CN116925098A

CN116925098A - Small molecule inhibitor targeting ubiquitin-specific protease 1 (USP 1) and application thereof

Info

Publication number: CN116925098A
Application number: CN202210371921.3A
Authority: CN
Inventors: 朱振东; 林光; 车超; 陈煌灿; 高振; 向德虎; 蒋顶; 张家银; 狄曼; 邓新平; 林镇金; 黎婷; 周梅; 师伟伟; 毕喜平; 杨震
Original assignee: Peking University Shenzhen Graduate School; Shenzhen Bay Laboratory
Current assignee: Peking University Shenzhen Graduate School; Shenzhen Bay Laboratory
Priority date: 2022-04-09
Filing date: 2022-04-09
Publication date: 2023-10-24

Abstract

The present application provides small molecules targeting ubiquitin-specific protease 1 (USP 1), and/or pharmaceutical compositions comprising the same, which are useful for treating diseases caused by diseases or disorders associated with ubiquitin-specific protease 1 (USP 1), such as, but not limited to, cancer, and other diseases or disorders associated with DNA damage, and the like, particularly cancers associated with BRCA1 or BRCA2 mutations.

Description

Small molecule inhibitor targeting ubiquitin-specific protease 1 (USP 1) and application thereof

Technical Field

The present application relates to the field of chemical drug synthesis and pharmacological applications, and to inhibitors of ubiquitin-specific protease 1 for the treatment of diseases or disorders related to ubiquitin-specific protease 1 (USP 1). In particular, the present application relates to compounds and compositions thereof that inhibit USP1, methods of treating diseases or conditions associated with USP1, and methods of their chemical synthesis.

Background

Ubiquitin is a small protein consisting of 76 amino acids. Ubiquitination refers to the process of specifically modifying a target protein by ubiquitin protein under the action of a series of special enzymes. Typically, polyubiquitin proteins are degraded by proteasomes, whereas monoubiquitin proteins are involved in the regulation of cellular pathways. Ubiquitination is a reversible process, called deubiquitination, involving a series of deubiquitination enzymes (DUBs). They regulate various cellular processes by removing ubiquitin proteins from target proteins.

DUBs are encoded by approximately 100 human genes and are divided into 7 families (USP, UCH, SENP, JAMM, OUT, MJD, MINDY), the largest of which is ubiquitin-specific protease (USP), with more than 50 protein members.

USP1 is a deubiquitin enzyme in the ubiquitin specific protease (USP 1) family. The full length, human USP1 protein consists of 785 amino acids, whose deubiquitinase activity is derived mainly from the catalytic triplet consisting of Cys90, his593 and Asp 751. USP1 itself is relatively inactive and only when bound to UAF1 (USP 1 related factor 1) as a heterodimeric complex, forms complete deubiquitinase activity and thus plays a role in DNA damage repair. Multiple studies have shown that USP1 is associated with processes such as tumor growth, survival, differentiation, etc. For example, the USP1/UAF1 complex can stabilize Proliferating Cell Nuclear Antigen (PCNA) by deubiquitination, which plays a role in trans-injury synthesis (TLS) (t., nijman, s.m., michandani, k.d., galardy, p.j., cohn, m.a., haas, w., D' Andrea, a.d. (2006) Regulation of monoubiquitinated PCNA by DUB autocleage. Nat Cell Biol,8 (4), 339-347.). Fanconi anemia complement protein D2 (FANCD 2) is a key protein in the Fanconi Anemia (FA) pathway, USP1 can stabilize FANCD2 by deubiquitination, regulating the FA pathway. These cellular pathways play a critical role in DNA damage repair induced by DNA crosslinkers (e.g., cisplatin and mitomycin C). DNA cross-linking repair requires deubiquitination of FANCD2 (Nijman, s.m., huang, t.t., dirac, a.m., brummelkamp, t.r., kerkhoven, r.m., D' Andrea, a.d., & Bernards, r. (2005) The deubiquitinating enzyme USP1 regulates the Fanconi anemia path.mol Cell,17 (3), 331-339). The PCNA and FANCD2 regulated DNA Damage Response (DDR) pathways are essential for repair of DNA damage caused by DNA crosslinkers such as cisplatin, mitomycin C, butylene oxide, ionizing radiation, and ultraviolet radiation.

