 43

[0213]

[0214] Compound 43 was prepared using a synthetic method similar to that in Example 37, with a yield of 32%. 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.26(s,1H),7.54–7.48(m,1H),7.45(t,J=7.3Hz,1H),7.40(d,J=10.5Hz,1H),7.19(dd,J=15.7,6.3Hz,2H),7.06(d,J=7.6Hz,1 H),6.90(d,J=7.6Hz,1H),6.85(d,J=7.8Hz,1H),6.70(d,J=7.7Hz,1H),6. 64(t,J=7.5Hz,1H),6.54(t,J=7.4Hz,1H),5.64(s,1H),4.11(s,2H).HRMS m / z(ESI)calcd for C 19 H 15 FN2[M+H] + 291.3489 found 291.3484.

[0215] Example 44, Synthesis of Compound 44

[0216]

[0217] 4-Bromo-2,6-difluorobenzaldehyde (1.00 g, 4.52 mmol, 1.00 eq), 1,2-dimethylpiperazine (0.60 mL, 4.52 mmol, 1.00 eq), and K₂CO₃ (1.87 g, 13.6 mmol, 3.00 eq) were dissolved in acetonitrile and reacted at 70 °C for 4 hours. The reaction was monitored by TLC until completion. The solvent was removed under reduced pressure, and the intermediate (1.26 g, 3.99 mmol, 88%) was obtained by column chromatography.

[0218] Intermediate j was prepared using a synthesis method similar to that in Example 30.

[0219] Compound 44 was prepared using a synthetic method similar to that in Example 37, with a yield of 21%. Compound 44... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.99(s,1H),7.58(d,J=7.5Hz,2H),7.44(t,J=6.9Hz,2H),7.34( t,J=6.9Hz,1H),6.93(s,1H),6.82(d,J=7.8Hz,1H),6.65–6.55(m,3H),6.50(t,J=7.3 Hz,1H),5.64(s,1H),4.26(s,2H),2.94(t,J=12.3Hz,2H),2.79(t,J=11.2Hz,2H),2. 43(d,J=10.6Hz,2H),2.35(t,J=10.2Hz,1H),2.24(s,4H),1.04(d,J=5.3Hz,3H).HRMS m / z(ESI)calcd for C 25 H 28 N4[M+H] + 385.2387 found: 385.2383.

[0220] Example 45, Synthesis of Compound 45

[0221]

[0222] Intermediate 1 was prepared using a synthesis method similar to that in Example 30.

[0223] Compound 45 was prepared using a synthetic method similar to that in Example 2, with a yield of 42%. Compound 45... 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ7.53(dd,J=14.6,7.3Hz,1H),7.36(t,J=8.3Hz,4H),7.24(dt,J=15.1,8.1Hz,2H),6.75( dt,J=8.0,3.9Hz,1H),6.57(d,J=7.9Hz,1H),6.37(t,J=6.4Hz,2H),6.12(s,1H),4.47(d,J=3.8Hz,2H).HRMS m / z(ESI)calcd forC 19 H 14 FNO[M+H] + 292.3329 found 292.3326.

[0224] Example 46, Synthesis of Compound 46

[0225]

[0226] Compound 46 was prepared using a synthetic method similar to that in Example 45, with a yield of 29%. Compound 46... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.43(d,J=8.5Hz,2H),7.27(dd,J=17.3,7.4Hz,2H),7.15(t,J=7.5Hz,1H),7.04(d,J=8.5Hz,2H),6.72(t,J=7.4Hz,1H),6.5 HRMS m / z(ESI)calcd for C 24 H 25 N3O[M+H] + 372.4915 found 372.4917.

[0227] Example 47, Synthesis of Compound 47

[0228]

[0229] Compound 47 was prepared using a synthetic method similar to that in Example 45, with a yield of 33%. Compound 47... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, CDCl3)1 H NMR (400MHz, DMSO) δ7.41(d,J=8.7Hz,2H),7.08(s,1H),7.03(d,J=9.1Hz,3H),6.71(dd,J=10.8,4.3Hz,1H),6.52(d,J=6.9Hz,1H),6.44( HRMS m / z(ESI)calcd for C 25 H 27 N3O[M+H] + 386.5185 found 386.5187.

[0230] Example 48, Synthesis of Compound 48

[0231]

[0232] Compound 48 was prepared using a synthetic method similar to that in Example 37, with a yield of 29%. Compound 48... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, CDCl3) 1 H NMR (400MHz, DMSO) δ8.18(s,1H),7.45(d,J=7.9Hz,2H),7.30(d,J=8.6Hz,1H),7.23(s,1H),6.93(dd,J=16.8,8.2Hz,3H),6.84(d,J=8.0Hz,1 H),6.69(d,J=7.7Hz,1H),6.62(t,J=7.4Hz,1H),6.51(t,J=7.2Hz,1H),5.63(s,1H),4.12(s,2H),3.14(m,4H),2.46(m,4H),2.23(s,3H).HRMS m / z(ESI)calcd forC 24 H 26 N4[M+H] + 371.5075 found 371.5078.

[0233] Example 49, Synthesis of Compound 49

[0234]

[0235] 3-Fluoro-4-carboxybenzoic acid (1.00 g, 5.95 mmol, 1.00 eq), 1-(2-pyridyl)piperazine (0.91 mL, 5.95 mmol, 1.00 eq), HATU (2.71 g, 7.14 mmol, 1.20 eq), and DIEA (3.09 mL, 17.8 mmol, 3.00 eq) were dissolved in dichloromethane and reacted at room temperature for 4 hours. The reaction was monitored by TLC until completion. The solvent was removed under reduced pressure, and the intermediate n (1.30 g, 4.15 mmol, 70%) was obtained by column chromatography.

