A class of compounds and their use in treating SOS1-mediated diseases

Abstract

This invention belongs to the field of pharmaceutical technology, specifically relating to a class of compounds and their use in treating SOS1-mediated diseases. This invention provides a class of compounds having the structure shown in Formula I. The compounds with the structure shown in Formula I provided by this invention exhibit excellent binding affinity for the SOS1 protein and can be used to treat various SOS1-mediated tumor diseases. Formula I.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a class of compounds and their use in treating SOS1-mediated diseases. Background Technology

[0002] Kirsten rat sarcoma virus oncogene homolog (KRAS) is a guanine nucleotide-binding protein with guanosine triphosphatase activity. It regulates nucleotide cycling by binding GDP or GTP, achieving dynamic functional switching. KRAS mutations drive approximately one-seventh of human cancers, primarily including 90% of pancreatic ductal adenocarcinomas, 44% of colorectal cancers, and 29% of non-small cell lung cancers. KRAS mutations lead to the accumulation of KRAS-GTP, further activating downstream signaling pathways and promoting tumor growth, division, and proliferation. Son of Sevenless Homolog 1 (SOS1) is a guanine nucleotide exchanger involved in regulating the KRAS nucleotide cycle. SOS1 converts KRAS to its active state by dissociating KRAS-GDP and promoting GTP loading. Activated KRAS-GTP participates in the interaction of various downstream effector proteins, thereby affecting tumor cell survival. SOS1 plays a crucial role in the initiation, maintenance, and development of KRAS-driven tumors, and its high expression is associated with low patient survival rates. The deletion or knockout of SOS1 significantly reduced tumor volume and weight in pathological animal models carrying KRAS mutations, a phenomenon not observed in KRAS wild-type models, indicating that SOS1 is a relatively safe target. Since the KRAS mutation sites and the SOS1-KRAS binding interface do not overlap, SOS1 can broadly target multiple KRAS mutants, providing a mechanistic basis for targeting specific and multi-site KRAS mutants. Furthermore, inhibiting SOS1 can address the problem of tumor drug resistance caused by the upregulation of upstream RTK and other signaling pathways. Currently, SOS1 is an important target for treating KRAS-driven tumors. However, there are few reports on SOS1 inhibitors, and a lack of organic compounds with excellent binding affinity to the SOS1 protein. Summary of the Invention

[0003] The purpose of this invention is to provide a class of compounds and their use in treating SOS1-mediated diseases. The compounds provided by this invention exhibit excellent binding affinity to the SOS1 protein and can be used to treat a variety of SOS1-mediated tumor diseases, showing significant effects in treating KRAS-driven tumors.

[0004] To achieve the above objectives, the present invention provides the following technical solution: This invention provides a class of compounds having the structure shown in Formula I: Formula I; R4 in Equation I is selected from Naphthyl or C3-10 cycloalkyl; X, Y, and Z are independently selected from C or N, and R2 is selected from substituted or unsubstituted cyclohexenyl, hydrogen, C1-20 alkyl, halogen, cyano, methyl formate, halogen-substituted C1-10 alkyl, C1-10 alkoxy, methanesulfonyl, cyclopentenyl, cyclohexenone, phenyl, naphthyl, furanyl, thiophene, 3,6-dihydrothiopyranyl, 3,6-dihydro-2H-thiophenopyranyl, substituted or unsubstituted 1,2,3,6-tetrahydropyridyl or 3,6-dihydropyranyl. The substituent of the substituted cyclohexenyl is selected from halogen, C1-10 alkyl or halogen-substituted C1-10 alkyl, and the substituent on the substituted 1,2,3,6-tetrahydropyridyl is selected from formyl, benzyl or toluenesulfonyl. R1 is selected from substituted or unsubstituted 4-10 membered heterocyclic groups, hydrogen, C1-20 alkyl, C1-20 alkoxy, or substituted amino groups. The heteroatoms on the substituted or unsubstituted 4-10 membered heterocyclic groups are selected from one or more of N, O, and S. The number of heteroatoms is 1 to 3, and the heteroatoms can be the same or different. The substituents on the substituted 4-10 membered heterocyclic groups are selected from one or more of hydroxyl, C1-10 alkoxy, halogen, cyano, and C1-10 alkyl. The substituents on the substituted amino groups are selected from C1-10 alkyl or amino-substituted C1-10 alkyl. R3 is selected from C1-10 alkyl, C1-10 alkoxy, 5-8 member nitrogen heterocyclic group, C1-10 alkyl-substituted amino group or hydrogen.

[0005] The compounds of Formula I provided by this invention exhibit excellent binding affinity to the SOS1 protein and can be used to treat a variety of SOS1-mediated tumor diseases, showing significant effects in the treatment of KRAS-driven tumors. Attached Figure Description

[0006] Figure 1 The results show the activity assays of compounds H2 and H3 in the HCT116 cell xenograft tumor model. Figure 2 The flowchart shows the preparation process of the compound with the structure shown in Formula I provided by this invention. Detailed Implementation

[0007] This invention provides a class of compounds having the structure shown in Formula I: Formula I; R4 in Equation I is selected from Naphthyl or C3-10 cycloalkyl; X, Y, and Z are independently selected from C or N, and R2 is selected from substituted or unsubstituted cyclohexenyl, hydrogen, C1-20 alkyl, halogen, cyano, methyl formate, halogen-substituted C1-10 alkyl, C1-10 alkoxy, methanesulfonyl, cyclopentenyl, cyclohexenone, phenyl, naphthyl, furanyl, thiophene, 3,6-dihydrothiopyranyl, 3,6-dihydro-2H-thiophenopyranyl, substituted or unsubstituted 1,2,3,6-tetrahydropyridyl or 3,6-dihydropyranyl. The substituent of the substituted cyclohexenyl is selected from halogen, C1-10 alkyl or halogen-substituted C1-10 alkyl, and the substituent on the substituted 1,2,3,6-tetrahydropyridyl is selected from formyl, benzyl or toluenesulfonyl. R1 is selected from substituted or unsubstituted 4-10 membered heterocyclic groups, hydrogen, C1-20 alkyl, C1-20 alkoxy, or substituted amino groups. The heteroatoms on the substituted or unsubstituted 4-10 membered heterocyclic groups are selected from one or more of N, O, and S. The number of heteroatoms is 1 to 3, and the heteroatoms can be the same or different. The substituents on the substituted 4-10 membered heterocyclic groups are selected from one or more of hydroxyl, C1-10 alkoxy, halogen, cyano, and C1-10 alkyl. The substituents on the substituted amino groups are selected from C1-10 alkyl or amino-substituted C1-10 alkyl. R3 is selected from C1-10 alkyl, C1-10 alkoxy, 5-8 member nitrogen heterocyclic group, C1-10 alkyl-substituted amino group or hydrogen.

[0008] In this invention, R4 is preferably selected from substituted or unsubstituted phenyl, C3-6 cycloalkyl, pyridyl, or naphthyl. In R4, the C3-10 cycloalkyl group is preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0009] In this invention, in R4: the pyridyl group can be 2-pyridyl, 3-pyridyl, or 4-pyridyl. The naphthyl group is an alpha-substituted or beta-substituted naphthyl group. The substituents on the substituted phenyl group are preferably selected from substituted or unsubstituted cyclohexenyl, C1-20 alkyl, halogen, cyano, methyl formate, halogen-substituted C1-10 alkyl, C1-10 alkoxy, methanesulfonyl, cyclopentenyl, and cyclohexenone (in the examples, these can be...) ), phenyl, naphthyl, furanyl, thiophene, 3,6-dihydrothiopyranyl (in the examples, it can be ) ), 3,6-dihydro-2H-thiophenopyranyl (in the examples, it can be ) The substituted or unsubstituted 1,2,3,6-tetrahydropyridyl or 3,6-dihydropyranyl groups are used. Among the substituents on the substituted phenyl group: C1-20 alkyl groups are preferably C1-15 alkyl groups, more preferably C1-10 alkyl groups, and in the examples, they can be methyl, ethyl, n-propyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, pentyl, or hexyl. The halogen is preferably selected from F, Cl, Br, or I. The halogen-substituted C1-10 alkyl group is preferably a halogen-substituted C1-5 alkyl group, and in the examples, it can be halogen-substituted methyl, halogen-substituted ethyl, halogen-substituted n-propyl, halogen-substituted cyclopropyl, halogen-substituted n-butyl, halogen-substituted isobutyl, halogen-substituted tert-butyl, halogen-substituted pentyl, or halogen-substituted hexyl. The halogen on the halogen-substituted C1-10 alkyl group is preferably selected from F, Cl, Br, or I, and in the examples, it can be trifluoromethyl. The C1-10 alkoxy group is preferably selected from methoxy, ethoxy, cyclopropyloxy, or cyclobutyloxy.

[0010] In this invention, the substituent of the substituted cyclohexenyl group is preferably selected from one or more of halogens, C1-10 alkyl groups, and halogen-substituted C1-10 alkyl groups, more preferably halogens, C1-10 alkyl groups, or halogen-substituted C1-10 alkyl groups. Among the substituents of the substituted cyclohexenyl group: the halogen is preferably selected from F, Cl, Br, or I. The C1-10 alkyl group can be methyl, ethyl, n-propyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, pentyl, or hexyl. The halogen-substituted C1-10 alkyl group is preferably a halogen-substituted C1-5 alkyl group, and in the examples, it can be halogen-substituted methyl, halogen-substituted ethyl, halogen-substituted n-propyl, halogen-substituted cyclopropyl, halogen-substituted n-butyl, halogen-substituted isobutyl, halogen-substituted tert-butyl, halogen-substituted pentyl, or halogen-substituted hexyl.

[0011] In this invention, the substituents on the substituted 1,2,3,6-tetrahydropyridyl group are preferably selected from one or more of formyl, benzyl and toluenesulfonyl groups.

[0012] In this invention, the substituents on the substituted phenyl group are preferably selected from substituted or unsubstituted cyclohexenyl, methyl, F, Cl, cyano, methyl formate, trifluoromethyl, methoxy, methylsulfonyl, cyclopentenyl, cyclohexenyl, cyclohexenone, phenyl, naphthyl, furanyl, thiophene, 3,6-dihydrothiopyranyl, 3,6-dihydro-2H-thiophenopyranyl, formyl-substituted 1,2,3,6-tetrahydropyridyl, benzyl-substituted 1,2,3,6-tetrahydropyridyl, toluenesulfonyl-substituted 1,2,3,6-tetrahydropyridyl, or 3,6-dihydropyranyl. The substituents on the substituted cyclohexenyl group are selected from one or more of methyl, F, trifluoromethyl, and tert-butyl. The number of substituents on the substituted cyclohexenyl group is 1, 2, 3, or 4. The substituents on the substituted cyclohexenyl group can be the same or different.

[0013] In this invention, In the text: X, Y, and Z are selected from C; R2 can be selected from methyl, ... , , Or any of the following structures: .

[0014] In this invention, R2 is most preferably selected from 3,3,5,5-dimethylcyclohexenyl.

[0015] In this invention, R1 is preferably selected from hydrogen, substituted or unsubstituted tetrahydropyrrole, methoxy, ethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropyl, cyclobutyl, dimethyl-substituted amino, methylethyl-substituted amino ( ), cyclobutyl-substituted amino groups, cyclopentyl-substituted amino groups, cyclohexyl-substituted amino groups, cycloheptyl-substituted amino groups, substituted or unsubstituted 1,2,3,6-tetrahydropyridyl groups, , , , , , , , , , or In this invention, the substituent of the substituted tetrahydropyrrolyl group is preferably a C1-20 alkyl group, more preferably a C1-15 alkyl group, and even more preferably a C1-10 alkyl group. In the examples, it can be methyl, ethyl, n-propyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, pentyl, or hexyl. The substituent on the substituted 1,2,3,6-tetrahydropyridyl group is selected from halogens, methyl, hydroxyl, methoxy, and cyano groups. The halogen is preferably selected from F, Cl, Br, or I.

[0016] In this invention, R3 is preferably selected from... Any one of them.

[0017] In this invention, the compound is preferably selected from any one of the following compounds: .

[0018] The compound of formula I provided by this invention preferably contains R4 ( The compound of Formula I provided by this invention consists of a quinazoline ring and an amino (preferably aniline) structure. The quinazoline core of the compound of Formula I interacts with SOS1 to form a π-π stack. The "NH" group of the amino (preferably aniline) forms a hydrogen bond with Asn879 as the anchor point. The chiral α-methyl group (compound H3) on the aniline occupies the hydrophobic pocket near Met878 of SOS1. 3,3,5,5-dimethylcyclohexene is located in the hydrophobic back pocket of SOS1 and forms a hydrophobic interaction with SOS1.

[0019] This invention provides a method for preparing compounds with the structure shown in Formula I as described in the above-mentioned technical solution. In this invention, when R4 is... When, the preparation route of the compound with the structure shown in Formula I is as follows Figure 2 As shown, with Figure 2 Compound A in R4 is the starting material (i.e., initial material A). When R4 is naphthyl or C3~10 cycloalkyl, the preparation route of the compound with the structure shown in Formula I is the same as... Figure 2 Similar, only Figure 2 The substituents in compound A ( The radical can be replaced with a naphthyl or a C3-10 cycloalkyl group. In this invention, unless otherwise specified, all raw materials / components are commercially available products well-known to those skilled in the art.