In chicken DT40 cells, studies of knocking out USP1 and UAF1 respectively or together showed that all three clones showed similar sensitivity to chemical cross-linking agents, topoisomerase poison camptothecins and poly (A-dP) ribose polymerase inhibitors (PARP), indicating that the USP1/UAF1 complex is a regulator of cell response to DNA damage. Disruption of NHEJ in UAF 1-deficient cells restores the resistance of the cells to camptothecin and PARP inhibitors. The results of the study indicate that the USP1/UAF1 complex promotes HR, at least in part, by inhibiting NHEJ. (Murai, J., yang, K., dejsuchong, D., hirota, K., takeda, S., & D' Andrea, A.D. (2011) & The USP1/UAF1 complex promotes double-strand break repair through homologous recombination. Mol Cell Biol,31 (12), 2462-2469.)

Deubiquitinase USP1 promotes stability of ID protein and stem cell characteristics in osteosarcoma. USP1 binds, de-ubiquitinates, stabilizing ID1, ID2 and ID3.USP1 promotes maintenance and radiation resistance of tumor stem cells in glioblastomas by stabilizing ID1 and CHEK1, and plays a role in regulating proliferation and differentiation by deubiquitination and stabilizing DNA binding Inhibitors (IDs) that antagonize basic helix-loop-helix (BHLH) transcription factors. In osteosarcoma cells, knockout of the USP1 gene can lead to destabilization of the ID protein, cell cycle arrest and osteogenic differentiation. In contrast, high expression of USP1 by mesenchymal stem cells stabilizes ID protein, inhibits osteoblast differentiation, and promotes proliferation. Additionally, USP1 defects can result in reduced bone mass in mice (Williams, s.a., maecker, h.l., french, d.m., liu, j., gregg, a., silverstein, l.b., dixit, v.m. (2011). USP1 deubiquitinates ID proteins to preserve a mesenchymal stem cell program in ossarcoma.cell, 146 (6), 918-930). In summary, small molecule inhibitors targeting USP1 and their use in compositions are likely to be therapeutic approaches to cancer and other USP1 related diseases.

Disclosure of Invention

The present invention provides compounds of formula (I), or enantiomers, diastereomers, tautomers, salts, crystalline forms, solvates, and/or isotopically-substituted derivatives thereof, as inhibitors of USP 1:

wherein, the liquid crystal display device comprises a liquid crystal display device,

x is selected from: -S-, -O-, -NH-;

y is selected from: -CH ₂ -、-NR ^ya -、-C≡C-、-CH＝CH-；

R ^ya Selected from: hydrogen, C1-C4 straight chain alkyl;

preferably, R ^ya Selected from: hydrogen, methyl, ethyl, propyl;

preferably, R ^ya Selected from: hydrogen, methyl;

when Y is selected from-NR ^ya -、-CH ₂ -when n is 0 or 1;

when Y is selected from-C.ident.C-, -CH=CH-, n is 0;

R ₁ selected from: -H, -NR ^1a R ^1b 、-OR ^1c 、-CH ₂ R ^1d ；

R ^1a 、R ^1b 、R ^1c 、R ^1d Are identical or different and are selected, independently of one another, from: hydrogen, C1-C4 straight chain alkyl;

preferably, R ^1a 、R ^1b 、R ^1c 、R ^1d Are identical or different and are selected, independently of one another, from: hydrogen, methyl, ethyl, propyl;

further preferably, R ^1a 、R ^1b 、R ^1c 、R ^1d Are identical or different and are selected, independently of one another, from: hydrogen, methyl, ethyl;

R ₂ selected from phenyl, pyrimidinyl, said phenyl, pyrimidinyl being substituted with a substituent R ^2a One or more of the same or different substitutions;