[0236] Intermediate n was synthesized using a similar method to that in Example 37 to obtain compound 49, with a yield of 29%. 1 The H NMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.29(s,1H),8.13(d,J=4.3Hz,1H),7.56(t,J=7.8Hz,1H),7.03(d,J=7.5Hz,1H),6.96(s,1H),6.84(t,J=8.3 HRMS m / z(ESI)calcd for C 24 H 26 N4[M+H] + 371.5075 found 371.5078.

[0237] Example 50, Synthesis of Compound 50

[0238]

[0239] Compound 50 was prepared using a synthetic method similar to that in Example 37, with a yield of 39%. Compound 50... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, CDCl3) 1H NMR (400MHz, DMSO) δ7.81(d,J=2.1Hz,1H),7.73(d,J=8.2Hz,1H),7.28(d,J=8.5H z,2H),7.10(d,J=8.1Hz,1H),7.04(d,J=8.6Hz,2H),6.97–6.89(m,2H),6.75(t,J =7.3Hz,1H),6.52(d,J=6.9Hz,1H),6.39(t,J=7.5Hz,1H),6.13(s,1H),4.47(d,J =4.0Hz,2H),3.93(s,3H),3.25–3.18(m,4H),2.49–2.44(m,4H),2.24(s,3H).HRMS m / z(ESI)calcd for C 28 H 29 N5O[M+H] + 452.5815 found 452.5817.

[0240] Example 51, Synthesis of Compound 51

[0241]

[0242] Compound 51 was prepared using a synthetic method similar to that in Example 44, with a yield of 29%. Compound 51... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.00(s,1H),7.52–7.46(m,1H),7.41(dd,J=15.5,8.8Hz,2H),7.17(t,J=8.8Hz,1H),6.95(s,1H),6.81(d,J=7. HRMS m / z(ESI)calcd for C 24 H 25 FN4[M+H] + 389.4979 found 389.4976.

[0243] Example 52, Synthesis of Compound 52

[0244]

[0245] Compound 52 was prepared using a synthetic method similar to that in Example 44, with a yield of 31%. Compound 52... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.99(d,J=2.1Hz,1H),7.58(d,J=6.2Hz,2H),7.45(t,J=6.2Hz,2H),7.34(t,J=6.4Hz,1H),6.94(s,1H),6.83(d,J=6. HRMS m / z(ESI)calcd for C 24 H 26 N4[M+H] + 371.2231found:371.2224.

[0246] Example 53, Synthesis of Compound 53

[0247]

[0248] Compound 53 was prepared using a synthetic method similar to that in Example 44, with a yield of 26%. Compound 53... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, CDCl3) 1 H NMR (400MHz, DMSO) δ8.00(s,1H),7.49(t,J=7.7Hz,1H),7.39(d,J=6.7Hz,1H),7.27(d,J=7.7Hz,2H),6.88–6.81(m,2H ),6.62(d,J=7.6Hz,2H),6.51(t,J=7.5Hz,2H),5.65(s,1H),4.27(s,2H),2.87(s,4H),2.61(s,4H),2.29(s,3H).HRMS m / z(ESI)calcd for C 24 H 25 FN4[M+H] + 389.4979 found 389.4977.

[0249] Example 54, Synthesis of Compound 54

[0250]

[0251] Compound 54 was prepared using a synthetic method similar to that in Example 44, with a yield of 28%. 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.01(s,1H),7.54–7.38(m,3H),7.18(t,J=8.3Hz,1H),6.97(s,1H),6.82(d,J=7.7Hz,1H),6.66( HRMS m / z(ESI)calcd for C 23 H 22 FN3O[M+H] + 376.4549 found 376.4547.

[0252] Example 55, Synthesis of Compound 55

[0253]

[0254] Compound 55 was prepared using a synthetic method similar to that in Example 37, with a yield of 38%. Compound 55... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, CDCl3) 1 H NMR (400MHz, DMSO) δ8.52(s,1H),7.56–7.40(m,3H),7.21(t,J=7.8Hz,1H),7.08(s,1H),6.88(d,J=7.9H z,1H),6.81(d,J=10.9Hz,1H),6.76–6.65(m,2H),6.60(t,J=7.4Hz,1H),5.72(s,1H),4.16(s,2H).HRMS m / z(ESI)calcd for C 13 H 10 BrFN2[M+H] + 294.1469 found 294.1466.

[0255] Example 56, Synthesis of Compound 56

[0256]

[0257] Compound 56 was prepared using a synthetic method similar to that in Example 37, with a yield of 28%. Compound 56... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.60(d,J=3.6Hz,1H),7.52(dd,J=14.4,7.4Hz,1H),7.37(t,J=9.3Hz,2H),7.24(t,J=8.1Hz,1H),7.16(d, J=7.7Hz,1H),6.94(d,J=7.9Hz,1H),6.79–6.70(m,2H),6.62(dt,J=14.5,7.0Hz,2H),5.74(s,1H),4.17(d,J=2.6Hz,2H).HRMS m / z(ESI)calcd for C 19 H 14 F2N2[M+H] + 309.3393 found 309.3396.

[0258] Example 57, Synthesis of Compound 57

[0259]

[0260] Compound 57 was prepared using a synthetic method similar to that in Example 37, with a yield of 25%. Compound 57... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.15(s,1H),7.53(dd,J=14.2,7.3Hz,1H),7.41–7.28(m,2H),7.24(t,J=8.6Hz,1H),7.08–6.99(m,2H) HRMS m / z(ESI)calcd for C 19 H 14 F2N2[M+H] + 309.3393 found 309.3391.

[0261] Example 58, Synthesis of Compound 58

[0262]

[0263] Compound 58 was prepared using a synthetic method similar to that in Example 44, with a yield of 26%. Compound 58... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, CDCl3) 1 H NMR (400MHz, DMSO) δ8.00(s,1H),7.49(t,J=6.8Hz,1H),7.38(s,1H),7.28(t,J=7.6Hz,2H),6.83(d,J=10.8Hz,2H),6.67–6.45 HRMS m / z(ESI)calcd for C 25 H 27 FN4[M+H] + 403.2293 found: 403.2291.