[0020] In this invention, when R4 is In this invention, the method for preparing the compound with the structure shown in Formula I preferably includes the following steps: (a) Starting material A is Suzuki coupled with substituted benzene ring, substituted naphthyl ring, substituted 3,6-dihydro-2H-pyran, substituted cyclopentene, substituted cyclohexene, substituted furan, substituted 5,6-dihydro-2H-thiophenopyran, and substituted thiophene, and then hydrolyzed with trifluoroacetic acid to obtain intermediate B.

[0021] After obtaining intermediate B, (b) intermediate B undergoes a substitution reaction with 6-bromoquinazoline or 6-bromo-2-methylquinazoline under alkaline conditions to obtain intermediate C; (c) intermediate C is coupled with a substituted cycloalkyl group containing boric acid via Suzuki coupling, or with an oxygen-containing substituted cycloalkyl group, a nitrogen-containing substituted cycloalkyl group, a nitrogen-containing substituted cycloalkyl group, or a substituted azacycloalkyl group to prepare the final product via Buchwald-Hartwig coupling.

[0022] Alternatively, after obtaining intermediate B, (d) intermediate B undergoes a substitution reaction with 6-bromo-2-chloroquinazoline under basic conditions to obtain intermediate E; (e) intermediate E undergoes a nucleophilic aromatic substitution reaction with CsF to obtain intermediate F; (f) intermediate F reacts with alkyl alcohols, alkylamines, or aziridines under basic conditions to obtain intermediate G; (g) intermediate G undergoes Suzuki coupling with a substituted cycloalkyl group containing boric acid, or Buchwald-Hartwig coupling with an oxygen-containing substituted cycloalkyl group, a nitrogen-containing substituted cycloalkyl group, a nitrogen-containing substituted cycloalkyl group, or a substituted aziridine to prepare the final product.

[0023] In this invention, when R4 is naphthyl or C3~10 cycloalkyl, the substituents in compound A ( Replace ) with naphthyl or C3~10 cycloalkyl, and prepare the final product according to the above steps (a)~(g).

[0024] This invention provides the use of the compounds described above, their isotopes, pharmaceutically acceptable hydrates, solvates, polymorphs, or salts in the preparation of SOS1 inhibitors. The isotopes are compounds with the structure shown in Formula I in which any one or more atoms are substituted with isotopes, preferably deuterium.

[0025] This invention provides the use of the compounds, their isotopes, pharmaceutically acceptable hydrates, solvates, polymorphs, or salts described above in the preparation of medicaments for treating SOS1-mediated diseases. The isotopes are compounds with the structure shown in Formula I in which any one or more atoms are substituted with isotopes, preferably deuterium.

[0026] In this invention, the SOS1-mediated disease preferably includes a tumor. The tumor is a KRAS-driven tumor. In an embodiment of this invention, the tumor may be colorectal cancer.

[0027] This invention provides a drug comprising the compound described in the above-described technical solution, its isotopes, its pharmaceutically acceptable hydrates, solvates, polymorphs or salts, and pharmaceutically acceptable excipients. The isotopes are compounds with the structure shown in Formula I in which any one or more atoms are substituted with isotopes, preferably deuterium.

[0028] To further illustrate the present invention, the technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0029] Example 1: Preparation of representative intermediate B1 The starting materials [(1R)-1-(4-bromophenyl)ethyl] tert-butyl carbamate (1 equiv) and cyclohexen-1-ylboronic acid were added to a two-necked flask, followed by 20 mL of anhydrous DMF. The reaction system was purged twice with N2, and Pd(dppf)Cl2·CH2Cl2 (0.2 equiv) and cesium carbonate (3 equiv) were added under N2 conditions. After the addition was complete, the system was purged three more times with N2. Finally, the reaction was heated to 85 °C under N2 conditions for 12 h. After the reaction was completed by TLC monitoring, the reaction solution was cooled to room temperature, and the system was extracted three times with dichloromethane and water. The organic phases were combined. The organic phases were washed successively with water and saturated brine, and dried with anhydrous sodium sulfate. The desiccant was removed by filtration, and the product was concentrated under reduced pressure and purified by Biotage Isolera Prime equipped with a 200-300 mesh silica gel column. The reaction solution was directly evaporated to dryness to obtain a brown crude product, which was used directly in the next reaction. The crude product was dissolved in 10 mL of anhydrous dichloromethane, and a dichloromethane solution containing trifluoroacetic acid (5 equiv) was added. The reaction was carried out at room temperature for 6 h. After concentration under reduced pressure, the product was purified by Biotage Isolera Prime equipped with a 200-300 mesh silica gel column (dichloromethane (DCM) / methanol (MeOH) = 1:9, v:v) to obtain a brown solid with a yield of 68%. 1 H NMR (400 MHz, CDCl3) δ 8.92 (s, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 5.55-5.45 (m, 1H), 4.12-4.03 (m, 1H), 1.94-1.86(m, 2H), 1.41 (s, 2H), 1.22 (s, 3H), 1.05 (s, 6H), 0.93 (s, 6H). 13 C NMR (100MHz, CDCl3) δ 147.42, 140.23, 134.03, 126.38, 126.38, 125.42, 125.42, 120.61,59.58, 49.47, 47.62, 32.41, 32.41, 31.13, 30.58, 30.58, 24.67, 22.78. Example 2: Preparation of representative intermediate C1 Compound B1 (1 equiv) and 6-bromo-2-methylquinazoline (0.9 equiv) were added to a round-bottom flask, followed by N,N-diisopropylethylamine (DIPEA, 3 equiv) in 20 mL of anhydrous N,N-dimethylformamide (DMF) as solvent. After addition, the mixture was heated to 80 °C and reacted for 12 h. After the reaction was complete as monitored by TLC, the reaction solution was cooled to room temperature and extracted three times with ethyl acetate and water. The organic phases were combined. The organic phase was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the mixture was concentrated under reduced pressure and purified by Biotage Isolera Prime (petroleum ether (PE) / ethyl acetate (EA) = 5:7, v:v) using a 200–300 mesh silica gel column to give a pale yellow solid in 73% yield. 1 H NMR (400 MHz, CDCl3) δ 8.89 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.1 Hz,2H), 7.13-7.03 (m, 1H), 6.65 (s, 1H), 6.08-5.89 (m, 1H), 5.71 (s, 1H), 5.48-5.38 (m, 1H), 2.36 (s, 3H), 2.09 (s, 2H), 1.76 (d, J = 7.1 Hz, 3H), 1.34 (s, 2H), 1.01 (s, 6H), 0.96 (s, 6H). Example 3: Preparation of representative end product compound D1 Compound C1 (1 equiv) and tetrahydropyrrole (1.1 equiv) were added to a two-necked flask, followed by 20 mL of anhydrous dioxane. The reaction system was purged twice with N2, and tris(dibenzylindeneacetone)palladium (0.1 equiv) and cesium carbonate (3 equiv) were added under N2 conditions. After the addition was complete, the system was purged three more times with N2. Finally, the reaction was heated to 90 °C for 8 h under N2 protection. After the reaction was complete as monitored by TLC, the reaction solution was cooled to room temperature and extracted three times with dichloromethane and water. The organic phases were combined. The organic phase was washed successively with water and saturated brine and dried with anhydrous sodium sulfate. The desiccant was removed by filtration, and the solution was concentrated under reduced pressure and purified by Biotage Isolera Prime with a 200-300 mesh silica gel column (PE / EA = 1:1, v:v) to give a white solid in 82% yield. 1H NMR (400 MHz, DMSO) δ 8.79 (d, J = 7.9 Hz, 1H), 8.56 (d, J = 6.2 Hz, 2H), 8.44-8.27 (m, 2H), 7.34 (s, 1H), 7.31-7.21 (m, 2H), 7.21 – 7.09 (m, 2H),5.65 (s, 2H), 1.94 (s, 1H), 1.03 (dd, J = 5.4, 2.9 Hz, 2H), 0.94-0.69 (m,2H). 13C NMR (100 MHz, DMSO) δ 160.46 (d, J = 245.2 Hz), 159.29 (d, J = 244.0Hz), 155.04 (2C), 148.25, 143.95, 143.95, 133.12, 131.61, 130.37 (d, J = 3.3Hz), 130.31, 125.14 (d, J = 3.5 Hz), 124.92, 118.74, 117.80, 115.94 (d, J =20.9 Hz), 113.60, 42.07, 11.02, 9.24 (2C). HRMS m / z (ESI) calculated forC 21 H 17 FN4, 345.1515, [M + H] + , found: 345.1505. Example 4: Preparation of representative intermediate E1 Compound B1 (1 equiv) and 6-bromo-2-chloroquinazoline (0.9 equiv) were added to a round-bottom flask, followed by DIPEA (3 equiv) in 20 mL of anhydrous DMF as solvent. After the addition was complete, the mixture was heated to 40 °C and reacted for 12 h. After the reaction was monitored by TLC until complete, the reaction solution was cooled to room temperature and extracted three times with ethyl acetate and water. The organic phases were combined. The organic phase was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the mixture was concentrated under reduced pressure and purified by Biotage Isolera Prime with a 200-300 mesh silica gel column (PE / EA = 7:3, v:v) to give a pale yellow solid in 81% yield. 1 H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 2.1 Hz, 1H), 7.73 (dd, J = 8.9, 2.1 Hz, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.37 (d, J = 0.9 Hz, 4H), 6.20 (d, J = 7.7 Hz, 1H), 5.78 (t, J = 1.7 Hz, 1H), 5.64-5.56 (m, 1H), 2.12 (d, J = 1.7 Hz, 2H), 1.69 (d, J =6.8 Hz, 3H), 1.40 (s, 2H), 1.08 (s, 6H), 1.02 (s, 6H). Example 5: Preparation of representative intermediate F1 Compound E1 (1 equiv) was added to a round-bottom flask, followed by cesium fluoride (3 equiv), and 20 mL of anhydrous dimethyl sulfoxide (DMSO) was used as the solvent. After the addition was complete, the mixture was heated to 70 °C and reacted for 12 h. After the reaction was monitored by TLC until complete, the reaction solution was cooled to room temperature, and the system was extracted three times with ethyl acetate and water. The organic phases were combined. The organic phase was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the mixture was concentrated under reduced pressure and purified by Biotage Isolera Prime with a 200–300 mesh silica gel column (PE / EA = 7:3, v:v) to give a white solid in 93% yield. 1 H NMR (400MHz, CDCl3) δ 8.08 (dd, J= 4.2, 2.2 Hz, 1H), 7.63 (dd, J = 8.9, 2.1 Hz, 1H), 7.40 (d, J = 8.9 Hz, 1H), 7.38-7.33 (m, 2H), 7.32-7.28 (m, 2H), 6.95-6.85 (m,1H), 5.74 (t, J = 1.7 Hz, 1H), 5.65-5.57 (m, 1H), 2.08 (d, J = 1.8 Hz, 2H), 1.66(d, J = 6.8 Hz, 3H), 1.38 (s, 2H), 1.07 (s, 6H), 1.00 (s, 6H). Example 6: Preparation of representative intermediate G1 Compound F1 (1 equiv) and anhydrous methanol (2 equiv) were added to a flask, followed by cesium fluoride (3 equiv) and 1,4-diazabicyclo[2.2.2]octane (3 equiv), with 20 mL of anhydrous tetrahydrofuran (THF) as solvent. After the addition was complete, the mixture was heated to 60 °C and reacted for 6 h. After the reaction was monitored by TLC until complete, the reaction solution was cooled to room temperature, and the system was extracted three times with ethyl acetate and water. The organic phases were combined. The organic phase was washed successively with water and saturated brine, and dried with anhydrous sodium sulfate. The drying agent was removed by filtration, and the mixture was concentrated under reduced pressure and purified by Biotage Isolera Prime with a 200-300 mesh silica gel column (PE / EA = 7:3, v:v) to give a white solid in 81% yield. 1 H NMR (400 MHz, CDCl3) δ 8.00-7.96(m, 1H), 7.59 (dd, J = 8.9, 2.2 Hz, 1H), 7.44 (d, J = 8.9 Hz, 1H), 7.33-7.27 (m,4H), 6.52-6.44 (m, 1H), 5.74 (t, J = 1.8 Hz, 1H), 5.57-5.49 (m, 1H), 3.98 (s,3H), 2.09 (d, J = 1.8 Hz, 2H), 1.58 (d, J= 7.0 Hz, 3H), 1.38 (s, 2H), 1.07 (s, 6H), 1.00 (s, 6H). Example 7: Preparation of representative end product compound H1 Compound G1 (1 equiv) and tetrahydropyrrole (1.1 equiv) were added to a two-necked flask, followed by 20 mL of anhydrous dioxane. The reaction system was purged twice with N2, and tris(dibenzylindeneacetone)palladium (0.1 equiv) and cesium carbonate (3 equiv) were added under N2 conditions. After the addition was complete, the system was purged three more times with N2. Finally, the reaction was heated to 90 °C for 8 h under N2 protection. After the reaction was complete as monitored by TLC, the reaction solution was cooled to room temperature and extracted three times with dichloromethane and water. The organic phases were combined. The organic phase was washed successively with water and saturated brine and dried with anhydrous sodium sulfate. The desiccant was removed by filtration, and the solution was concentrated under reduced pressure and purified by Biotage Isolera Prime with a 200–300 mesh silica gel column (PE / EA = 1:1, v:v) to give a white solid in 55% yield. 1 H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 9.2 Hz, 1H), 7.38-7.31 (m, 4H), 7.05 (dd, J = 9.2, 2.6 Hz, 1H), 6.48 (d, J = 2.7 Hz, 1H), 6.02 (d, J = 7.7 Hz, 1H), 5.76 (t, J = 1.7 Hz, 1H), 5.68-5.59 (m, 1H), 3.98 (s, 3H), 3.31 -3.19 (m, 4H), 2.11 (d, J = 1.8 Hz, 2H), 1.99-1.91 (m, 4H), 1.61 (d, J = 6.8 Hz, 3H), 1.39 (s,2H), 1.07 (s, 6H), 1.01 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 160.5, 159.8,144.6, 143.1, 142.1, 142.1, 141.9, 134.0, 134.0, 132.6, 127.5, 126.4, 126.4,125.5, HRMS (ESI) calcd for C 31 H 40 N4O[M+H] + 485.3280, found: 485.3277. All final products were prepared according to the methods described above.