R ^2a selected from: hydrogen, C1-C4 straight-chain alkyl or alkoxy, C3-C4 branched-chain alkyl or alkoxy, C3-C4 cycloalkyl or alkoxy, halogenated C1-C4 straight-chain alkyl or alkoxy, halogenated C3-C4 branched-chain alkyl or alkoxy, halogenated C3-C4 cycloalkyl or alkoxy;

Preferably, R ^2a Selected from: hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropyl, cyclopropyl, isopropoxy, and cyclopropaneOxy, trifluoromethyl, trifluoromethoxy, trichloromethyl, trichloromethoxy;

further preferably, R ^2a Selected from: isopropyl, methoxy, isopropoxy, trifluoromethoxy, cyclopropyl;

R ₃ selected from: phenyl, said phenyl being substituted by a substituent R ^3a One or more of the same or different substitutions;

R ^3a selected from: hydrogen, pyrazolyl, imidazolyl, triazolyl; the pyrazolyl, imidazolyl and triazolyl are substituted by the substituent R ₄ One or more of the same or different substitutions;

R ₄ selected from: hydrogen, C1-C4 straight-chain alkyl, C3-C4 branched-chain alkyl, halogenated C1-C4 straight-chain alkyl, halogenated C3-C4 branched-chain alkyl;

preferably, R ₄ Selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trichloromethyl;

further preferably, R ₄ Selected from: hydrogen, methyl, isopropyl, trifluoromethyl.

In a preferred embodiment, the present invention relates to a compound of general formula (I) of a USP1 inhibitor, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, wherein:

X is selected from: -S-, -O-, -NH-.

y is selected from: -CH ₂ -、-NH-、-NCH ₃ -、-C≡C-、-CH＝CH-。

R ₁ selected from: -H, -NHCH ₃ 、-NCH ₃ CH ₃ 、-OCH ₃ 、-CH ₃ 。

R ₂ selected from: isopropylphenyl, isopropyloxyphenyl, methoxyphenyl, trifluoromethoxyphenyl, and cyclopropylmethoxypyrimidinyl.

R ₃ selected from:

When X is selected from: -in the case of S-, the process,

y is selected from: -CH ₂ -、-NR ^ya -、-C≡C-；

R ^ya Selected from: hydrogen, C1-C4 straight chain alkyl;

preferably, R ^ya Selected from: hydrogen, methyl, ethyl, propyl;

further preferably, R ^ya Selected from: hydrogen, methyl;

when Y is selected from-NR ^ya -、-CH ₂ -when n is 0 or 1;

when Y is selected from-C≡C-, n is 0;

R ₁ selected from: -H, -NR ^1a R ^1b 、-OR ^1c 、-CH ₂ R ^1d ；

preferably, R ^1a 、R ^1b 、R ^1c 、R ^1d Are identical or different and are selected, independently of one another, from: hydrogen, methyl, ethyl, propyl; further preferably, R ^1a 、R ^1b 、R ^1c 、R ^1d Are identical or different and are selected, independently of one another, from: hydrogen, methyl, ethyl; r is R ₂ Selected from phenyl, pyrimidinyl, said phenyl, pyrimidinyl being substituted with a substituent R ^2a One or more of the same or different substitutions;

preferably, R ^2a Selected from: hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropyl, cyclopropyl, isopropoxy, cyclopropyloxy, trifluoromethyl, trifluoromethoxy, trichloromethyl, trichloromethoxy;

further preferably, R ₄ Selected from: hydrogen, methyl, isopropyl, trifluoromethyl;

x is selected from: in the case of the-O-phase,

y is selected from: -CH ₂ -、-C≡C-、-CH＝CH-；

When Y is selected from-CH ₂ -when n is 0 or 1;

when Y is selected from-c≡c-, -ch=ch-, n is 0;

R ₁ selected from: -H;

R ₂ selected from phenyl groups, said phenyl groups being substituted by a substituent R ^2a One or more of the same or different substitutions;

still more preferably, R ^2a Selected from: isopropyl, trifluoromethoxy;