[0264] Example 59, Synthesis of Compound 59

[0265]

[0266] Compound 59 was prepared using a synthetic method similar to that in Example 44, with a yield of 28%. Compound 59... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.01 (s, 1H), 7.53–7.37 (m, 3H), 7.17 (t, J = 8.1Hz, 1H), 6.96 (s ,1H),6.83(d,J=7.7Hz,1H),6.61(dd,J=21.9,7.0Hz,3H),6.53(d,J=6.1Hz,1H),5 .66(s,1H),4.27(s,2H),2.95(t,J=12.4Hz,2H),2.82(d,J=9.6Hz,2H),2.46(d,J= 10.2Hz,1H),2.36(t,J=11.1Hz,1H),2.28–2.20(m,4H),1.05(d,J=3.2Hz,3H).HRMS m / z(ESI)calcd for C 25 H 27 FN4[M+H] + 403.2293 found: 403.2290.

[0267] Example 60, Synthesis of Compound 60

[0268]

[0269] Compound 60 was prepared using a synthetic method similar to that in Example 44, with a yield of 23%. Compound 60... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.00 (s, 1H), 7.61 (dd, J = 7.2, 5.7Hz, 2H), 7.27 (t, J = 8.3Hz, 2H), 6.91(s,1H),6.83(d,J=7.8Hz,1H),6.63(d,J=7.6Hz,1H),6.61–6.55(m,2H),6.51(t, J=7.3Hz,1H),5.65(s,1H),4.26(s,2H),2.95(t,J=12.2Hz,2H),2.79(t,J=10.8Hz,2H ),2.49–2.42(m,1H),2.36(t,J=10.1Hz,1H),2.24(s,4H),1.04(d,J=5.8Hz,3H).HRMS m / z(ESI)calcd for C 25 H 27 FN4[M+H] + 403.2293 found: 403.2290.

[0270] Example 61, Synthesis of Compound 61

[0271]

[0272] Compound 61 was prepared using a synthetic method similar to that in Example 44, with a yield of 20%. Compound 61... 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ8.02(s,1H),7.63(s,1H),7.57(d,J=7.5Hz,1H),7.46(ddd,J=27.5,15 .9,5.5Hz,2H),6.96(s,1H),6.82(d,J=5.5Hz,1H),6.61(dd,J=18.6,7.7Hz,3H),6.53(d,J =7.1Hz,1H),5.66(s,1H),4.27(s,2H),2.95(t,J=12.3Hz,2H),2.82(d,J=8.7Hz,2H),2.46 (d,J=9.1Hz,1H),2.36(t,J=11.4Hz,1H),2.25(d,J=2.7Hz,4H),1.05(d,J=2.7Hz,3H).HRMS m / z(ESI)calcd for C 25 H 27 ClN4[M+H] + 419.1997 found: 419.1991.

[0273] Example 62, Synthesis of Compound 62

[0274]

[0275] Compound 62 was prepared using a synthetic method similar to that in Example 44, with a yield of 26%. Compound 62... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.03 (s, 1H), 7.50–7.33 (m, 3H), 7.19 (d, J = 6.8Hz, 1H), 6.98 (s, 1H),6.87(d,J=6.4Hz,1H),6.64(dd,J=19.8,10.8Hz,3H),6.55(t,J=7.2Hz,1H),5. 68(s,1H),4.31(s,2H),2.99(t,J=12.3Hz,2H),2.84(t,J=10.5Hz,2H),2.48(d,J=9 .8Hz,1H),2.42(d,J=2.2Hz,4H),2.29(d,J=2.3Hz,4H),1.08(d,J=3.0Hz,3H).HRMS m / z(ESI)calcd for C 26 H 30 N4[M+H] + 399.2544 found: 399.2541.

[0276] Example 63, Synthesis of Compound 63

[0277]

[0278] Compound 63 was prepared using a synthetic method similar to that in Example 44, with a yield of 22%. 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.99 (s, 1H), 7.45–7.31 (m, 3H), 7.18 (d, J = 6.5Hz, 1H), 6.93 (s, 1H), 6.83 (d ,J=6.3Hz,1H),6.60(dd,J=19.3,9.8Hz,3H),6.50(t,J=6.2Hz,1H),5.63(s,1H),4.26(s,2H),2. 94(t,J=12.2Hz,2H),2.81(d,J=9.3Hz,2H),2.67(dd,J=7.4,2.4Hz,2H),2.43(d,J=9.7Hz,1H), 2.35(t,J=11.1Hz,1H),2.24(d,J=2.3Hz,4H),1.22(t,J=7.2Hz,3H),1.04(d,J=2.8Hz,3H).HRMS m / z(ESI)calcd forC 27 H 32 N4[M+H] + 413.2700 found: 413.2696.

[0279] Example 64, Synthesis of Compound 64

[0280]

[0281] Compound 64 was prepared using a synthetic method similar to that in Example 44, with a yield of 27%. Compound 64... 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ10.33(s,1H),9.59(t,J=8.1Hz,1H),9.29(s,1H),9.22(d,J=4.9Hz,2H),9.18(d,J=7.9Hz,1H),9.07(d,J=8.4Hz,1H),8.96(d,J =6.0Hz,2H),8.91(d,J=7.6Hz,1H),8.85(t,J=7.4Hz,1H),7.98(s,1H),6. 63(d,J=3.4Hz,2H),6.12(s,4H),5.31(s,6H),5.22(t,J=4.5Hz,4H).HRMS m / z(ESI)calcd for C 25 H 28 N4O[M+H] + 401.5335 found 401.5338.

[0282] Example 65, Synthesis of Compound 65

[0283]

[0284] Compound 65 was prepared using a synthetic method similar to that in Example 37, with a yield of 29%. Compound 65... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.91(d,J=3.0Hz,1H),7.95–7.87(m,2H),7.50(d,J=6.6Hz,1H),7.46(dd,J=7.7,3.1Hz,1H),7.23(dd,J=7.5,3.5Hz,2H) HRMS m / z(ESI)calcd for C 18 H 14 FN3[M+H] + 292.3369 was found.