[0030] Compound D2 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.42(d, J = 7.2 Hz, 2H), 7.35-7.29 (m, 3H), 7.24 (t, J = 7.2 Hz, 1H), 7.14 (d, J = 2.8Hz, 1H), 6.41 (d, J = 7.6 Hz, 1H), 5.71-5.64 (m, 1H), 3.75 (s, 3H), 1.66 (d, J =6.8 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 158.1, 157.6, 153.4, 144.8, 143.4,129.9, 128.7, 128.7, 127.4, 126.4, 126.4, 123.7, 115.4, 100.5, 55.8, 50.0,21.6. HRMS m / z (ESI) calculated for C 17 H 17 N3O, 280.1450, [M + H] +, found:280.1435. Compound D3 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.45(d, J = 7.2 Hz, 2H), 7.39 (d, J = 7.2 Hz, 1H), 7.37 (t, J = 7.2 Hz, 2H), 7.29 (t, J =7.2 Hz, 1H), 7.02 (s, 1H), 6.10 - 6.04 (m, 1H), 5.87 (s, 1H), 4.60 (d, J = 4.8Hz, 1H), 1.70 (d, J = 6.8 Hz, 1H), 1.37 - 1.26 (m, 4H); 13 C NMR (101 MHz, CDCl3) δ157.96, 156.55, 153.37, 144.51, 143.29, 132.58, 128.78, 128.78, 127.53,126.39, 126.39, 123.70, 118.25, 101.78, 69.42, 50.17, 29.71, 21.74, 21.74.HRMS m / z (ESI) calculated for C 19 H 19 N3O, 320.1311, [M + H] + , found: 320.1300. Compound D4 1 H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.41(d, J = 7.6 Hz, 2H), 7.30 (t, J= 7.2 Hz, 2H), 7.26 - 7.21 (m, 2H), 7.14 (s, 1H), 6.73 (s, 1H), 5.72 - 5.65 (m, 1H), 4.57 - 4.51 (m, 1H), 2.32 - 2.31 (m, 2H), 2.13 - 2.04 (m, 2H), 1.81 - 1.73 (m, 1H), 1.65 (d, J = 6.8 Hz, 3H), 1.52 - 1.45 (m, 1H); 13 C NMR (101 MHz, CDCl3) δ 158.2, 155.4, 153.3, 144.4, 143.5, 129.6, 128.6, 128.6, 127.3, 126.4, 126.4, 123.8, 115.6, 102.7, 71.7, 50.0, 30.4, 30.4, 21.6, 13.2. HRMS m / z (ESI) calculated for C 20 H 21 N3O , 320.1763, [M + H] + , found: 320.1747. Compound D5 1 H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.44(d, J = 7.6 Hz, 2H), 7.37 - 7.34 (m, 3H), 7.30 - 7.27 (m, 1H), 7.01 (d, J = 2.4 Hz, 1H), 5.88 (d, J = 6.8 Hz, 1H), 5.68 - 5.61 (m, 1H), 4.85 - 4.81 (m, 1H), 1.90 - 1.87 (m, 4H), 1.83 - 1.78 (m, 2H), 1.68 (d, J = 6.8 Hz, 3H), 1.65 - 1.61 (m, 2H); 1313C NMR (101 MHz, CDCl3) δ 157.9, 156.0, 153.2, 144.2, 143.4, 129.9, 128.8, 128.8, 127.5, 126.3, 126.3, 123.9, 115.4, 103.1, 79.9, 50.1, 32.8, 32.8, 23.4, 23.0, 21.8. HRMS m / z (ESI) calculated for C 21 H 23 N3O, 334.1919, [M + H] + , found: 334.1902. Compound D6 1 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.72 (d, J J = 8.8 Hz, 1H), 7.43 (d, J J = 7.6 Hz, 2H), 7.31 (t, J J = 8.0 Hz, 3H), 7.25 (d, J J = 6.4 Hz, 1H), 7.20 (d, J J = 2 Hz, 1H), 6.68 (d, J J = 7.2 Hz, 1H), 5.73 - 5.66 (m, 1H), 3.70 (d, J J = 6.8 Hz, 2H), 2.34 - 2.23 (m, 1H), 1.77 - 1.73 (m, 2H), 1.66 (d, J J = 6.8 Hz, 3H), 1.56 - 1.53 (m, 4H), 1.24 - 1.17 (m, 2H); 13 13C NMR (101 MHz, CDCl3) δ 158.2, 157.3, 153.3, 144.4, 143.5, 129.6, 128.6, 128.6, 127.3, 126.5, 126.5, 124.0, 115.5, 101.4, 72.7, 50.0, 38.9, 29.4, 29.4, 25.4, 25.4, 21.6. HRMS m / z (ESI) calculated for C 22 H 25N3O, 348.2076, [M + H] + , found: 348.2059. Compound D7 1 H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.77 (d, J = 9.2 Hz, 1H), 7.44(d, J = 7.2 Hz, 2H), 7.37-7.33 (m, 3H), 7.29 (d, J = 7.2 Hz, 1H), 7.12 (d, J = 2.4Hz, 1H), 6.07-6.01 (m, 1H), 5.68-5.61 (m, 1H), 4.38-4.32 (m, 1H), 2.36 (s,2H), 1.97-1.94 (m, 2H), 1.81-1.75 (m, 2H), 1.69(d, J = 6.8 Hz, 3H), 1.58-1.51(m, 2H), 1.38-1.33 (m, 2H); 13 C NMR (101 MHz, CDCl3) δ 158.0, 155.7, 153.1,143.9, 143.3, 129.6, 128.8, 128.8, 127.5, 126.4, 126.4, 124.0, 115.5, 104.5,76.1, 50.2, 31.7, 31.6, 25.5, 23.5, 23.5, 21.7. HRMS m / z (ESI) calculated forC 22 H 25 N3O, 348.2076, [M + H] + , found: 348.2058. Compound D8 1 H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.74(t, J= 8.8 Hz, 2H), 7.46 - 7.42 (m, 3H), 7.38 - 7.34 (m, 2H), 7.29 (d, J = 7.2 Hz, 1H), 6.06 (d, J = 6.4 Hz, 1H), 5.69 - 5.62 (m, 1H), 1.70 (d, J = 6.8 Hz, 3H); 13 C NMR(101 MHz, CDCl3) δ 158.6, 155.4, 149.3, 143.2, 132.6, 128.8, 128.8, 128.5, 127.6, 126.3, 126.3, 126.0, 120.5, 114.8, 50.2, 21.8. HRMS m / z (ESI) calculated for C 16 H 15 N3, 250.1344, [M + H] + , found: 250.1331. Compound D9 1 H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.46 - 7.43 (m, 3H), 7.39 - 7.35 (m, 3H), 7.29 (t, J = 7.2 Hz, 1H), 5.98 (d, J = 7.2 Hz, 1H), 5.67 - 5.62 (m, 1H), 2.06 - 1.99 (m, 1H), 1.70 (d, J = 6.8 Hz, 3H), 1.05 - 1.01(m, 2H), 0.78 - 0.74 (m, 2H); 13 C NMR (101 MHz, CDCl3) δ 158.1, 154.5, 147.7, 143.3, 142.1, 130.6, 128.8, 128.8, 128.4, 127.5, 126.4, 126.4, 117.1, 114.6, 50.0, 21.7, 15.8, 9.4, 9.4. HRMS m / z (ESI) calculated for C 19H 19 N3, 290.1657, [M + H] + , found: 290.1642. Compound D10 1 H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.62(s, 1H), 7.47-7.43 (m, 3H), 7.31 (t, J = 7.2 Hz, 2H), 7.25-7.22 (t, J = 7.2 Hz,1H), 6.74 (s, 1H), 5.74-5.67 (m, 1H), 2.71-2.62 (m, 2H), 2.49-2.42 (m, 1H),1.96-1.89 (m, 2H), 1.80-1.72 (m, 2H), 1.68(d, J = 7.2 Hz, 3H), 1.65-1.58 (m,2H); 13 C NMR (101 MHz, CDCl3) δ 158.6, 154.7, 147.8, 143.5, 139.5, 133.8,128.7, 128.7, 127.9, 127.4, 126.4, 126.4, 119.9, 114.9, 50.0, 42.9, 37.1,28.1, 28.1, 21.7, 18.3. HRMS m / z (ESI) calculated for C 21 H 23 N3, 318.1970, [M +H] + , found: 318.1953. Compound D11 1 H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.46 (d, J = 7.2 Hz, 2H), 7.35 (t, J= 7.2 Hz, 2H), 7.31 - 7.27 (m, 2H), 6.60 (d, J = 2.0Hz, 1H), 5.93 (d, J = 5.6 Hz, 1H), 5.71 - 5.64 (m, 1H), 3.03 (s, 6H), 1.70 (d, J =6.8 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 157.5, 151.5, 148.7, 143.6, 141.6, 128.9, 128.7, 128.7, 127.4, 126.4, 126.4, 121.1, 115.7, 98.5, 50.0, 40.8, 40.8, 21.8. HRMS m / z (ESI) calculated for C 18 H 20 N4, 293.1766, [M + H] + , found: 293.1750. Compound D12 H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.43(d, J = 7.6 Hz, 2H), 7.31 (t, J = 7.2 Hz, 2H), 7.28 - 7.21 (m, 2H), 6.71 (s, 1H), 6.32 (d, J = 6.8 Hz, 1H), 5.72 - 5.65 (m, 1H), 3.41 (dd, J = 14.0 Hz, 6.8 Hz, 2H), 2.89 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H), 1.09 (t, J = 6.8 Hz, 3H); 1313C NMR (101 MHz, CDCl3) δ 157.5, 151.6, 147.4, 143.8, 141.7, 129.1, 128.6, 128.6, 127.2, 126.4, 126.4, 121.0, 116.1, 98.8, 49.8, 47.1, 37.8, 21.8, 11.4. HRMS m / z (ESI) calculated for C 19 H 22 N4, 307.1923, [M + H] + , found: 307.1907. Compound D13 1 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.61 (d, J J = 8.8 Hz, 1H), 7.42(d, J J = 7.6 Hz, 2H), 7.32 (t, J J = 7.2 Hz, 2H), 7.26 - 7.22 (m, 1H), 6.99 (d, J J = 8.8Hz, 1H), 6.62 (d, J J = 0.8 Hz, 1H), 6.19 (d, J J = 7.2 Hz, 1H), 5.69 - 5.62 (m, 1H), 4.27 (s, 1H), 3.90 - 3.83 (m, 1H), 2.39 - 2.33 (m, 2H), 1.82 - 1.74 (m, 3H), 1.71 - 1.63 (m, 4H); 13 13C NMR (101 MHz, CDCl3) δ 157.5, 151.7, 145.4, 143.7, 142.6, 129.3, 128.6, 128.6, 127.3, 126.3, 126.3, 122.5, 116.1, 98.0, 49.9, 48.7, 31.0, 31.0, 21.9, 15.2. HRMS m / z (ESI) calculated for C 20 H 22 N4, 319.1923, [M +H] + , found: 319.1907. Compound D14 1 H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.43(d, J = 8.0 Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.26 - 7.22 (m, 1H), 7.03 (dd, J = 9.2Hz, 2.0 Hz, 1H), 6.67 (d, J = 2.0 Hz, 1H), 6.13 (d, J = 7.6 Hz, 1H), 5.69 - 5.62(m, 1H), 4.03 (s, 1H), 3.80 - 3.74 (m, 1H), 2.01 - 1.92 (m, 2H), 1.71 - 1.63 (m,5H), 1.62 - 1.54 (m, 2H), 1.51 - 1.39 (m, 2H); 13 C NMR (101 MHz, CDCl3) δ 157.4,151.5, 146.2, 143.7, 142.4, 129.2, 128.6, 128.6, 127.3, 126.3, 126.3, 122.8,116.1, 98.0, 54.6, 49.9, 33.3, 33.3, 24.0, 24.0, 21.9. HRMS m / z (ESI)calculated for C 21 H 24 N4, 333.2079, [M + H] + , found: 333.2061. Compound D15 1 H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.44(d, J = 7.2 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.30 - 7.26 (m, 1H), 7.03 (dd,J = 8.8 Hz, 2.0 Hz, 1H), 6.61 (d, J = 1.6 Hz, 1H), 5.86 (s, 1H), 5.67 - 5.60 (m, 1H), 3.48 (s, 1H), 3.37 - 3.33 (m, 1H), 2.08 - 2.00 (m, 2H), 1.78 - 1.72 (m, 2H), 1.70 - 1.65 (m, 4H), 1.65 - 1.58 (m, 2H), 1.43 - 1.36 (m, 3H); 13 C NMR (101 MHz, CDCl3) δ 157.3, 151.3, 145.6, 143.6, 141.9, 129.2, 128.7, 128.7, 127.3, 126.4, 126.4, 122.5, 116.0, 98.2, 51.6, 50.0, 33.2, 33.1, 26.9, 25.8, 24.8, 21.8. HRMS m / z(ESI) calculated for C 22 H 26 N4, 347.2236, [M + H] + , found: 347.2220. Compound D16 1 H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.62 (d, J = 9.2 Hz, 1H), 7.43(d, J = 8.0 Hz, 2H), 7.33 (t, J = 7.2 Hz, 2H), 7.27 - 7.23 (m, 1H), 7.01 (d, J = 8.8 Hz, 1H), 6.60 (s, 1H), 6.03 (d, J = 7.2 Hz, 1H), 5.67 - 5.60 (m, 1H), 3.72 (s, 1H), 3.50 - 3.45 (m, 1H), 1.98 - 1.90 (m, 2H), 1.68 - 1.63 (m, 4H), 1.62 - 1.54 (m, 4H), 1.53 - 1.40 (m, 5H); 1313C NMR (101 MHz, CDCl3) δ 157.4, 151.5, 145.5, 143.8, 142.3, 129.3, 128.7, 128.7, 127.3, 126.3, 126.3, 122.7, 116.2, 98.2, 53.5, 49.9, 34.5, 34.4, 28.5, 28.5, 24.2, 24.2, 21.9. HRMS m / z (ESI) calculated for C 23 H 28 N4, 