R ^3a selected from: hydrogen, pyrazolyl, imidazolyl, triazolyl; the pyrazolyl, imidazolyl and triazolyl are substituted by the substituent R ₄ One or more of the same or different substitutions; r is R ₄ Selected from: hydrogen, C1-C4 straight-chain alkyl, C3-C4 branched-chain alkyl, halogenated C1-C4 straight-chain alkyl, halogenated C3-C4 branched-chain alkyl;

x is selected from: in the case of the-NH-phase,

y is selected from: -CH ₂ -、-C≡C-；

When Y is selected from-CH ₂ -when n is 0 or 1;

when Y is selected from-C≡C-, n is 0;

R ₁ selected from: -H;

still more preferably, R ^2a Selected from: isopropyl, trifluoromethoxy;

In a preferred embodiment, the present invention relates to a compound of general formula (I) of a USP1 inhibitor, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, wherein: the compound is selected from:

/>

in another embodiment, the invention also relates to pharmaceutical compositions comprising one or more compounds of the above general formula (I) according to the invention, or enantiomers, diastereomers, tautomers, salts, crystalline forms, solvates and/or isotopically substituted derivatives thereof.

In another embodiment, the invention also relates to a pharmaceutical composition comprising one or more compounds of the above general formula (I) according to the invention, or enantiomers, diastereomers, tautomers, salts, crystalline forms, solvates and/or isotopically substituted derivatives thereof, and/or optionally a pharmaceutically acceptable carrier, excipient or diluent.

In another embodiment, the present invention also relates to a method for the treatment and/or prophylaxis of a disease or condition caused by the activity of ubiquitin-specific protease 1 (USP 1), said method comprising administering to a subject an effective amount of a compound relating to the general formula (I) above, or an enantiomer, diastereomer, tautomer, salt, crystal form, solvate and/or isotopically substituted derivative thereof.

In another embodiment, the present invention also relates to the use of a compound according to the present invention comprising one or more of the above general formula (I), or an enantiomer, diastereomer, tautomer, salt, crystal form, solvate and/or isotopically substituted derivative thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of a disease caused by ubiquitin-specific protease 1 (USP 1) activity, comprising administering to a subject an effective amount of at least one compound according to the present invention, or an enantiomer, diastereomer, tautomer, salt, crystal form, solvate and/or isotopically substituted derivative thereof.

In another embodiment, the present invention also relates to a method for treating and/or preventing a disease or disorder caused by ubiquitin-specific protease 1 (USP 1) activity comprising administering to a subject an effective amount of at least one pharmaceutical composition according to the present invention.

In another embodiment, the present invention also relates to the use of a pharmaceutical composition comprising one or more of the above-mentioned pharmaceutical compositions according to the present invention for the manufacture of a medicament for the treatment and/or prevention of a disease caused by ubiquitin specific protease 1 (USP 1) activity comprising administering to a subject an effective amount of at least one pharmaceutical composition according to the present invention.

In a preferred embodiment, the disease is: cancer, or a disease or disorder associated with DNA damage. In particular cancers associated with BRCA1 or BRCA2 mutations.

General synthesis of target molecules scheme 1:

intermediate A-2 (R) ₁ =h): taking 5g of raw material A-1, naHCO ₃ (4 g,2.0 eq), 50mL of methanol were added to a 100mL reaction flask, followed by 250mg of 10% Pd/C and hydrogen displacement 3 times. After 24h at room temperature 250mg of 10% Pd/C are added.

After 24h at room temperature, intermediate A-2 was obtained by filtration through celite.

Intermediate A-2 (R) ₁ ＝NR ^1a R ^1b ): raw material A-1 (5 g,1 eq) was taken, and secondary amine HNR ^1a R ^1b (1.1 eq), TEA (2.2 eq) was added to a 100mL reaction tube, 50mL DMF was added, and the reaction was carried out at 70℃for 12h. After the reaction, cooling to room temperature, adding ethyl acetate for dilution, adding water, extracting with ethyl acetate for 3 times, combining organic phases, backwashing with saturated saline water for 3 times, drying with anhydrous sodium sulfate, and separating and purifying by silica gel column chromatography to obtain an intermediate A-2.