[0285] Example 66, Synthesis of Compound 66

[0286]

[0287] Compound 66 was prepared using a synthetic method similar to that in Example 44, with a yield of 28%. Compound 66...1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.00(d,J=2.4Hz,1H),7.50(t,J=8.0Hz,1H),7.39(d,J=7.0Hz,1H),7.33–7.24(m,2H),6.87(d,J=2.1Hz,1H),6.82( HRMS m / z(ESI)calcd for C 23 H 22 FN3O[M+H] + 376.4549 found 376.4546.

[0288] Example 67, Synthesis of Compound 67

[0289]

[0290] Compound 67 was prepared using a synthetic method similar to that in Example 44, with a yield of 30%. Compound 67... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.00(s,1H),7.62(ddd,J=8.6,5.5,2.6Hz,2H),7.28(td,J=8.8,2.7Hz,2H),6.93(d,J=3.0Hz,1H),6.82(d,J= HRMS m / z(ESI)calcd for C 23 H 22 FN3O[M+H] + 376.4549 found 376.4552.

[0291] Example 68, Synthesis of Compound 68

[0292]

[0293] Compound 68 was prepared using a synthetic method similar to that in Example 44, with a yield of 33%. Compound 68... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.01(d,J=3.0Hz,1H),7.63–7.54(m,2H),7.46(td,J=7.9,3.2Hz,2H),6.96(s,1H),6.83(dd,J=7.9,2.9Hz HRMS m / z(ESI)calcd for C 23 H 22 ClN3O[M+H] + 392.9065 found 392.9067.

[0294] Example 69, Synthesis of Compound 69

[0295]

[0296] Compound 69 was prepared using a synthetic method similar to that in Example 44, with a yield of 30%. Compound 69... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO-d6) δ7.99(d,J=2.4Hz,1H),7.46–7.30(m,3H),7.16(d,J=7.4Hz,1H),6.96(s,1H),6.82(dd,J=7.5,2.8Hz,1H),6.68–6.54(m, HRMS m / z(ESI)calcd for C 24 H 25 N3O[M+H] + 372.4915 found 372.4919.

[0297] Example 70, Synthesis of Compound 70

[0298]

[0299] Compound 70 was prepared using a synthetic method similar to that in Example 44, with a yield of 26%. Compound 70... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.00 (s, 1H), 7.42 (s, 1H), 7.36 (q, J = 7.3Hz, 2H), 7.22 (d, J = 5.8Hz, 1H), 6.93 (s,1H),6.83(d,J=7.8Hz,1H),6.63(d,J=7.6Hz,1H),6.57(d,J=10.2Hz,2H),6.51(t,J=7.3Hz,1 H),5.64(s,1H),4.27(s,2H),2.94(dd,J=15.2,9.8Hz,3H),2.80(t,J=9.6Hz,2H),2.45(t,J=10. 6Hz,1H),2.36(t,J=10.7Hz,1H),2.24(s,4H),1.26(d,J=6.8Hz,6H),1.04(d,J=5.4Hz,3H).HRMS m / z(ESI)calcd forC 28 H 34 N4[M+H] + 427.2857 found: 427.2853.

[0300] Example 71, Synthesis of Compound 71

[0301]

[0302] Compound 71 was prepared using a synthetic method similar to that in Example 44, with a yield of 31%. Compound 71... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.00(s,1H),7.43(s,1H),7.42–7.33(m,2H),7.23(d,J=7.1Hz,1H),6.95(s,1H),6.83(d,J=7.6Hz,1H),6 .64–6.54(m,3H),6.50(t,J=7.7Hz,1H),5.63(s,1H),4.28(s,2H),3.77(s,4H),2.88(s,4H),1.26(dd,J=7.0,2.2Hz,7H).HRMS m / z(ESI)calcd for C 26 H 29 N3O[M+H] +400.5455 found 400.5453.

[0303] Example 72, Synthesis of Compound 72

[0304]

[0305] Compound 72 was prepared using a synthetic method similar to that in Example 44, with a yield of 27%. Compound 72... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.97(d,J=3.0Hz,1H),7.34(td,J=7.9,3.0Hz,1H),7.14(d,J=7.8Hz,1 H),7.09(d,J=2.3Hz,1H),6.98–6.93(m,1H),6.90(dt,J=8.1,2.8Hz,1H),6.85–6.78(m,1H) ,6.64–6.54(m,3H),6.53–6.47(m,1H),5.63(d,J=3.6Hz,1H),4.28(d,J=3.3Hz,2H),4.08( qd,J=7.0,3.1Hz,2H),3.76(s,4H),2.87(m,J=3.9Hz,4H),1.35(td,J=7.0,3.0Hz,3H).HRMS m / z(ESI)calcd for C 25 H 27 N3O2[M+H] + 402.5175 found 402.5179.

[0306] Example 73, Synthesis of Compound 73

[0307]

[0308] Compound 73 was prepared using a synthetic method similar to that in Example 44, with a yield of 25%. Compound 72... 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO-d6) δ7.97(d,J=2.2Hz,1H),7.34(td,J=8.0,2.3Hz,1H),7.13(d,J=7.8 Hz,1H),7.07(q,J=2.2Hz,1H),6.95(d,J=2.3Hz,1H),6.91(dd,J=6.6,4.0Hz,1H),6.82(d, J=7.7Hz,1H),6.65–6.55(m,3H),6.51(t,J=7.5Hz,1H),5.64(d,J=3.6Hz,1H),4.76–4.62 (m,1H),4.28(d,J=3.6Hz,2H),3.77(s,4H),2.88(s,4H),1.30(dd,J=6.0,2.3Hz,6H).HRMS m / z(ESI)calcd for C 26 H 29 N3O2[M+H] + 416.5445 found 416.5448.