361.2392, [M + H] + , found: 361.2376. Compound D17 ; 1 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.67 (d, J J = 9.2 Hz, 1H), 7.42(d, J J = 7.6 Hz, 2H), 7.32 (t, J J = 7.2 Hz, 2H), 7.26 - 7.23 (m, 1H), 6.91 (dd, J J = 8.8Hz, 2.0 Hz, 1H), 6.49 (d, J J = 2.0 Hz, 1H), 6.16 (d, J J = 7.6 Hz, 1H), 5.70 - 5.63(m, 1H), 3.88 (t, J J = 7.2 Hz, 4H), 2.38 - 2.30 (m, 2H), 1.65 (d, J J = 6.8 Hz, 3H); 13 13C NMR (101 MHz, CDCl3) δ 157.5, 151.8, 150.0, 143.7, 142.5, 129.2, 128.6, 128.6, 127.3, 126.4, 126.4, 119.5, 115.8, 97.7, 52.5, 52.5, 49.9, 21.8, 16.7. HRMS m / z (ESI) calculated for C 19 H 20 N4, 305.1766, [M + H] +, found: 305.1751. Compound D18 1 H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.73 (d, J J = 9.2 Hz, 1H), 7.47(d, J J = 7.6 Hz, 2H), 7.39 - 7.34 (m, 2H), 7.31 - 7.28 (m, 1H), 7.12 (dd, J J = 8.8 Hz,2.0 Hz, 1H), 6.38 (d, J J = 2.4 Hz, 1H), 5.76 (s, 1H), 5.70 - 5.63 (m, 1H), 3.38(t, J J = 6.4 Hz, 4H), 2.08 - 2.05 (m, 4H), 1.71 (d, J J = 6.8 Hz, 3H); 13 C NMR (101 MHz,CDCl3) δ 157.3, 157.3, 150.7, 146.1, 143.6, 128.9, 128.7, 128.7, 127.4,126.4, 126.4, 120.7, 115.9, 96.9, 50.0, 48.0, 48.0, 25.5, 25.5, 21.9. HRMS m / z (ESI) calculated for C 20 H 22 N4, 319.1923, [M + H] + , found: 319.1907. Compound D19 1 H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.67 (d, J J = 9.2 Hz, 1H), 7.46 - 7.39 (m, 3H), 7.31 (t, J J = 7.2 Hz, 2H), 7.26 - 7.21 (m, 1H), 7.03 (d, J J = 1.2 Hz,1H), 6.60 (d, J= 7.2 Hz, 1H), 5.74 - 5.67 (m, 1H), 3.08 (t, J = 5.2 Hz, 4H), 1.67(d, J = 7.2 Hz, 3H), 1.65 - 1.59 (m, 4H), 1.56 - 1.48 (m, 2H); 13 C NMR (101 MHz, CDCl3) δ 158.0, 152.7, 150.4, 143.7, 143.5, 128.7, 128.6, 128.6, 127.3, 126.5, 126.5, 125.2, 115.6, 103.6, 50.7, 50.7, 49.9, 25.7, 25.7, 24.1, 21.7. HRMS m / z (ESI) calculated for C 21 H 24 N4, 333.2079, [M + H] + , found: 333.2062. Compound D20 1 H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.46 - 7.41 (m, 3H), 7.35 (t, J = 7.2 Hz, 2H), 7.30 - 7.27 (m, 1H), 6.93 (d, J = 2.4 Hz, 1H), 6.08 (d, J = 7.2 Hz, 1H), 5.72 - 5.65 (m, 1H), 3.85 (t, J = 5.2 Hz, 4H), 3.19(t, J = 4.8 Hz, 4H), 1.69 (d, J = 6.8 Hz, 3H); 1313C NMR (101 MHz, CDCl3) δ 157.9, 153.1, 149.4, 144.2, 143.4, 129.3, 128.7, 128.7, 127.4, 126.5, 126.5, 124.1, 115.4, 103.0, 66.7, 66.7, 50.0, 50.0, 50.0, 21.6. HRMS m / z (ESI) calculated for C 20 H 22 N4O, 335.1872, [M + H] + , found: 335.1855. Compound D21 ; 1 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.70 (d, J J = 9.2 Hz, 1H), 7.44 (d, J J = 7.2 Hz, 2H), 7.39 - 7.31 (m, 3H), 7.29 - 7.24 (m, 1H), 7.01 (d, J J = 2.4 Hz, 1H), 6.33 (d, J J = 7.2 Hz, 1H), 5.73 - 5.66 (m, 1H), 3.49 (t, J J = 4.8 Hz, 4H), 2.70 (t, J J = 4.8 Hz, 4H), 1.68 (d, J J = 6.8 Hz, 3H); 13 13C NMR (101 MHz, CDCl3) δ 157.9, 153.2, 149.6, 144.1, 143.4, 129.3, 128.7, 128.7, 127.4, 126.4, 126.4, 125.5, 115.5, 104.8, 52.3, 52.3, 49.9, 27.0, 27.0, 21.6. HRMS m / z (ESI) calculated for C 20 H 22 N4S, 351.1643, [M + H] + , found: 351.1628. Compound D22 1 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.73 (d, J J = 9.2 Hz, 1H), 7.47 - 7.42 (m, 3H), 7.35 (t, J J = 7.2 Hz, 2H), 7.30 - 7.26 (m, 1H), 7.00 (d, J J = 2.4 Hz, 1H), 6.15 (d, J J = 6.8 Hz, 1H), 5.72 - 5.65 (m, 1H), 3.34 (t, J J = 6.0 Hz, 4H), 2.15 - 2.05 (m, 4H), 1.69 (d, J J = 7.2 Hz, 3H); 13 13C NMR (101 MHz, CDCl3) δ [157.9, 153.3, 148.6, 144.2, 143.4, 129.4, 128.7, 128.7, 127.5, 126.5, 126.5, 125.4, 121.5, 115.4, 104.5, 50.0, 47.1, 33.9, 33.7, 33.5, 21.6. HRMS m / z (ESI) calculated for C 21 1 22 H + F2N4, 369.1891, [M + H] Compound D23 1 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.72 (d, J J = 8.8 Hz, 1H), 7.46(d, J J = 6.4 Hz, 3H), 7.38 - 7.27 (m, 3H), 6.9 (s, 1H), 6.04 (d, J J = 6.4 Hz, 1H), 5.72 - 5.65 (m, 1H), 3.19 (s, 4H), 3.03 (s, 4H), 1.69 (d, J J = 6.4 Hz, 3H), 1.19(s, 1H);13 13C NMR (101 MHz, CDCl3) δ 157.8, 153.1, 149.9, 144.2, 143.6, 129.3, 128.7, 128.7, 127.4, 126.4, 126.4, 124.6, 115.4, 103.3, 50.5, 50.5, 49.9, 45.9, 45.9, 21.7. HRMS m / z (ESI) calculated for C 20 H 23 N5, 334.2032, [M + H] + , found: 334.2016. Compound D24 1 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.69 (d, J J = 9.2 Hz, 1H), 7.45(d, J J = 7.2 Hz, 2H), 7.36 - 7.31 (m, 2H), 7.28 - 7.27 (m, 1H), 7.26 - 7.23 (m, 1H), 6.66 (d, J J = 2.4 Hz, 1H), 6.00 (d, J J = 7.6 Hz, 1H), 5.71 - 5.64 (m, 1H), 3.63 - 3.56(m, 4H), 3.06 - 3.02 (m, 2H), 2.85 - 2.81 (m, 2H), 1.94 - 1.88 (m, 2H), 1.68 (d, J J = 6.8 Hz, 3H), 1.26 (s, 1H); 13 13C NMR (101 MHz, CDCl3) δ 157.4, 151.6, 146.9, 143.8, 141.8, 129.5, 128.6, 128.6, 127.3, 126.4, 126.4, 120.3, 116.2, 97.7, 52.0, 49.8, 48.4, 48.2, 47.9, 29.5, 21.8. HRMS m / z (ESI) calculated for C 21 H 25 N5, 348.2188, [M + H] +, found: 348.2172. Compound D25 1 H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.44(d, J = 7.6 Hz, 2H), 7.44-7.39 (m, 1H), 7.31 (t, J = 7.2 Hz, 2H), 7.25-7.21 (m,1H), 7.06 (s, 1H), 6.65 (d, J = 6.8 Hz, 1H), 5.74-5.67 (m, 1H), 3.59 (d, J = 12.0Hz, 2H), 2.62 (t, J = 12.0 Hz, 2H), 1.67 (d, J = 6.8 Hz, 3H), 1.66-1.60 (m, 2H),1.44 (s, 1H), 1.32-1.22 (m, 2H), 0.94 (d, J = 6.4 Hz, 3H); 13 C NMR (101 MHz,CDCl3) δ 158.0, 152.7, 150.1, 143.6, 143.4, 128.6, 128.6, 128.6, 127.3,126.5, 126.5, 125.1, 115.6, 103.7, 50.0, 50.0, 49.9, 33.9, �3.9, 30.5, 21.8,21.6. HRMS m / z (ESI) calculated for C 22 H 26 N4, 347.2236, [M + H][[ID=^0]] + , found:347.2220. Compound D26 1 H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.44(d, J= 7.6 Hz, 2H), 7.39 (dd, J = 9.2 Hz, 2.4 Hz, 1H), 7.32 (t, J = 7.2 Hz, 2H),7.26 - 7.22 (m, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H), 5.71 - 5.64(m, 1H), 3.81 - 3.75 (m, 1H), 3.52 - 3.45 (m, 2H), 2.96 - 2.80 (m, 4H), 1.95 - 1.87(m, 2H), 1.67 (d, J = 6.8 Hz, 3H), 1.65 - 1.59 (m, 1H); 13 C NMR (101 MHz, CDCl3) δ157.9, 152.7, 149.6, 143.5, 143.5, 128.7, 128.7, 128.7, 127.3, 126.4, 126.4,125.1, 115.5, 103.8, 67.1, 50.0, 47.4, 47.4, 34.0, 33.9, 21.7. HRMS m / z (ESI)calculated for C 21 H 24 N4O, 349.2028, [M + H] + , found: 349.2011. Compound D27 1 H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.44(d, J = 7.6 Hz, 2H), 7.42 - 7.39 (m, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.26 - 7.22 (m,1H), 7.06 (s, 1H), 6.49 (d, J= 6.8 Hz, 1H), 5.72 - 5.65 (m, 1H), 3.49 - 3.42 (m, 2H), 3.36 - 3.29 (m, 4H), 2.96 - 2.88 (m, 2H), 1.97 - 1.90 (m, 2H), 1.71 - 1.63 (m, 5H); 13 C NMR (101 MHz, CDCl3) δ 157.9, 152.8, 149.7, 143.5, 128.8, 128.6, 128.6, 127.3, 126.4, 126.4, 125.1, 115.5, 103.8, 75.5, 55.6, 50.0, 47.2, 47.2, 30.4, 30.4, 21.6. HRMS m / z (ESI) calculated for C 22 H 26 N4O, 363.2185, [M + H] + , found: 363.2169. Compound D28 1 H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.47 - 7.42 (m, 3H), 7.35 (t, J = 7.6 Hz, 2H), 7.29 - 7.26 (m, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.13 (d, J = 7.2 Hz, 1H), 5.72 - 5.65 (m, 1H), 4.23 - 4.17 (m, 1H), 3.50 - 3.43 (m, 2H), 3.12 - 3.05 (m, 2H), 2.22 - 2.14 (m, 2H), 2.03 - 1.94 (m, 2H), 1.69 (d, J = 6.8 Hz, 3H); 1313C NMR (101 MHz, CDCl3) δ 157.8, 153.2, 149.4, 144.2, 143.5, 129.3, 128.7, 128.7, 127.4, 126.5, 126.5, 125.2, 115.4, 103.9, 56.6, 50.0, 47.4, 47.4, 34.8, 34.8, 21.7. HRMS m / z (ESI) calculated for C 21 H 23 ClN4, 367.1689, [M + H] + , found: 367.1674. Compound D29 1 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.70 (d, J J = 8.8 Hz, 1H), 7.45(d, J J = 7.6 Hz, 2H), 7.42 - 7.37 (m, 1H), 7.33 (t, J J = 7.2 Hz, 2H), 7.27 - 7.23 (m,1H), 7.06 (s, 1H), 6.47 (d, J J = 7.6 Hz, 1H), 5.73 - 5.66 (m, 1H), 3.37 - 3.28 (m,2H), 3.13 - 3.05 (m, 2H), 2.78 - 2.71 (m, 1H), 2.03 - 1.88 (m, 4H), 1.68 (d, J J = 6.8Hz, 3H); 13 13C NMR (101 MHz, CDCl3) δ 158.0, 153.4, 149.3, 144.4, 143.5, 129.2, 128.7, 128.7, 127.4, 126.5, 126.5, 125.5, 121.2, 115.5, 104.8, 50.0, 48.2, 48.1, 28.5, 28.4, 25.9, 21.7. HRMS m / z (ESI) calculated for C 22 H 23 N5, 358.2032, [M + H] + , found: 358.2016. Compound D30 1 H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.44(d, J = 7.6 Hz, 2H), 7.33 (t, J = 7.6 Hz, 2H), 7.27 - 7.23 (m, 1H), 7.04 (dd, J = 9.2Hz, 2.0 Hz, 1H), 6.65 (d, J = 1.6 Hz, 1H), 6.17 (d, J = 7.6 Hz, 1H), 5.69 - 5.62(m, 1H), 3.09 (t, J = 6.8 Hz, 2H), 2.71 (t, J = 6.8 Hz, 2H), 2.03 (s, 2H), 1.69 - 1.62 (m, 6H), 1.55 - 1.47 (m, 2H); 13 C NMR (101 MHz, CDCl3) δ 157.4, 151.8,146.5, 143.7, 142.9, 129.4, 128.6, 128.6, 127.3, 126.4, 126.4, 122.7, 116.1,97.1, 49.8, 43.7, 41.5, 30.5, 26.3, 21.7. HRMS m / z (ESI) calculated forC 20 H 25 N5, 336.2188, [M + H] + , found: 336.2171. Compound D31 1 H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.43(d, J = 7.6 Hz, 2H), 7.31 (t, J= 7.6 Hz, 2H), 7.25 - 7.21 (m, 2H), 6.70 (d, J = 2.0Hz, 1H), 6.36 (d, J = 7.2 Hz, 