Intermediate A-4: raw material A-2 (5 mmol,1.0 eq) and boric acid A-3 (7.5 mmol,1.5 eq) Pd (dppf) were taken ₂ Cl ₂ (0.25mmol,0.05eq)，K ₂ CO ₃ (15 mmol,3.0 eq) was added sequentially to a 50mL reaction tube, 1,4-dioxane/water (v/v=5:1, 10 mL), N2 protected, and reacted at 90℃for 16h. After the reaction, cooling to room temperature, filtering, spin-drying, and obtaining an intermediate A-4 through silica gel column chromatography.

Intermediate A-5: raw material a-4 (2 mmol,1.0 eq), NIS (4 mmol,2.0 eq) was taken in a 50ml reaction tube, acOH: TFA (v/v=5:1, 10 ml) was added and the reaction was heated at reflux for 12h. TLC monitoring, reaction was not completely supplemented with appropriate amounts of NIS and TFA. After the reaction was completed, cooled to room temperature, the reaction was poured into ice water, ph=9-10 was adjusted with sodium bicarbonate, extraction was performed 3 times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and isolated by silica gel column chromatography to give intermediate a-5.

Target molecule a-7: raw material A-5 (0.1 mmol,1.0 eq), raw material alkyne A-6 (0.1 mmol,1.0 eq), pd (PPh ₃ ) ₂ Cl ₂ (5% mol) CuI (10% mol) was added to a 10mL reaction tube, followed by 1mL triethylamine, nitrogen protection, and reaction at room temperature for 16 hours. After the reaction, ethyl acetate is added for dilution, water is used for washing for 2 times, the organic phase is dried by anhydrous sodium sulfate, and the compound A-7 is obtained through separation and purification of preparative thin layer chromatography.

Target molecule a-8: 10-20mg of raw material A-7 is taken and dissolved in methanol or ethyl acetate, 3-5mg of 10% Pd/C is added, hydrogen is replaced for 3 times, and the reaction is carried out for 6-12 hours at room temperature. After the reaction, the organic phase is dried by spin-drying through diatomite filtration, and the compound A-8 is obtained through separation and purification of preparative thin layer chromatography.

General synthesis of target molecules scheme 2:

intermediate B-2, 5g of raw material B-1, naHCO ₃ (1 g,2.0 eq), 50mL of methanol were added to a 100mL reaction flask, followed by 250mg of 10% Pd/C and hydrogen displacement 3 times. After 16h at room temperature, the mixture was filtered through celite and separated by silica gel column chromatography to give intermediate B-2 (610 mg,74% yield). ¹ H NMR(400MHz,DMSO-d ₆ )δ12.05(s,1H),8.82(d,J＝0.8Hz,1H),8.00(t,J＝2.9Hz,1H),6.58(ddd,J＝2.6,1.6,0.8Hz,1H)。

Intermediate B-3: intermediate B-2 (0.61 g,15 mmol), (Boc) ₂ O (18 mmol,1.2 eq) was dissolved in 25ml THF, TEA (22.5 mmol,1.5 eq) and DMAP (0.15 mmol,0.01 eq) was added and reacted at room temperature for 2h. After the reaction, directly stirring the sample with silica gel, and separating and purifying by silica gel column chromatography to obtain an intermediate B-3 (700 mg,69% yield). ¹ H NMR(500MHz,Chloroform-d)δ9.24(s,1H),8.01(s,1H),6.73(dd,J＝3.7,0.7Hz,1H),1.70(s,9H)。

Intermediate B-4 Synthesis of intermediate A-4 by reference to general scheme 1.