[0309] Example 74, Synthesis of Compound 74

[0310]

[0311] Compound 74 was prepared using a synthetic method similar to that in Example 2, with a yield of 40%. Compound 74... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.54(t,J=7.5Hz,2H),7.48(d,J=7.7Hz,2H),7.42(t,J=7.0Hz,1H),7.12(t,J=7.8Hz ,2H),6.88(d,J=8.0Hz,1H),6.68(t,J=7.3Hz,1H),5.89(s,1H),4.27(d,J=2.2Hz,2H),2.17(s,3H).HRMS m / z(ESI)calcd forC 17 H 15 N3S[M+H] + 294.1060 found: 294.1054.

[0312] Example 75, Synthesis of Compound 75

[0313]

[0314] Compound 75 was prepared using a synthetic method similar to that in Example 37, with a yield of 28%. Compound 75...1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.84 (s, 1H), 7.51 (d, J = 4.8Hz, 4H), 7.35 (dt, J = 8.8, 4.4Hz, 1H), 6.99 (dd, J = 6.9, 2. 0Hz,1H),6.85(dd,J=5.9,2.9Hz,1H),6.68(m,2H),5.44(s,1H),3.89(d,J=1.8Hz,2H),2.05(s,3H).HRMS m / z(ESI)calcd for C 17 H 16 N4[M+H] + 277.1448 found: 277.1440.

[0315] Example 76, Synthesis of Compound 76

[0316]

[0317] Compound 76 was prepared using a synthetic method similar to that in Example 37, with a yield of 31%. Compound 76... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.14(s,1H),7.63(m,1H),7.52(d,J=3.5Hz,4H),7.37(m,1H),7.33(d,J= 8.0Hz,1H),6.70(dd,J=7.8,4.6Hz,1H),6.00(s,1H),3.99(d,J=2.9Hz,2H),2.08(s,3H).HRMS m / z(ESI)calcd for C 16 H 15 N5[M+H] + 278.1401 found: 278.1396.

[0318] Example 77, Synthesis of Compound 77

[0319]

[0320] Compound 77 was prepared using a synthetic method similar to that in Example 37, with a yield of 35%. Compound 77... 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ7.68(s,1H),7.51(d,J=4.2Hz,4H),7.35(dt,J=8.1,4.2Hz,1H),6.87(d,J=7.8Hz,1H),6. 66(d,J=6.6Hz,1H),6.61(t,J=7.5Hz,1H),4.81(s,1H),3.96(d,J=1.4Hz,2H),2.21(s,3H),2.05(s,3H).HRMS m / z(ESI)calcd forC 18 H 18 N4[M+H] + 291.1605 found: 291.1598.

[0321] Example 78, Synthesis of Compound 78

[0322]

[0323] Compound 78 was prepared using a synthetic method similar to that in Example 37, with a yield of 47%. Compound 78... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.72(d,J=2.6Hz,1H),7.51(t,J=3.3Hz,4H),7.35(td,J=5.0,2.3Hz,1H),6.88(dd,J=7.9,2.7Hz,1H),6. 67(s,1H),6.50(d,J=8.0Hz,1H),5.35(s,1H),3.88(s,2H),2.14(d,J=2.3Hz,3H),2.04(d,J=3.0Hz,3H).HRMSm / z(ESI)calcd for C 18 H 18 N4[M+H] + 291.1605 found: 291.1598.

[0324] Example 79, Synthesis of Compound 79

[0325]

[0326] Compound 79 was prepared using a synthetic method similar to that in Example 37, with a yield of 47%. Compound 79... 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ7.72(s,1H),7.51(m,4H),7.35(s,1H),6.82(s,1H),6.75(d,J=7.8 Hz,1H),6.49(d,J=7.8Hz,1H),5.29(s,1H),3.86(s,2H),2.11(s,3H),2.04(s,3H).HRMS m / z(ESI)calcd for C 18 H 18 N4[M+H] + 291.1605 found: 291.1597.

[0327] Example 80, Synthesis of Compound 80

[0328]

[0329] Compound 80 was prepared using a synthetic method similar to that in Example 37, with a yield of 47%. Compound 80... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.63(d,J=8.0Hz,2H),7.54(t,J=7.1Hz,2H),7.38(t,J=7.3Hz,1H),6.80(m ,1H),6.68(d,J=5.3Hz,3H),5.40(s,1H),3.89(s,2H),2.12(s,3H),2.07(d,J=1.3Hz,3H).HRMS m / z(ESI)calcd for C 18 H 18 N4[M+H] + 291.1605 found: 291.1598.

[0330] Example 81, Synthesis of Compound 81

[0331]

[0332] Compound 81 was prepared using a synthetic method similar to that in Example 37, with a yield of 47%. Compound 81... 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ8.08(s,1H),7.51(d,J=2.6Hz,4H),7.37(d,J=3.4Hz,1H),6.93(d,J=11.3H z,1H),6.86(t,J=6.1Hz,1H),6.50(t,J=8.2Hz,1H),5.46(s,1H),3.87(s,2H),2.05(s,3H).HRMS m / z(ESI)calcd for C 17 H 15 FN4[M+H] + 295.1354 found: 295.1348.

[0333] Example 82, Synthesis of Compound 82

[0334]

[0335] Compound 82 was prepared using a synthetic method similar to that in Example 37, with a yield of 47%. Compound 82... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.82(d,J=2.2Hz,1H),7.50(d,J=3.2Hz,4H),7.36(m,1H),6.78(dd,J=8.5,2.9Hz,1H ),6.71(d,J=2.7Hz,1H),6.30(d,J=8.5Hz,1H),5.15(s,1H),3.83(s,2H),3.60(s,3H),2.03(s,3H).HRMS m / z(ESI)calcd forC 18 H 18 N4O[M+H] + 307.1554 found: 307.1547.