1H), 5.73 - 5.66 (m, 1H), 3.41 (t, J = 6.0 Hz, 2H),1.76 - 1.70 (m, 4H), 1.66 (d, J = 6.8 Hz, 3H), 1.54 - 1.47 (m, 4H); 13 C NMR (101 MHz, CDCl3) δ 157.5, 151.2, 147.3, 143.9, 141.3, 129.2, 128.6, 128.6, 127.2, 126.4, 126.4, 120.1, 116.4, 97.3, 49.8, 49.4, 49.4, 27.6, 27.6, 27.1, 27.1, 21.8. HRMS m / z (ESI) calculated for C 22 H 26 N4, 347.2236, [M + H] + , found: 347.2220. Compound D32 1 H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.69 (d, J = 9.6 Hz, 1H), 7.45(d, J = 7.6 Hz, 2H), 7.36 - 7.31 (m, 2H), 7.28 - 7.26 (m, 1H), 7.25 - 7.22 (m, 1H), 6.62 (d, J = 2.4 Hz, 1H), 6.17 (d, J = 7.2 Hz, 1H), 5.73 - 5.65 (m, 1H), 3.47 (t, J = 6.0 Hz, 4H), 1.78 - 1.72 (m, 4H), 1.68 (d, J = 6.8 Hz, 3H), 1.58 - 1.48 (m, 6H); 13CNMR (101 MHz, CDCl3) δ 157.4, 151.0, 146.8, 143.8, 140.7, 128.9, 128.6, 128.6, 127.2, 126.4, 126.4, 120.3, 116.1, 97.0, 50.6, 50.6, 49.9, 27.0, 26.8, 26.8, 26.6, 26.6, 21.8. HRMS m / z (ESI) calculated for C 23 H 28 N4, 361.2392, [M +H] + , found: 361.2375. Compound D33 1 H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.71 (d, J = 9.6 Hz, 1H), 7.44(d, J = 7.2 Hz, 2H), 7.37 - 7.32 (m, 2H), 7.29 - 7.27 (m, 1H), 7.26 - 7.23 (m, 1H), 6.56 (d, J = 2.8 Hz, 1H), 5.84 (d, J = 7.2 Hz, 1H), 5.71 - 5.64 (m, 1H), 3.52 (t, J = 5.6 Hz, 4H), 1.79 - 1.73 (m, 4H), 1.68 (d, J = 6.8 Hz, 3H), 1.67 - 1.61 (m, 4H), 1.49 - 1.42 (m, 4H); 13 C NMR (101 MHz, CDCl3) δ 157.3, 151.3, 146.4, 143.8, 141.5, 129.3, 128.7, 128.7, 127.3, 126.3, 126.3, 120.7, 116.1, 97.5, 54.7, 54.7, 49.8, 26.5, 26.5, 26.3, 26.3, 25.4, 25.4, 22.0. HRMS m / z (ESI) calculated for C 24 H 30N4, 375.2549, [M + H] + , found: 375.2531. Compound D34 1 H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.13(dd, J = 9.2 Hz, 2.4 Hz, 1H), 6.42 (d, J = 2.4 Hz, 1H), 5.61 (d, J = 8.4 Hz, 1H),4.44-4.38 (m, 1H), 3.35 (dd, J = 8.8 Hz, 6.0 Hz, 4H), 2.06-2.02 (m, 4H), 1.91-1.85 (m, 1H), 1.82-1.72 (m, 3H), 1.69-1.63 (m, 第1页,共2页 10 / 12 / 2023 1H), 1.60-1.50 (m, 1H), 1.26(d, J = 6.8 Hz, 3H), 1.24-1.18 (m, 2H), 1.17-1.02 (m, 3H); 13 C NMR (101 MHz,CDCl3) δ 157.8, 151.2, 146.0, 141.1, 129.1, 120.4, 116.1, 97.1, 50.7, 47.9,47.9, 43.2, 29.6, 29.1, 26.5, 26.3, 26.2, 25.5, 25.5, 17.9; HRMS (ESI) calcdfor C 20 H 28 N4[M+H] + 325.2392, found: 325.2375. Compound D35 1 H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 4.4 Hz, 1H), 8.35 (s, 1H), 7.84(d, J It should be noted that the content you provided seems to be a chemical analysis record. If you have any further questions about chemical content or need more accurate translation in a specific context, it is recommended to consult a professional in the chemical field.= 6.8 Hz, 1H), 7.73 - 7.68 (m, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.0Hz, 1H), 7.25 - 7.20 (m, 1H), 6.95 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 6.38 (d, J = 2.4Hz, 1H), 5.69 - 5.62 (m, 1H), 3.14 - 3.07 (m, 2H), 3.05 - 2.98 (m, 2H), 1.95 - 1.89(m, 4H), 1.68 (d, J = 6.8 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 162.6, 157.6, 150.6, 149.0, 145.6, 140.8, 136.9, 128.6, 122.3, 122.1, 120.2, 116.3, 97.9, 51.2, 47.4, 47.4, 25.4, 25.4, 22.5; HRMS (ESI) calcd for C 19 H 21 N5[M + H] + 320.1875, found: 320.1859. Compound D36 1 H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.45 (s, 1H), 8.38 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.23 - 7.18 (m, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.72 - 6.55 (m, 2H), 5.72 - 5.64 (m, 1H), 3.25 - 3.17 (m, 4H), 1.97 - 1.90 (m, 4H), 1.68 (d, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 157.4, 155.2,150.6, 148.2, 146.1, 140.9, 139.5, 134.3, 128.8, 123.4, 120.7, 116.1, 97.6,48.0, 47.8, 47.8, 25.4, 25.4, 21.8; HRMS (ESI) calcd for C 19 H 21 N5[M+H] + 320.1875, found: 320.1859. Compound D37 1 H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 5.6 Hz, 2H), 8.31 (s, 1H), 7.69(d, J = 9.2 Hz, 1H), 7.36 (d, J = 6.0 Hz, 2H), 7.02 (d, J = 9.2 Hz, 1H), 6.53 (d, J =2.0 Hz, 1H), 6.39 (s, 1H), 5.62-5.55 (m, 1H), 3.29-3.33 (m, 4H), 2.10-2.04(m, 4H), 1.70 (d, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 157.4, 153.0,149.9, 149.9, 146.2, 139.4, 127.9, 121.6, 121.5, 121.5, 120.9, 115.6, 97.3,49.5, 48.0, 48.0, 25.5, 25.5, 21.9; HRMS (ESI) calcd for C 19 H 21 N5[M+H] + 320.1875, found: 320.1859. Compound D38 11H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.16 - 8.11 (m, 1H), 7.86 - 7.82 (m, 1H), 7.78 (d, J J = 8.0 Hz, 1H), 7.67 (d, J J = 9.2 Hz, 1H), 7.62 (d, J J = 6.8 Hz, 1H), 7.48 - 7.39 (m, 3H), 7.07 (dd, J J = 9.2 Hz, 2.4 Hz, 1H), 6.46 - 6.38 (m, 1H), 6.33 (d, J J = 2.4 Hz, 1H), 5.95 (d, J J = 7.6 Hz, 1H), 3.26 - 3.21 (m, 4H), 1.98 - 1.93 (m, 4H), 1.81 (d, J J = 6.4 Hz, 3H); 13 13C NMR (101 MHz, CDCl3) δ 157.0, 151.2, 146.0, 141.3, 138.7, 134.0, 131.6, 129.1, 128.7, 128.3, 126.6, 125.9, 125.2, 123.7, 122.8, 120.5, 116.1, 97.3, 47.9, 47.9, 46.0, 25.5, 25.5, 20.3; HRMS(ESI) calcd for C 24 18H 24 N4[M + H]+ + 369.2079, found: 369.2064. Compound D39 1 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.84 (s, 1H), 7.81 - 7.75 (m, 3H), 7.69 (d, J J = 9.2 Hz, 1H), 7.58 - 7.54 (m, 1H), 7.46 - 7.41 (m, 2H), 7.10 - 7.06 (m, 1H), 6.46 (d, J J = 2.0 Hz, 1H), 6.07 (d, J= 5.6 Hz, 1H), 5.84 - 5.77 (m, 1H), 3.28 (t, J = 6.4 Hz, 4H), 2.00 - 1.95 (m, 4H), 1.75 (d, J = 6.8 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 157.4, 151.0, 146.1, 141.2, 141.1, 133.4, 132.7, 129.1, 128.4, 127.9, 127.6, 126.1, 125.8, 125.2, 124.6, 120.6, 116.1, 97.2, 50.0, 47.9, 47.9, 25.5, 25.5, 21.7; HRMS (ESI) calcd for C 24 H 24 N4[M + H] + 369.2079, found: 369.2065. Compound D40 <​​​​​​​​​​​​​​​21 H 24 N4[M+H] + 333.2079, found: 333.2072. Compound D41 1 H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.39-7.33 (m, 2H), 7.04 (dd, J = 9.1, 2.6 Hz, 1H), 6.96-6.88 (m, 3H), 6.72 (d, J = 2.8Hz, 1H), 5.71-5.63 (m, 1H), 3.21-3.11 (m, 4H), 1.93-1.84 (m, 4H), 1.61 (d, J =7.0 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 163.0, 157.6, 150.9, 146.1, 141.1,139.8, 128.8, 128.8, 128.1, 120.5, 116.4, 115.2, 115.2, 98.1, 49.2, 47.8,47.8, 25.4, 25.4, 21.8; HRMS (ESI) calcd for C 20 H 21 FN4[M+H] + 337.1828, found: 337.1822. Compound D42 1 H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.64 (d, J = 9.1 Hz, 1H), 7.32(d, J = 8.5 Hz, 2H), 7.21-7.16 (m, 2H), 7.04 (dd, J = 9.2, 2.6 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.71 (d, J= 2.6 Hz, 1H), 5.67 - 5.59 (m, 1H), 3.27 - 3.14 (m, 4H), 1.95 - 1.88 (m, 4H), 1.60 (d, J = 7.0 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 157.6, 150.8, 146.2, 142.6, 140.9, 132.6, 128.7, 128.5, 128.5, 127.8, 127.8, 120.6, 116.3, 98.0, 49.3, 47.8, 47.8, 25.4, 25.4, 21.8; HRMS (ESI) calcd for C 20 H 21 ClN4[M + H] + 353.1533, found: 353.1527. Compound D43 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.64 (d, J = 9.1 Hz, 1H), 7.51(d, J = 8.5 Hz, 2H), 7.49 - 7.43 (m, 3H), 7.06 (dd, J = 9.1, 2.5 Hz, 1H), 6.92 (d, J = 2.8 Hz, 1H), 5.73 - 5.66 (m, 1H), 3.23 - 3.16 (m, 4H), 1.92 - 1.84 (m, 4H), 1.64(d, J = 7.0 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 157.7, 150.6, 150.2, 146.2, 141.0, 132.1, 132.1, 128.5, 127.2, 127.2, 120.6, 119.1, 116.4, 110.3, 98.6, 49.8, 47.8, 47.8, 25.4, 25.4, 21.8; HRMS (ESI) calcd for C 21 H 21 N5[M + H] +344.1875, found: 344.1868. Compound D44 1 H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.69(d, J = 9.1 Hz, 1H), 7.48 (d, J = 8.3 Hz, 2H), 7.11 (dd, J = 9.1, 2.5 Hz, 1H), 6.54(d, J = 2.6 Hz, 1H), 6.21 (d, J = 7.5 Hz, 1H), 5.72-5.65 (m, 1H), 3.88 (s, 3H), 3.36-3.27 (m, 4H), 2.03-1.97 (m, 4H), 1.67 (d, J = 6.9 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 166.9, 157.3, 150.8, 149.3, 146.2, 141.2, 129.9, 129.9, 129.1, 129.0, 126.3, 126.3, 120.7, 116.1, 97.2, 52.1, 49.8, 47.9, 47.9, 25.5, 25.5, 22.1; HRMS (ESI) calcd for C 22 H 24 N4O2[M+H] + 377.1978, found: 377.1966. Compound D45 1 H NMR (400 MHz, CDCl3) δ 8.96-8.80 (m, 1H), 8.01 (s, 1H), 7.67 (q, J =8.2 Hz, 4H), 7.30 (d, J= 8.0 Hz, 1H), 6.79 (s, 1H), 6.34 - 6.15 (m, 1H), 5.65 - 5.55 (m, 1H), 3.19 (s, 4H), 2.04 (s, 4H), 1.79 (d, J = 7.0 Hz, 3H); 13 C NMR (101MHz, CDCl3) δ 158.8, 146.7, 146.3, 144.3, 130.3, 130.0, 128.0, 127.5, 127.5, 125.7, 125.7, 121.4, 120.0, 114.0, 100.1, 52.0, 47.7, 47.7, 25.4, 25.4, 21.3; HRMS (ESI) calcd for C 21 H 21 F3N4[M + H] + 387.1797, found: 387.1790. Compound D46 1 H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.64 (d, J = 9.1 Hz, 1H), 7.34(d, J = 8.8 Hz, 2H), 7.01 (dd, J = 9.1, 2.6 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.78(d, J = 8.8 Hz, 2H), 6.70 (d, J = 2.6 Hz, 1H), 5.71 - 5.63 (m, 1H), 3.70 (s, 3H), 3.17 - 3.09 (m, 4H), 1.88 - 1.83 (m, 4H), 1.63 (d, J = 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 158.6, 157.7, 151.0, 146.1, 140.9, 136.0, 128.6, 127.6, 127.6,120.3, 116.4, 113.8, 113.8, 98.3, 55.2, 49.3, 47.8, 47.8, 25.4, 25.4, 21.6;HRMS (ESI) calcd for C 21 H 24 N4O [M+H] + 349.2028, found: 349.2020. Compound D47 1 H NMR (400 MHz, DMSO- d 6) δ 8.22 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H), 7.88(d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 9.0 Hz, 1H), 7.23-7.18(m, 2H), 5.70-5.62 (m, 1H), 3.43-3.33 (m, 4H), 3.18 (s, 3H), 2.05-1.99 (m,4H), 1.64 (d, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, DMSO- d 6) δ 157.8, 151.9, 150.7,146.3, 141.3, 139.5, 128.6, 127.5, 127.5, 127.4, 127.4, 120.9, 116.5, 100.3,49.7, 48.4, 48.4, 44.1, 25.4, 25.4, 22.8; HRMS (ESI) calcd for C 21 H 24 N4O2S [M+H] + 397.1698, found: 397.1695. Compound D48 1 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.67 (d, J J = 9.0 Hz, 1H), 7.36(s, 4H), 7.06 (dd, J J = 9.1, 2.6 Hz, 1H), 6.54 (d, J J = 2.8 Hz, 1H), 6.36 (d, J J = 7.6Hz, 1H), 6.14 - 6.10 (m, 1H), 5.69 - 5.61 (m, 1H), 3.28 - 3.19 (m, 4H), 2.68 - 2.61(m, 2H), 2.52 - 2.46 (m, 2H), 2.00 - 1.92 (m, 6H), 1.65 (d, J J = 6.9 Hz, 3H); 13 13C NMR(101 MHz, CDCl3) δ 157.5, 150.9, 146.1, 142.2, 142.0, 140.9, 135.8, 128.8,126.3, 126.3, 126.0, 125.7, 125.7, 120.5, 116.2, 97.6, 49.7, 47.9, 47.9,33.3, 33.2, 25.5, 25.5, 23.3, 21.6; HRMS (ESI) calcd for C 25 H 28 N4[M + H] + 385.2392, found: 385.2389. Compound D49 1 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.66 (d, J J = 9.1 Hz, 1H), 7.38 - 7.33 (m, 2H), 7.32 - 7.28 (m, 2H), 7.05 (dd, J J = 9.1, 2.6 Hz, 1H), 6.53 (d, J J = 2.6Hz, 1H), 6.37 (d, J= 7.6 Hz, 1H), 6.09 - 6.05 (m, 1H), 5.71 - 5.63 (m, 1H), 3.25 - 3.19 (m, 4H), 2.38 - 2.32 (m, 2H), 2.20 - 2.14 (m, 2H), 1.97 - 1.89 (m, 4H), 1.77 - 1.71 (m, 2H), 1.65 (d, J = 6.9 Hz, 4H), 1.63 - 1.59 (m, 1H); 13 C NMR (101 MHz, CDCl3) δ 157.5, 151.0, 146.0, 141.9, 141.6, 141.1, 136.1, 128.9, 126.3, 126.3, 125.0, 125.0, 124.7, 120.4, 116.2, 97.6, 49.6, 47.9, 47.9, 27.3, 25.9, 25.4, 25.4, 23.0, 22.1, 21.6; HRMS (ESI) calcd for C 26 H 30 N4[M + H] + 399.2549, found: 399.2548. Compound D50 1 H NMR (400 MHz, CDCl3) δ 8.96 (d, J = 7.8 Hz, 1H), 7.89 (s, 1H), 7.56 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 9.5 Hz, 1H), 6.80 (d, J = 2.3 Hz, 1H), 6.19 - 6.07 (m, 2H), 5.62 - 5.52 (m, 1H), 4.30 (d, J = 2.9 Hz, 2H), 3.91 (t, J = 5.4 Hz, 2H), 3.19 (t, J = 6.6 Hz, 4H), 2.56 - 2.41 (m, 2H), 2.08 - 2.01 (m, 4H), 1.79 (d, J= 7.0 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 158.6, 146.4,144.2, 141.2, 139.9, 133.6, 128.0, 127.4, 127.4, 124.9, 124.9, 122.7, 121.2,119.9, 113.8, 100.3, 65.8, 64.4, 51.9, 47.6, 47.6, 27.1, 25.5, 25.5, 21.2. Compound D51 1 H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.71 (d, J = 9.1 Hz, 1H), 7.57(d, J = 1.4 Hz, 1H), 7.57 - 7.54 (m, 3H), 7.51 (d, J = 8.4 Hz, 2H), 7.42 (td, J =6.9, 1.8 Hz, 2H), 7.36 - 7.31 (m, 1H), 7.11 (dd, J = 9.1, 2.6 Hz, 1H), 6.48 (d, J =2.6 Hz, 1H), 6.07 (d, J = 7.0 Hz, 1H), 5.77 - 5.69 (m, 1H), 3.35 - 3.28 (m, 4H),2.04 - 1.98 (m, 4H), 1.72 (d, J = 6.9 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 156.4,149.9, 145.1, 141.7, 140.1, 139.7, 139.2, 128.0, 128.0, 127.7, 126.3, 126.3,126.2, 126.0, 126.0, 125.8, 125.8, 119.6, 115.1, 96.2, 48.6, 46.9, 46.9,24.4, 24.4, 20.8; HRMS (ESI) calcd for C 26 H 26 N4[M + H] +395.2236, found: 395.2232. Compound D52 1 H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.92-7.86 (m, 2H), 7.83 (dt, J = 8.3, 1.1 Hz, 1H), 7.72 (d, J = 9.1 Hz, 1H), 7.58-7.55 (m, 2H), 7.52-7.48 (m,1H), 7.47-7.44 (m, 3H), 7.42-7.38 (m, 2H), 7.11 (dd, J = 9.1, 2.6 Hz, 1H), 6.53(d, J = 2.6 Hz, 1H), 6.17 (d, J = 7.6 Hz, 1H), 5.85-5.77 (m, 1H), 3.38-3.26 (m,4H), 2.03-1.98 (m, 4H), 1.77 (d, J = 6.9 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ157.4, 150.9, 146.2, 142.7, 139.9, 139.7, 133.8, 131.6, 130.3, 130.3, 129.0,128.3, 127.7, 126.9, HRMS (ESI) calcd for C 30 H 28 N4[M+H] + 445.2392, found: 445.2389. Compound D53 1 H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.43(dd,J = 7.4, 2.4 Hz, 2H), 7.34 - 7.27 (m, 2H), 7.25 - 7.20 (m, 1H), 7.11 (d, J = 8.1Hz, 1H), 6.57 (s, 1H), 6.43 (s, 1H), 5.73 - 5.65 (m, 1H), 3.93 (s, 1H), 3.35(s, 1H), 3.17 - 3.07 (m, 1H), 2.03 (s, 2H), 1.92 (s, 1H), 1.70 - 1.62 (m, 4H),1.13 (d, J = 5.9 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 157.5, 150.8, 145.4, 143.8,140.7, 128.7, 128.6, 128.6, 127.2, 126.4, 126.4, 120.8, 116.3, 97.9, 53.8,49.9, 48.3, 33.0, 23.2, 21.8, 19.0; HRMS (ESI) calcd for C 21 H 24 N4[M + H] + 333.2079, found: 333.2073. Compound D54 1 H NMR (400 MHz, CDCl3) δ 9.25 (d, J = 7.8 Hz, 1H), 7.85 (s, 1H), 7.67(s, 1H), 7.61 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 7.42 (s, 1H), 7.24(s, 1H), 6.90 (s, 1H), 6.64 (d, J = 1.9 Hz, 1H), 6.10 (d, J = 9.0 Hz, 1H), 5.59 - 5.51 (m, 1H), 3.19 (s, 4H), 2.02 (s, 4H), 1.80 (d, J = 7.1 Hz, 3H); 1313C NMR (101 MHz, CDCl3) δ 158.6, 146.3, 144.1, 143.8, 141.1, 138.5, 132.0, 128.0, 127.8, 127.8, 126.0, 126.0, 126.0, 121.1, 119.9, 113.9, 108.7, 100.6, 52.0, 47.6, 47.6, 25.5, 25.5, 21.3; HRMS (ESI) calcd for C 24 H 24 N4O [M+H] + 385.2028, found: 385.2024. Compound D55 1 1H NMR (400 MHz, DMSO- d d6) δ 8.20 (s, 1H), 8.10 (d, J J = 7.9 Hz, 1H), 7.77 (dd, J J = 3.1, 1.4 Hz, 1H), 7.66 - 7.62 (m, 2H), 7.59 (dd, J J = 5.0, 2.9 Hz, 1H), 7.55 (d, J J = 8.9 Hz, 1H), 7.50 (dd, J J = 5.0, 1.5 Hz, 1H), 7.48 - 7.45 (m, 2H), 7.21 - 7.15 (m, 2H), 5.70 - 5.61 (m, 1H), 3.42 - 3.32 (m, 4H), 2.03 - 1.96 (m, 4H), 1.63 (d, J J = 7.1 Hz, 3H); 13 13C NMR (101 MHz, DMSO- d d6) δ 157.9, 150.9, 146.3, 144.5, 141.9, 141.4, 134.0, 128.7, 127.4, 127.1, 127.1, 126.6, 126.4, 126.4, 121.0, 120.8, 116.6, 100.4, 49.3, 48.4, 48.4, 25.4, 25.4, 22.7; HRMS (ESI) calcd for C 24 H24 N4S [M+H] + 401.1800, found: 401.1794. Compound D56 1 H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.65 (d, J = 9.1 Hz, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.28-7.22 (m, 2H), 7.05 (dd, J = 9.1, 2.5 Hz, 1H), 6.60 (d, J = 2.6 Hz, 1H), 6.55 (d, J = 7.9 Hz, 1H), 6.13-6.08 (m, 1H), 5.73-5.64 (m, 1H), 3.30-3.26 (m, 2H), 3.25-3.18 (m, 4H), 2.82 (t, J = 5.8 Hz, 2H), 2.65-2.59 (m,2H), 1.96-1.90 (m, 4H), 1.65 (d, J = 6.9 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ157.5, 150.9, 146.1, 142.8, 141.6, 141.0, 137.8, 128.8, 126.4, 126.4, 125.6,125.6, 121.4, 120.5, 116.3, 97.8, 49.5, 47.9, 47.9, 28.5, 26.2, 25.5, 25.4,25.4, 21.7; HRMS (ESI) calcd for C 25 H 28 N4S [M+H] + 417.2113, found: 417.2107. Compound D57 1 H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.64 (d, J= 9.1 Hz, 1H), 7.40 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 9.8 Hz, 2H), 6.72 (s, 1H), 5.81 (s, 1H), 5.72 - 5.64 (m, 1H), 3.19 (s, 4H), 2.69 - 2.56 (m, 4H), 2.17 - 2.04 (m, 2H), 1.92 - 1.86 (m, 4H), 1.66 (d, J = 7.0 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 157.7, 150.5, 146.2, 143.0, 140.1, 139.4, 135.8, 128.1, 126.6, 125.3, 125.3, 125.3, 122.7, 120.5, 118.7, 116.2, 98.3, 49.8, 47.9, 47.9, 35.0, 30.5, 25.8, 25.4, 25.4, 21.7; HRMS (ESI) calcd for C 26 H 28 F2N4 [M + H] + 435.2360, found: 435.2357. Compound D58 1 H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 7.05 (dd, J = 9.2, 2.6 Hz, 1H), 6.58 (d, J = 2.7 Hz, 1H), 6.51 (d, J = 8.7 Hz, 1H), 6.04 - 5.99 (m, 1H), 5.72 - 5.63 (m, 1H), 3.24 (t, J= 6.7 Hz, 4H), 2.54 - 2.11 (m, 6H), 1.97 - 1.93 (m, 4H), 1.66 (d, J = 6.8 Hz, 4H); 13 C NMR (101 MHz, CDCl3) δ 157.5, 150.8, 146.1, 142.7, 140.9, 140.2, 136.2, 129.4, 128.8, 126.4, 126.4, 125.2, 125.2, 121.1, 120.5, 116.2, 97.6, 49.6, 47.9, 47.9, 38.1, 26.4, 25.5, 25.5, 24.7, 21.7, 14.1; HRMS (ESI) calcd for C 27 H 29 F3N4[M + H] + 467.2423, found: 467.2422. Compound D59 1 H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.66 (d, J = 9.1 Hz, 1H), 7.37 - 7.30 (m, 4H), 7.06 (dd, J = 9.1, 2.5 Hz, 1H), 6.54 (d, J = 2.8 Hz, 1H), 6.42 - 6.36(m, 1H), 5.95 - 5.91 (m, 1H), 5.71 - 5.63 (m, 1H), 3.98 (s, 4H), 3.25 - 3.21 (m, 4H), 2.64 - 2.58 (m, 2H), 2.46 - 2.42 (m, 2H), 1.96 - 1.92 (m, 4H), 1.88 (t, J = 6.5Hz, 2H), 1.65 (d, J = 6.9 Hz, 3H); 1313C NMR (101 MHz, CDCl3) δ 157.5, 151.0, 146.1, 142.3, 141.2, 140.4, 135.9, 128.9, 126.3, 126.3, 125.4, 125.4, 121.5, 120.5, 116.2, 107.7, 97.6, 64.4, 64.4, 49.5, 47.9, 47.9, 36.2, 31.3, 26.7, 25.5, 25.5, 21.6; HRMS (ESI) calcd for C 28 H 32 N4O2 [M+H] + 457.2604, found: 457.2599. Compound D60 1 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.67 (d, J J = 9.1 Hz, 1H), 7.41 (dd, J J = 8.4, 1.8 Hz, 2H), 7.31 - 7.27 (m, 2H), 7.08 (dd, J J = 9.1, 2.6 Hz, 1H), 6.63 (t, J J = 2.5 Hz, 1H), 6.56 (t, J J = 6.8 Hz, 1H), 6.01 - 5.94 (m, 1H), 5.72 - 5.64 (m, 1H), 4.18 (d, J J = 3.4 Hz, 1H), 4.07 (d, J J = 3.5 Hz, 1H), 3.76 (t, J J = 5.9 Hz, 1H), 3.59 (d, J J = 5.8 Hz, 1H), 3.32 - 3.22 (m, 4H), 2.55 - 2.44 (m, 2H), 2.11 (d, J J = 12.5 Hz, 3H), 2.00 - 1.93 (m, 4H), 1.66 (d, J J = 7.0 Hz, 3H); 1313C NMR (101 MHz, CDCl3) δ 169.2, 157.5, 150.9, 146.1, 143.2, 141.0, 139.0, 136.3, 134.5, 128.8, 126.5, 126.5, 125.0, 125.0, 125.0, 120.5, 116.2, 97.8, 49.5, 47.9, 47.9, 43.3, 42.2, 27.8, 25.5, 25.5, 21.9, 21.5; HRMS (ESI) calcd for C 27 H 31 N5O [M+H]+ + 442.2607, found: 442.2603. Compound D61 1 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.64 (d, J J = 9.0 Hz, 1H), 7.38 - 7.32 (m, 4H), 7.31 (d, J J = 2.0 Hz, 1H), 7.30 - 7.26 (m, 3H), 7.25 - 7.21 (m, 1H), 7.02 (dd, J J = 9.2, 2.6 Hz, 1H), 6.68 - 6.54 (m, 2H), 6.00 - 5.96 (m, 1H), 5.72 - 5.64 (m, 1H), 3.59 (s, 2H), 3.23 - 3.14 (m, 4H), 3.12 (q, J J = 2.9 Hz, 2H), 2.66 (t, J J = 5.7 Hz, 2H), 2.51 - 2.45 (m, 2H), 1.92 - 1.85 (m, 4H), 1.63 (d, J J = 7.0 Hz, 3H); 13 13C NMR (101 MHz, Chloroform - d) δ 157.6, 150.9, 146.1, 142.5, 141.0, 139.7,138.2, 134.5, 129.2, 129.2, 128.8, 128.3, 128.3, 127.2, 126.4, 126.4, 125.0,125.0, 121.7, 120.5, 116.3, 98.0, 62.7, 53.3, 49.9, 49.6, 47.9, 47.9, 28.0,25.5, 25.5, 21.6; HRMS (ESI) calcd for C 32 H 35 N5[M+H] + 490.2971, found: 490.2969. Compound D62 1 H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.63(d, J = 9.3 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.17 (d, J =8.4 Hz, 2H), 7.01 (dd, J = 9.1, 2.2 Hz, 1H), 6.94 (d, J = 6.8 Hz, 1H), 6.73 (d, J =2.6 Hz, 1H), 5.88-5.84 (m, 1H), 5.73-5.64 (m, 1H), 3.70-3.64 (m, 2H), 3.26-3.15 (m, 6H), 2.51-2.45 (m, 2H), 2.38 (s, 3H), 1.90-1.85 (m, 4H), 1.65 (d, J =6.9 Hz, 3H); 1313C NMR (101 MHz, CDCl3) δ 157.7, 150.5, 146.2, 143.8, 143.3, 140.3, 138.6, 134.8, 132.9, 129.7, 129.7, 128.2, 127.7, 127.7, 126.5, 126.5, 124.9, 124.9, 120.5, 118.6, 116.3, 98.3, 53.6, 49.6, 47.9, 47.9, 45.3, 43.0, 27.4, 25.4, 25.4, 21.5; HRMS (ESI) calcd for C 32 H 35 N5O2S [M+H] + 554.2590, found: 554.2586. Compound D63 1 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.66 (d, J J = 9.1 Hz, 1H), 7.38 - 7.31 (m, 4H), 7.04 (dd, J J = 9.1, 2.6 Hz, 1H), 6.57 (t, J J = 2.9 Hz, 1H), 6.53 - 6.46 (m, 1H), 6.05 - 5.99 (m, 1H), 5.71 - 5.63 (m, 1H), 3.23 - 3.17 (m, 4H), 2.40 - 2.34 (m, 2H), 1.96 (dt, J J = 4.6, 2.4 Hz, 2H), 1.94 - 1.89 (m, 4H), 1.64 (d, J J = 6.9 Hz, 3H), 1.49 (t, J J = 6.4 Hz, 2H), 0.94 (s, 6H); 1313C NMR (101 MHz, CDCl3) δ 157.6, 151.0, 146.1, 142.0, 141.1, 134.6, 128.9, 126.3, 126.3, 125.1, 125.1, 123.7, 120.4, 116.3, 97.8, 49.6, 47.9, 47.9, 39.9, 35.8, 28.4, 28.2, 28.2, 25.5, 25.5, 25.0, 21.6; HRMS (ESI) calcd for C 28 H 34 N4[M+H] + 427.2862, found: 427.2858. Compound D64 1 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.64 (d, J J = 9.1 Hz, 1H), 7.35(d, J J = 8.4 Hz, 2H), 7.29 (d, J J = 8.4 Hz, 2H), 7.02 (dd, J J = 9.2, 2.6 Hz, 1H), 6.66(dd, J J = 7.7, 2.6 Hz, 1H), 6.62 (d, J J = 2.6 Hz, 1H), 6.10 - 6.03 (m, 1H), 5.72 - 5.64(m, 1H), 3.22 - 3.12 (m, 4H), 2.49 - 2.32 (m, 2H), 2.24 - 2.15 (m, 1H), 1.97 - 1.87(m, 6H), 1.64 (d, J J = 6.9 Hz, 3H), 1.34 - 1.24 (m, 2H), 0.89 (s, 9H); 1313C NMR (101MHz, CDCl3) δ 157.6, 150.9, 146.1, 141.9, 141.1, 140.9, 135.9, 128.7, 126.3, 126.3, 125.0, 125.0, 124.8, 120.4, 116.3, 98.0, 49.6, 47.9, 47.9, 43.8, 32.2, 28.8, 27.5, 27.3, 27.3, 27.3, 25.5, 25.5, 24.4, 21.5; HRMS (ESI) calcd for C 30 H 38 N4[M+H] + 455.3175, found: 455.3170. Compound D65 1 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.65 (d, J J = 9.0 Hz, 1H), 7.40(d, J J = 8.5 Hz, 2H), 7.31 (d, J J = 8.4 Hz, 2H), 7.15-7.08 (m, 1H), 7.00 (dd, J J = 9.1, 2.5 Hz, 1H), 6.74 (s, 1H), 5.76-5.68 (m, 2H), 3.14-3.05 (m, 4H), 2.11(d, J J = 1.8 Hz, 2H), 1.86-1.79 (m, 4H), 1.64 (d, J J = 7.0 Hz, 3H), 1.38 (s, 2H), 1.06 (s, 6H), 1.00 (s, 6H); 1313C NMR (101 MHz, CDCl3) δ 157.8, 151.0, 146.1, 142.3, 141.9, 141.0, 133.8, 132.7, 128.7, 126.4, 126.4, 125.5, 125.5, 120.4, 116.5, 98.5, 49.7, 49.6, 47.8, 47.8, 41.4, 33.1, 31.7, 31.7, 30.9, 30.1, 30.1, 25.4, 25.4, 21.7; HRMS (ESI) calcd for C 30 H 38 N4[M+H] + 455.3175, found: 455.3170. Compound D66 1 1H NMR (400 MHz, CDCl3) δ 8.87 (d, J J = 7.8 Hz, 1H), 7.95 (s, 1H), 7.55 (d, J J = 8.1 Hz, 2H), 7.41 (d, J J = 8.1 Hz, 2H), 7.26 (s, 1H), 6.80 (s, 1H), 6.25 (d, J J = 8.5 Hz, 1H), 6.11 (s, 1H), 5.64 - 5.55 (m, 1H), 4.30 (d, J J = 2.8 Hz, 2H), 3.94 - 3.87 (m, 2H), 3.20 (s, 4H), 2.49 (s, 2H), 2.03 (d, J J = 6.5 Hz, 4H), 1.78 (d, J J = 7.0 Hz, 3H); 13 13C NMR (101 MHz, CDCl3) δ 158.6, 146.6, 144.3, 141.2, 139.8, 133.6, 127.9, 127.3, 127.3, 125.0, 125.0, 122.6, 121.4, 120.0, 113.9, 100.2, 65.8, 64.4, 51.9, 47.7, 47.7, 27.1, 25.5, 25.5, 21.2; HRMS (ESI) calcd for C25 H 28 N4O [M+H] + 401.2341, found: 401.2338. compound H2 1 H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 9.2 Hz, 1H), 7.37-7.31 (m, 4H), 7.05 (dd, J = 9.0, 2.6 Hz, 1H), 6.45 (d, J = 2.6 Hz, 1H), 5.95 (d, J = 7.7 Hz, 1H), 5.76 (t, J = 1.7 Hz, 1H), 5.70-5.61 (m, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.29-3.22(m, 4H), 2.12 (d, J = 1.8 Hz, 2H), 2.00-1.91 (m, 4H), 1.62 (d, J = 6.8 Hz, 3H),1.42-1.36 (m, 5H), 1.07 (s, 6H), 1.01 (s, 6H); 13 C NMR (101 MHz, CDCl3) δ160.1, 159.8, 144.5, 143.2, 142.1, 142.1, 142.0, 134.0, 134.0, 132.6, 127.6,126.4, 126.4, 125.5, HRMS (ESI) calcdfor C 32 H 42 N4O [M+H] + 499.3437, found: 499.3434. compound H3 11H NMR (400 MHz, CDCl3) δ 7.78 (d, J J = 9.0 Hz, 1H), 7.61 (d, J J = 8.4 Hz,2H), 7.37 (d, J J = 8.3 Hz, 2H), 7.10 - 7.03 (m, 1H), 6.08 (d, J J = 9.4 Hz, 1H), 5.74(t, J J = 1.7 Hz, 1H), 5.32 - 5.25 (m, 1H), 3.24 (d, J J = 5.1 Hz, 11H), 2.10 (d, J J = 1.7Hz, 2H), 1.98 - 1.91 (m, 4H), 1.86 (d, J J = 7.1 Hz, 3H), 1.38 (s, 2H), 1.05 (s,6H), 0.99 (s, 6H); 13 13C NMR (101 MHz, CDCl3) δ 158.4, 151.5, 144.5, 142.1,142.0, 133.9, 132.6, 127.0, 127.0, 126.4, 125.6, 125.6, 119.8, 119.6, 110.3,103.0, 52.3, 49.5, 49.5, 48.3, 41.4, 38.4, 33.0, 33.0, 31.6, 31.6, 30.8,30.0, 30.0, 25.4, 25.4, 22.4; HRMS (ESI) calcd for C 32 1H 43 N5[M + H] + 498.3597,found: 498.3597. Compound H4 1 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J J = 9.0 Hz, 1H), 7.54 (d, J J = 8.4 Hz,2H), 7.34 (d, J J = 8.3 Hz, 2H), 7.07 (s, 1H), 6.31 (d, J= 9.4 Hz, 1H), 5.73 (s,1H), 5.35 - 5.26 (m, 1H), 3.75 - 3.60 (m, 2H), 3.31 - 3.19 (m, 7H), 2.10 (d, J = 1.6Hz, 2H), 1.91 (t, J = 6.6 Hz, 4H), 1.83 (d, J = 7.1 Hz, 3H), 1.38 (s, 2H), 1.09(d, J = 7.1 Hz, 3H), 1.05 (s, 6H), 0.99 (s, 6H); 13 C NMR (101 MHz, CDCl3) δ158.4, 151.6, 144.5, 142.4, 141.9, 133.8, 132.6, 126.6, 126.6, 126.2, 125.3,125.3, 120.3, 119.9, 110.5, 102.6, 52.1, 49.5, 49.5, 48.3, 45.1, 41.4, 35.8,33.0, 31.6, 31.6, 30.8, 30.0, 30.0, 25.4, 25.4, 22.5, 12.4; HRMS (ESI) calcdfor C 33 H 45 N5[M + H] + 512.3753, found: 512.3755.[[ID=I7]] Compound H5 1 H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 6.8 Hz, 1H), 7.42 (d, J = 8.3 Hz,2H), 7.37 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 6.7 Hz, 1H), 7.16 (s, 1H), 6.23 (d, J =7.9 Hz, 1H), 5.75 (s, 1H), 5.33 - 5.24 (m, 1H), 3.68 (d, J = 9.9 Hz, 1H), 3.49(d, J= 5.3 Hz, 3H), 3.17 (t, J = 6.7 Hz, 4H), 2.11 (d, J = 1.6 Hz, 2H), 1.99 (t, J =6.5 Hz, 8H), 1.71 (d, J = 7.2 Hz, 3H), 1.38 (s, 2H), 1.06-0.98 (m, 12H); 13 C NMR(101 MHz, CDCl3) δ 158.2, 148.9, 144.0, 142.4, 141.6, 134.1, 132.5, 130.9,126.7, 126.7, 125.4, 125.4, 120.7, 118.2, 110.2, 104.0, 52.6, 52.1, 49.5,49.5, 49.1, 49.1, 41.4, 33.1, 31.5, 31.5, 30.8, 30.8, 30.0, 30.0, 30.0, 25.2,25.2, 21.7; HRMS (ESI) calcd for C 34 H 45 N5[M+H] + 524.3753, found: 524.3751. Affinity determination of the compounds (D1~D66, H1~H5) prepared in the above examples to SOS1 protein: Binding affinity was determined using a Biacore X100 instrument (GE Healthcare) via surface plasmon resonance (SPR) technology. SOS cat The protein was diluted to 50 μg / mL in immobilization buffer (10 mM Hepes, 150 mM NaCl, 3 mM EDTA, 0.005% Tween 20, pH 7.4) and covalently immobilized on a CM5 sensor chip (Cytiva) using amine coupling, with flow cell 1 set as the reference channel. All experiments were performed at 25°C. The analyte was serially diluted in flow buffer (PBS containing 5% DMSO, 3 mM EDTA, 0.05% surfactant P20, pH 7.4) at a flow rate of 30 μL / min in a flow path immobilized with SOS. cat The sample was introduced onto the sensing surface for 90 seconds, followed by 90 seconds of monitoring the dissociation process. Finally, the steady-state equilibrium dissociation constant (K0) was calculated using Biacore X100 evaluation software. D(Value). MRTX0902 was used as a positive control in this experiment.