Intermediate B-5 the intermediate B-4 obtained above was taken and dissolved in a suitable amount of dichloromethane, and trifluoroacetic acid (TFA/DCM, v/v=4:1) was added and reacted at room temperature for 2h. At the end of the reaction, a large amount of solvent is removed in vacuo, diluted with dichloromethane, placed in an ice bath, adjusted to ph=9-10 with saturated sodium bicarbonate, extracted 3 times with dichloromethane, the organic phases are combined and separated and purified by silica gel column chromatography to give compound B-5.

Intermediate B-6 the compound B-5 (2.5 mmol,1.0 eq) obtained above was dissolved in 5mL DMF, KOH (5 mmol,2.0 eq) was added, elemental iodine (3 mmol,1.2 eq) was added and the reaction was carried out at room temperature for 1-6h. And after the reaction is finished, adding water for quenching, adding ethyl acetate for dilution, extracting for 3 times by using ethyl acetate, combining organic phases, backwashing for 1 time by using saturated sodium thiosulfate, backwashing for 3 times by using saturated saline, drying the organic phases by using anhydrous sodium sulfate, and separating and purifying by using silica gel column chromatography to obtain an intermediate B-6.

Target molecule B-7 raw material B-6 (0.1 mmol,1.0 eq), alkyne (0.1 mmol,1.0 eq), pd (PPh ₃ ) ₂ Cl ₂ (5% mol) CuI (10% mol) was added to a 10ml reaction tube, followed by 0.5ml triethylamine and 0.5ml tetrahydrofuran, and reacted at 40℃for 16 hours under nitrogen. After the reaction, ethyl acetate is added for dilution, water is used for washing for 2 times, the organic phase is dried by anhydrous sodium sulfate, and the compound B-7 is obtained through separation and purification of preparative thin layer chromatography.

Target molecule B-8: reference is made to the procedure for the synthesis of A-8 in general scheme 1.

General synthesis of target molecules scheme 3:

general scheme 3 the procedure is as described in general scheme 1, except that the order of the reactions is different.

Intermediate C-1 (R) ₁ ＝OR ^1c ): weigh compound A-1 (1 equivalent), add 2 equivalents R ^1c ONa, adding solvent MeOH, reacting at 80 ℃ for 12 hours, concentrating after the reaction is finished, and passing through a column to obtain C-1.

Intermediate C-1 (R) ₁ =alkyl): weighing compound A-1 (1 equivalent), 0.1 equivalent Pd (dppf) 2Cl2,3 equivalent K2CO3,1.1 equivalent alkyl boric acid, evacuating, charging nitrogen, adding solvent dioxane/H under nitrogen atmosphere ₂ O, reaction at 90℃for 12h. After the reaction is completed, anhydrous sodium sulfate is dehydrated, an organic phase is concentrated and is passed through a column to obtain an alkylation product C-1.

Intermediate C-1 (R) ₁ ＝NHR ^1b ): weighing the compound A-1 (1 equivalent), 2 equivalents of alkylamine hydrochloride, 3 equivalents of DIPEA, solvent DMF, and 80 ℃ for 12 hours, extracting EtOAc and saturated saline after the reaction is completed, collecting an organic phase, concentrating, drying and passing through a column to obtain an alkylamine product C-1.

Intermediate synthesis scheme 1:

intermediate F-2: 4g of 1, 1-dibromo-3, 3-trifluoroacetone was taken and added to a 10mL reaction flask, followed by 1g of sodium acetate and 2mL of water in that order, and the reaction was carried out at 100℃for 1 hour. After the reaction, the reaction mixture was cooled to room temperature, and the reaction mixture 1 was used. 3g of terephthalaldehyde acetal was charged into a 250mL reaction flask, and 10mL of ammonia water and 50mL of methanol were sequentially added, followed by the above-mentioned reaction solution 1. After the reaction was carried out at room temperature for 1 hour, the reaction was carried out at 100℃for 1 hour. At the end of the reaction, cool to room temperature, remove a large amount of methanol in vacuo and dilute with 50ml of ethyl acetate. Subsequently, extraction was performed 3 times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and passed through a column to give the product F-2 (4 g,88% yield). ¹ H NMR(300MHz,Chloroform-d)δ7.81(dd,J＝8.4,3.0Hz,2H),7.53(dd,J＝8.3,2.5Hz,2H),7.43(d,J＝1.4Hz,1H),3.59(tddd,J＝16.5,14.0,7.1,4.6Hz,3H),3.31(s,1H),1.29-1.21(m,6H)。