[0336] Example 83, Synthesis of Compound 83

[0337]

[0338] Compound 83 was prepared using a synthetic method similar to that in Example 37, with a yield of 24%. Compound 83... 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ7.80(s,1H),7.56–7.48(m,4H),7.39–7.32(m,1H),7.02–6.95(m,1H),6.84(dd,J=5.8,2.9Hz ,1H),6.68(dd,J=6.4,2.9Hz,2H),5.43(s,1H),3.95(s,2H),2.90–2.78(m,1H),1.19(dd,J=6.8,2.6Hz,6H).HRMS m / z(ESI)calcdfor C 19 H 20 N4[M+H] + 305.1761 found: 305.1755.

[0339] Example 84, Synthesis of Compound 84

[0340]

[0341] Compound 84 was prepared using a synthetic method similar to that in Example 37, with a yield of 26%. Compound 84... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ7.81(s,1H),7.54–7.46(m,4H),7.34(dt,J=6.5,4.9Hz,1H),6.98(dd,J=4.9,2.6Hz,1H),6.85(dd,J=4.6,2. 7Hz,1H),6.72–6.64(m,2H),5.47(s,1H),4.01(s,2H),1.73(d,J=5.0Hz,1H),0.80(dd,J=5.9,2.4Hz,2H),0.76–0.69(m,2H).HRMS m / z(ESI)calcd for C 19 H 18 N4[M+H] + 303.1605 found: 303.1600.

[0342] Example 85, Synthesis of Compound 85

[0343]

[0344] Compound 85 was prepared using a synthetic method similar to that in Example 37, with a yield of 32%. Compound 85... 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ7.98(s,1H),7.63(d,J=8.1Hz,2H),7.60–7.54(m,4H),7.44(q,J=7.0Hz,3H),7.37(t,J=7 .3Hz,1H),7.04(d,J=7.1Hz,1H),6.85(d,J=6.5Hz,1H),6.72(p,J=8.0Hz,2H),5.48(s,1H),4.14(s,2H).HRMS m / z(ESI)calcdfor C 22 H 18 N4[M+H] + 339.1605 found: 339.1600.

[0345] Example 86, Synthesis of Compound 86

[0346]

[0347] Compound 86 was prepared using a synthetic method similar to that in Example 37, with a yield of 45%. Compound 86... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.85 (s, 1H), 8.06 (d, J = 8.0Hz, 2H), 7.43 (m, 4H), 7.16 (d, J = 7.5Hz, 2H), 6.7 7(d,J=7.6Hz,1H),6.69(t,J=7.4Hz,1H),6.63(t,J=7.3Hz,1H),5.78(s,1H),4.05(s,2H).HRMS m / z(ESI)calcd for C 18 H 15 N3[M+H] + 274.1339 found: 274.1335.

[0348] Example 87, Synthesis of Compound 87

[0349]

[0350] Compound 87 was prepared using a synthetic method similar to that in Example 37, with a yield of 42%. Compound 87... 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ8.53(s,1H),7.62(d,J=6.6Hz,2H),7.47(t,J=6.4Hz,2H),7.38(dd,J=7.5,5.5Hz,1H),7.08(s,1H ),6.90(d,J=7.2Hz,1H),6.72(dt,J=13.9,8.6Hz,3H),6.60(t,J=6.7Hz,1H),5.72(d,J=2.1Hz,1H),4.18(s,2H).HRMS m / z(ESI)calcd for C 19 H 15 FN2[M+H] + 291.1293 found: 291.1287.

[0351] Example 88, Synthesis of Compound 88

[0352]

[0353] Compound 88 was prepared using a synthetic method similar to that in Example 37, with a yield of 33%. Compound 88... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.14(s,1H),7.54–7.43(m,4H),7.38(t,J=6.4Hz,1H),7.06–6.94(m,2H),6.82(d,J=7. 8Hz,1H),6.69(d,J=7.6Hz,1H),6.63(t,J=7.4Hz,1H),6.52(t,J=7.3Hz,1H),5.65(s,1H),4.11(s,2H).HRMS m / z(ESI)calcd forC 19 H 15 FN2[M+H] + 291.1293 found: 291.1288.

[0354] Example 89, Synthesis of Compound 89

[0355]

[0356] Compound 89 was prepared using a synthetic method similar to that in Example 37, with a yield of 39%. Compound 89... 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ7.62(s,1H),7.56(d,J=7.1Hz,2H),7.51(t,J=6.7Hz,2H),7.43(t,J=6.6Hz,1 H),7.20(d,J=7.7Hz,1H),6.96(d,J=7.4Hz,1H),6.80–6.60(m,4H),5.77(s,1H),4.21(s,2H).HRMS m / z(ESI)calcd for C 19 H 15 FN2[M+H] + 291.1293 found: 291.1288.

[0357] Example 90, Synthesis of Compound 90

[0358]

[0359] Compound 90 was prepared using a synthetic method similar to that in Example 44, with a yield of 27%. Compound 90... 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.01(s,1H),7.59(d,J=7.7Hz,2H),7.45(t,J=7.6Hz,2H),7.34(t,J=7.2Hz,1H),6.97(s,1H),6.84(d,J=7. 7Hz,1H),6.59(dd,J=18.6,9.7Hz,3H),6.51(t,J=7.3Hz,1H),5.64(s,1H),4.30(s,2H),3.77(s,4H),2.88(d,J=3.9Hz,4H).HRMS m / z(ESI)calcd for C 23 H 23 N3O[M+H] + 358.1914 found: 358.1906.

[0360] Example 91, Synthesis of Compound 91

[0361]

[0362] Compound 91 was prepared using a synthetic method similar to that in Example 44, with a yield of 25%. Compound 91... 1 The HNMR and HRMS data are as follows: 1H NMR (400MHz, DMSO) δ8.03(s,1H),7.40(t,J=7.9Hz,1H),7.20(d,J=7.7Hz,1H),7.14(s,1 H),7.01–6.94(m,2H),6.87(d,J=7.6Hz,1H),6.65(dd,J=19.6,9.4Hz,3H),6.55(t,J=7.3 Hz,1H),5.69(s,1H),4.31(s,2H),3.86(s,3H),2.99(t,J=12.6Hz,2H),2.85(t,J=9.5Hz ,2H),2.53–2.46(m,1H),2.40(t,J=10.5Hz,1H),2.29(s,4H),1.08(d,J=6.1Hz,3H).HRMS m / z(ESI)calcd for C 26 H 30 N4O[M+H] + 415.2493 found: 415.2488.