[0031] Table 1. Affinity determination results of the compounds (D1~D66, H1~H5) of the present invention to SOS1 protein.

[0032] In vitro tumor cell proliferation inhibition activity assay of the compounds (D1~D66, H1~H5) prepared in the above examples The proliferative activity of colorectal cancer cell lines was assessed using the CCK-8 assay. SW620, SW837, GP2D, and HCT116 cells were cultured at 3 × 10⁶ cells per well. 4 Cells were seeded at a density of 1000 μL in 96-well plates and cultured for 24 hours to allow for full adhesion. The original culture medium was then discarded and replaced with fresh medium containing DMSO or different concentrations of the test compound, and cultured for another 120 hours. To quantitatively assess cell viability, 20 μL of CCK-8 reagent was added to each well. After a 2-hour reaction, the absorbance of each well was measured at 450 nm using a microplate reader (Thermo Fisher Scientific). The IC50 of the compound was calculated using GraphPad Prism 5.0 software. 50 The value was determined by using MRTX0902 as a positive control in this experiment.

[0033] Table 2. IC50 of the compounds of this invention against KRAS-mutant colorectal cancer. 50 Measurement results

[0034] Note: The experiment was repeated 3 times.

[0035] Activity assays of compounds H2 and H3 in an HCT116 cell xenograft model: Female BALB / c nude mice aged 6-8 weeks and weighing 18-22 g were subcutaneously inoculated with HCT116 cells (5 × 10⁻⁶ cells per mouse). 6 (cells). Wait until the tumor volume grows to approximately 100 mm. 3 Mice were then randomly assigned to six experimental groups (n = 6 per group) and received the following treatments: oral administration of saline, H2 (30 mg / kg), H2 (60 mg / kg), or MRTX0902 (60 mg / kg); or intraperitoneal injection of H3 (30 mg / kg) and H3 (60 mg / kg). Tumor volume and animal weight were measured every three days. At the end of the experiment, the tumors were dissected and weighed. The results are as follows: Figure 1 As shown. By Figure 1It can be seen that, compared with the positive control group MRTX0902, compounds H2 and H3 have better known effects on tumor growth in both the low-dose group (30 mg / kg) and the high-dose group (60 mg / kg), with compounds H2 and H3 showing particularly outstanding effects in the high-dose group (60 mg / kg).

[0036] As can be seen from the above embodiments, the compound provided by the present invention has the structure shown in Formula I. The compound with the structure shown in Formula I provided by the present invention exhibits excellent binding affinity for the SOS1 protein and can be used to treat various SOS1-mediated tumor diseases.

[0037] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. Other embodiments can be obtained based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A class of compounds, characterized in that, It has the structure shown in Equation I: Equation I; R4 in Equation I is selected from Naphthyl or C3-10 cycloalkyl; X, Y, and Z are independently selected from C or N, and R2 is selected from substituted or unsubstituted cyclohexenyl, hydrogen, C1-20 alkyl, halogen, cyano, methyl formate, halogen-substituted C1-10 alkyl, C1-10 alkoxy, methanesulfonyl, cyclopentenyl, cyclohexenone, phenyl, naphthyl, furanyl, thiophene, 3,6-dihydrothiopyranyl, 3,6-dihydro-2H-thiophenopyranyl, substituted or unsubstituted 1,2,3,6-tetrahydropyridyl or 3,6-dihydropyranyl. The substituent of the substituted cyclohexenyl is selected from halogen, C1-10 alkyl or halogen-substituted C1-10 alkyl, and the substituent on the substituted 1,2,3,6-tetrahydropyridyl is selected from formyl, benzyl or toluenesulfonyl. R1 is selected from substituted or unsubstituted 4-10 membered heterocyclic groups, hydrogen, C1-20 alkyl, C1-20 alkoxy, or substituted amino groups. The heteroatoms on the substituted or unsubstituted 4-10 membered heterocyclic groups are selected from one or more of N, O, and S. The number of heteroatoms is 1 to 3, and the heteroatoms can be the same or different. The substituents on the substituted 4-10 membered heterocyclic groups are selected from one or more of hydroxyl, C1-10 alkoxy, halogen, cyano, and C1-10 alkyl. The substituents on the substituted amino groups are selected from C1-10 alkyl or amino-substituted C1-10 alkyl. R3 is selected from C1-10 alkyl, C1-10 alkoxy, 5-8 member nitrogen heterocyclic group, C1-10 alkyl-substituted amino group or hydrogen.

2. The compound according to claim 1, characterized in that, R4 is selected from substituted or unsubstituted phenyl, C3-6 cycloalkyl, pyridyl, or naphthyl; the substituent on the substituted phenyl is selected from substituted or unsubstituted cyclohexenyl, C1-20 alkyl, halogen, cyano, methyl formate, halogen-substituted C1-10 alkyl, C1-10 alkoxy, methanesulfonyl, cyclopentenyl, cyclohexenone, phenyl, naphthyl, furanyl, thiophene, 3,6-dihydrothiopyranyl, 3,6-dihydro-2H-thienopyranyl, substituted or unsubstituted 1,2,3,6-tetrahydropyridyl, or 3,6-dihydropyranyl; the substituent on the substituted cyclohexenyl is selected from one or more of halogen, C1-10 alkyl, and halogen-substituted C1-10 alkyl; the substituent on the substituted 1,2,3,6-tetrahydropyridyl is selected from one or more of formyl, benzyl, and toluenesulfonyl.

3. The compound according to claim 2, characterized in that, The substituents on the substituted phenyl group are selected from substituted or unsubstituted cyclohexenyl, methyl, F, Cl, cyano, methyl formate, trifluoromethyl, methoxy, methylsulfonyl, cyclopentenyl, cyclohexenyl, cyclohexenone, phenyl, naphthyl, furanyl, thiophene, 3,6-dihydrothiopyranyl, 3,6-dihydro-2H-thiophenopyranyl, formyl-substituted 1,2,3,6-tetrahydropyridyl, benzyl-substituted 1,2,3,6-tetrahydropyridyl, toluenesulfonyl-substituted 1,2,3,6-tetrahydropyridyl, or 3,6-dihydropyranyl. The substituents on the substituted cyclohexenyl group are selected from one or more of methyl, F, trifluoromethyl, and tert-butyl. The number of substituents on the substituted cyclohexenyl group is 1 to 4, and the substituents on the substituted cyclohexenyl group can be the same or different.

4. The compound according to claim 1, characterized in that, R1 is selected from hydrogen, substituted or unsubstituted tetrahydropyrrolyl, methoxy, ethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropyl, cyclobutyl, dimethyl-substituted amino, methylethyl-substituted amino, cyclobutyl-substituted amino, cyclopentyl-substituted amino, cyclohexyl-substituted amino, cycloheptyl-substituted amino, substituted or unsubstituted 1,2,3,6-tetrahydropyridyl, , , , , , , , , , or The substituent of the substituted tetrahydropyrrole group is a C1-20 alkyl group; the substituent on the substituted 1,2,3,6-tetrahydropyridyl group is selected from one or more of halogen, methyl, hydroxy, methoxy and cyano groups.

5. The compound according to claim 1, characterized in that, R3 is selected from Any one of them.

6. The compound according to claim 1, characterized in that, Selected from any one of the following compounds: 。 7. The use of the compound, its isotope, pharmaceutically acceptable hydrate, solvate, polymorph or salt of any one of claims 1 to 6 in the preparation of an SOS1 inhibitor.

8. The use of the compound, its isotope, pharmaceutically acceptable hydrate, solvate, polymorph or salt of any one of claims 1 to 6 in the preparation of a medicament for treating SOS1-mediated diseases.

9. The application according to claim 8, characterized in that, The SOS1-mediated diseases include tumors.

10. A drug, characterized in that, Includes the compounds of any one of claims 1 to 6, their isotopes, pharmaceutically acceptable hydrates, solvates, polymorphs or salts, and pharmaceutically acceptable excipients.

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