Intermediate F-3: a25 mL reaction flask was taken, intermediate F-2 (1 g,3.18 mmol) above was added, and 15mL of anhydrous THF solution was added, and placed in an ice bath, 60% NaH (6.36 mmol,2.0 eq) was added. After stirring the reaction in an ice bath for 1h, the corresponding halide (6.36 mmol,2.0 eq) was added followed by 2h reaction from ice bath to room temperature. After the reaction, THF was added for dilution, water was added for quenching, followed by extraction with ethyl acetate for 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, and isolated and purified by silica gel column chromatography to give intermediate F-3.

Intermediate F-4: the intermediate F-3 obtained above was taken and dissolved in 10ml of THF, and 5M HCl solution was added dropwise in an ice bath. After the addition, the reaction was carried out at room temperature for 2 hours. At the end of the reaction, a large amount of THF solvent was removed in vacuo. Adding ethyl acetate for dilution, and adding saturated sodium bicarbonate solution for regulating the pH to be 8-9. Extracted 3 times by ethyl acetate, dried by anhydrous sodium sulfate, filtered and spin-dried to obtain an intermediate F-4, which is directly used in the next step.

Intermediate F-5: taking the intermediate F-4 obtained above, and sequentially adding K ₂ CO ₃ (3.0 eq) in 5ml of methanol, BThe estmann-Ohira reagent (1.5 eq) was reacted at room temperature for 1h. And after the reaction is finished, directly stirring a sample, passing through a column, and separating and purifying by silica gel column chromatography to obtain an intermediate F-5.

Intermediate L-1 when the halide in the step of synthesizing intermediate F-3 was MeI, the compound F-5 obtained above was intermediate L-1 (r=me) (180 mg,60% yield). ¹ H NMR(300MHz,Chloroform-d)δ7.65-7.57(m,4H),7.32(q,J＝1.2Hz,1H),3.78(s,3H),3.18(s,1H)。

Intermediate L-2 when the halide in the step of synthesizing intermediate F-3 was iPrBr, the compound F-5 obtained above was intermediate L-2 (r=ipr) (200 mg,66% yield). ¹ H NMR(300MHz,Chloroform-d)δ7.63-7.55(m,2H),7.52(d,J＝2.5Hz,2H),7.43(d,J＝1.3Hz,1H),4.55(p,J＝6.7Hz,1H),1.46(d,J＝6.7Hz,6H)。

Intermediate synthesis scheme 2:

intermediate F-7: raw material F-6 (1 g,5.60mmol, hydrochloride form) was taken and dissolved in 10mL Hexafluoroisopropanol (HFIP), raw material a (1.3 g,1.5 eq) was added and TEA (1.2 g,2.0 eq) was slowly added dropwise at room temperature. After the addition, the mixture was reacted at room temperature for 2 hours. After the completion of the reaction, water was added, diluted with ethyl acetate, extracted with ethyl acetate 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to give intermediate F-7 (1 g,53% yield). ¹ H NMR(300MHz,Chloroform-d)δ7.87-7.76(m,2H),7.73-7.59(m,2H),6.52(s,1H),2.44(d,J＝0.8Hz,3H)。

Intermediate F-8: taking the raw material F-7, adding 5ml of ethanol, adding 1ml of 1N NaOH solution, heating the reaction to 80 ℃ and reacting for 16 hours. Reaction junctionAnd (3) bundling, cooling to room temperature, slowly dropwise adding 1M HCl solution into an ice bath, and until solid is separated out, wherein the pH=3-4. Filtering, and vacuum-evacuating to remove water to obtain compound F-8 (310 mg,57% yield). ¹ H NMR(300MHz,Chloroform-d)δ8.34–8.16(m,2H),7.68–7.55(m,2H),6.51(s,1H),2.43(s,3H)。