[0363] Example 92, Synthesis of Compound 92

[0364]

[0365] Compound 92 was prepared using a synthetic method similar to that in Example 44, with a yield of 31%. 1 The HNMR and HRMS data are as follows: 1 H NMR (400MHz, DMSO) δ8.01(s,1H),7.82(s,1H),7.73(d,J=7.4Hz,2H),7.65–7.58(m,2H),7.55(d,J=7.5Hz,1H ),7.50(t,J=7.7Hz,2H),7.40(t,J=7.3Hz,1H),7.04(s,1H),6.83(d,J=7.3Hz,1H),6.69(s,1H),6.64(d,J=7 .6Hz,1H),6.59(t,J=6.9Hz,1H),6.52(t,J=6.9Hz,1H),5.66(s,1H),4.29(s,2H),2.96(t,J=13.1Hz,2H),2. 83(t,J=11.9Hz,2H),2.47(d,J=10.6Hz,1H),2.37(t,J=9.9Hz,1H),2.24(s,4H),1.04(d,J=6.1Hz,3H).HRMS m / z(ESI)calcd for C 31 H 32 N4[M+H]+ 461.2700 found: 461.2699.

[0366] The following specific experimental examples demonstrate the beneficial effects of the present invention.

[0367] Experimental Example 1: Study on the inhibitory rate of the compound of the present invention on Ferrottosis

[0368] 1. Experimental Methods

[0369] The Ferroptosis screening model primarily employs the MTT assay for cell viability. Ovarian cancer cell line ES-2 was collected and seeded into 96-well plates at a density of 3000 cells per well. After incubation at 37°C and 5% CO2 for 24 hours to confirm cell adhesion, different concentrations of the test compound and the ferroptosis inducer erastin (15 or 30 μM) were added to each well. Three replicates were set for each compound to ensure accuracy, and a positive control (Fer 10 μM), a blank control, and a solvent control were included. After 48 hours of treatment, cell viability was assessed using the MTT assay. The absorbance at 560 nm was measured using a microplate reader to calculate the inhibition rate of the drug against Ferroptosis. Generally, the absorbance value of the control group should be between 0.8 and 1.2 to be considered normal. After obtaining the absorbance data, the average of the three replicates was calculated, and the inhibition rate was calculated using the following formula:

[0370] Inhibition rate (IR) = [1 - (A experimental group - A blank) / (A solvent - A blank)] * 100%

[0371] The inhibition rate variation curve was fitted using GraphPad Prism 5 software, and the EC was calculated. 50 .

[0372] 2. Experimental Results

[0373] EC was performed on 92 compounds prepared in the examples. 50 EC test 50 The test result is the average of three tests (Fer-1 is the positive control group). The results are shown in the table below:

[0374] Table 1 EC of the compounds of the present invention 50 value

[0375]

[0376]

[0377] Table 1 shows that the compounds prepared in this invention have good inhibitory effects on ferroptosis and can be used to prepare ferroptosis inhibitors. Furthermore, most compounds showed better inhibitory effects on ferroptosis than the positive control group (Fer-1), with compounds 44, 48, 51, 58–63, 68, 70, 91, and 92 exhibiting particularly high EC50 values. 50 The EC50 value is less than 0.01 μM, and the EC50 of compound 59 is... 50 The value can reach 0.0008 μM.

[0378] Experimental Example 2: Study on the in vitro protection of cells from ferroptosis by the compound of this invention.

[0379] This experiment uses compound 59 as an example to study the in vitro protective activity of the compound of the present invention against ferroptosis.

[0380] 1. Experimental Methods

[0381] Cell viability was assessed using the MTT assay. First, ES2, AC16, HT1080, and PANC-1 cells were collected and seeded into 96-well plates at a concentration of 3000 cells per well. Cells were incubated at 37°C with 5% CO2 until adherence. After adherence, cells were treated with a specified concentration of a compound for 48 hours. Cell viability was assessed using the MTT assay. Finally, absorbance was measured at 560 nm using a multi-mode microplate reader. All data were calculated using GraphPad Prism software. All experiments were repeated three times.

[0382] 2. Experimental Results

[0383] In vitro, compound 59 can protect ES-2 (ovarian cancer cells), AC16 (human cardiomyocytes), HT1080 (human fibrosarcoma cell line), and PANC-1 (human pancreatic cancer cell line) from ferroptosis. Figure 1 The above results indicate that the compounds of the present invention can effectively protect cells from ferroptosis and can be applied to the treatment of ferroptosis-related diseases.

[0384] In summary, this invention synthesizes a class of compounds with good inhibitory effects on ferroptosis, which can be used to prepare ferroptosis inhibitors. They can also be used to prepare drugs for treating ferroptosis-related ischemia-reperfusion injury, drug-induced liver injury, acute kidney injury, kidney failure, liver and lung fibrosis, neurodegenerative diseases, stroke, myocarditis, myocardial infarction, heart failure, arthritis, chronic atrophic gastritis, and other diseases, and have broad market prospects.

Claims

1. The compound shown in Formula I, or a salt thereof, characterized in that, The structural formula of the compound is: in, In the diagram, when there is no dashed line, it represents a single bond; when there is a dashed line, it represents a double bond. A is selected from O, S, and NH; R 1 Selected from hydrogen, halogens, C 1～5 Alkyl, L 2 L 2 'R';L 2 Selected from none, C 1～5 Alkylene, phenyl; L 2 R′ is selected from none, -C(O)-; R′ is selected from unsubstituted or substituted by 1 to 3 Rs. A Substituted groups include: 3-6 membered saturated cycloalkyl groups, 3-6 membered saturated heterocyclic groups, 5-10 membered aromatic rings, and 5-10 membered heteroaromatic rings; R A Each is independently selected from halogens, C 1～5 Alkyl, C 1～5 Alkoxy, -NR C R D ; L is selected from none, C 1～5 Alkylene, phenyl, -C(O)-; The B ring is selected from 5-10 member aromatic rings, 5-10 member heteroaromatic rings, and 3-6 member saturated heterocycles; R 2 Each is independently selected from hydrogen and C. 1～5 Alkyl, C 1～5 Alkoxy, halogen, L 3 R″;L 3 Selected from none, -C(O)-; R″ selected from unsubstituted or substituted by 1 to 3 Rs B Substituted groups include: 3-6 membered saturated heterocycles, 5-10 membered aromatic rings, and 5-10 membered heteroaromatic rings; R B Each is independently selected from C 1～5 Alkyl, C 1～5 Alkoxy, -NR C R D ;R C R D Each is independently selected from hydrogen and C. 1～5 alkyl; n is selected from 1, 2, or 3; The C ring is selected from 5-10 quinary aromatic rings and 5-10 heterocyclic aromatic rings; R 3 Selected from hydrogen, halogens, C 1～5 Alkoxy, C 1～5 Alkyl, halogen-substituted C 1～5 Alkyl, -SO2NHR 5 L 4 R E , cyano; R 5 Selected from C 1～5 Alkyl; L 4 Selected from phenyl or phenyl; R E Selected from those that have not been replaced or have been replaced by 1 to 3 Rs F Substituted phenyl groups, 3- to 6-membered saturated heterocycles; R F Each is independently selected from C 1～5 Alkyl groups, 3- to 6-membered saturated heterocycles; D is selected from CH and N.

2. The compound or its salt according to claim 1, characterized in that, A is selected from O, S, and NH; R 1 Selected from hydrogen, halogens, C 1～3 Alkyl, L 2 L 2 'R';L 2 Selected from none, C 1～3 Alkylene, phenyl; L 2 R′ is selected from none, -C(O)-; R′ is selected from unsubstituted or substituted by 1 to 3 Rs. A The following groups are substituted: 3-6 membered saturated cycloalkyl groups, 3-6 membered saturated heterocyclic groups, 5-10 membered aromatic rings, 5-10 membered heteroaromatic rings, preferably: phenyl groups. R A Each is independently selected from halogens, C 1～3 Alkyl, C 1～3 Alkoxy, -NR C R D ; L is selected from none, C 1～3 Alkylene, phenyl, -C(O)-; Ring B is selected from 5-10 membered aromatic rings, 5-10 membered heteroaromatic rings, and 3-6 membered saturated heterocycles, preferably phenyl rings. R 2 Each is independently selected from hydrogen and C. 1～3 Alkyl, C 1～3 Alkoxy, halogen, L 3 R″;L 3 Selected from none, -C(O)-; R″ selected from unsubstituted or substituted by 1 to 3 Rs B The following groups are substituted: 3-6 membered heterocycles, 5-10 membered aromatic rings, 5-10 membered heteroaromatic rings, preferably phenyl. R B Each is independently selected from C 1～3 Alkyl, C 1～3 Alkoxy, -NR C R D ;R C R D Each is independently selected from hydrogen and C. 1～3 alkyl; n is selected from 1, 2, or 3; The C ring is selected from phenyl, R 3 Selected from hydrogen, halogens, C 1～3 Alkoxy, C 1～3 Alkyl, halogen-substituted C 1～3 Alkyl, -SO2NHR 5 L 4 R E , cyano; R 5 Selected from C 1～3 Alkyl; L 4 Selected from phenyl or phenyl; R E Selected from those that have not been replaced or have been replaced by 1 to 3 Rs F Substituted phenyl groups, 3- to 6-membered saturated heterocycles; R F Each is independently selected from C 1～3 Alkyl groups, 3- to 6-membered saturated heterocycles; D is selected from CH and N.

3. The compound or its salt according to claim 2, characterized in that, The compound is shown in Formula II: in, In the diagram, when there is no dashed line, it represents a single bond; when there is a dashed line, it represents a double bond. A, B, L, R 1 R 2 R 3 As described in claim 2.

4. The compound or its salt according to claim 3, characterized in that, The compound is shown in Formula III: in, In the diagram, when there is no dashed line, it represents a single bond; when there is a dashed line, it represents a double bond. A, L, R 1 R 2 R 3 As described in claim 3.

5. The compound or its salt according to claim 2, characterized in that, The compound is shown in Formula IV: in, In the diagram, when there is no dashed line, it represents a single bond; when there is a dashed line, it represents a double bond. A, B, L, R 1 R 2 R 3 As described in claim 2.

6. The compound or its salt according to claim 5, characterized in that, The compound is shown in formula V: in, In the diagram, when there is no dashed line, it represents a single bond; when there is a dashed line, it represents a double bond. A, L, R 1 R 2 R 3 As described in claim 5.

7. The compound or salt thereof according to any one of claims 1 to 6, characterized in that, The compound is selected from one of the following compounds:

8. Use of the compound of any one of claims 1 to 7, or a salt thereof, in the preparation of ferroptosis inhibitors, medicaments for the prevention and / or treatment of ferroptosis-related diseases.

9. The use according to claim 8, characterized in that, The diseases associated with ferroptosis are ischemia-reperfusion injury, drug-induced liver injury, acute kidney injury, kidney failure, hepatic or pulmonary fibrosis, neurodegenerative diseases, stroke, myocarditis, myocardial infarction, heart failure, arthritis, or chronic atrophic gastritis.

10. A pharmaceutical composition, characterized in that, The pharmaceutical composition is a formulation prepared by adding pharmaceutically acceptable excipients to the compound or salt thereof as the active ingredient according to any one of claims 1 to 7.

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