Intermediate F-9: the intermediate F-8 (310 mg,1.15 mmol) obtained above was taken in a 25mL reaction flask, and an anhydrous THF solution (10 mL) was added, and the reaction was placed in an ice bath and cooled to 0 ℃. Subsequently, lithium aluminum hydride (70 mg,1.5 eq) was added, and the mixture was slowly warmed to room temperature and reacted for 2 hours. After the reaction, the mixture was put in an ice bath, diluted with tetrahydrofuran, quenched with ice water, filtered, dried over anhydrous sodium sulfate and dried in vacuo to give Compound F-9 (290 mg) as the immediately next step.

Intermediate F-10: raw material F-9 was dissolved in 5mL of methylene chloride, and Dess-Martin reagent (1.2 eq) was added thereto and reacted at room temperature for 2 hours. After the reaction, the compound F-10 (330 mg) was directly obtained by silica gel column chromatography and purification, and the next step was performed.

Intermediate L-3: see also methods for intermediate F-5 synthesis to give compound L-3 (330 mg,88% yield). ¹ H NMR(300MHz,Chloroform-d)δ7.67-7.55(m,2H),7.50-7.39(m,2H),6.47(s,1H),3.17(s,1H),2.37(d,J＝0.8Hz,3H)。

Intermediate synthesis scheme 3:

intermediate F-12: raw material F-11 (1 g,10.4 mmol), raw material b (3.1 g,2.0 eq), cu (OAc) was taken ₂ (1.9g,1.0eq),TEA(2.1g,2.0eq),Molecular sieves (500 mg), 10mL of methylene chloride were added sequentially to a 50mL reaction flask, and the reaction was allowed to react overnight at 35-40 ℃. After the completion of the reaction, the mixture was cooled to room temperature, filtered, and purified by silica gel column chromatography to give Compound F-12 (1 g,75% yield). ¹ H NMR(400MHz,Chloroform-d)δ10.03(s,1H),8.01-7.92(m,2H),7.70-7.62(m,2H),6.05(s,1H),2.40(d,J＝0.9Hz,3H),2.30(s,3H)。

Intermediate L-4: see, intermediate F-5 synthesis to afford compound L-4 (500 mg,51% yield). ¹ H NMR(300MHz,Chloroform-d)δ7.62-7.51(m,2H),7.46-7.34(m,2H),6.00(s,1H),3.12(s,1H),2.32(d,J＝0.7Hz,3H),2.29(s,3H)。

Intermediate synthesis scheme 4:

intermediate F-14: dissolving raw material F-13 (500 mg,1.97 mmol) in 5mL of methanol, adding NaBH ₄ (112 mg,1.5 eq) was reacted at room temperature for 1h. At the end of the reaction, saturated ammonium chloride was added to quench, extraction was performed 3 times with ethyl acetate, and the organic phases were combined and purified by column chromatography on silica gel to give F-14 (450 mg,89% yield). ¹ H NMR(300MHz,Chloroform-d)δ7.56-7.48(m,2H),7.38(d,J＝8.2Hz,2H),7.30(t,J＝1.3Hz,1H),4.71(s,2H),3.73(s,3H)。

Intermediate L-5F-14 obtained above is dissolved in 5mL of dichloromethane solution, and CBr is added ₄ (690mg,1.2eq)，PPh ₃ (550 mg,1.2 eq) was reacted at room temperature for 2h. After the completion of the reaction, a large amount of the solvent was removed, diluted with methylene chloride, washed with water 2 times, and separated and purified by silica gel column chromatography to give L-5 (250 mg,44% yield). ¹ H NMR(300MHz,Chloroform-d)δ7.67-7.59(m,2H),7.57-7.46(m,2H),7.32(d,J＝1.3Hz,1H),4.53(s,2H),3.79(s,3H)。

Intermediate synthesis scheme 5:

intermediate F-15: referring to the synthesis of intermediate F-2, compound F-15 (457mg, 60% yield) was obtained. ¹ H NMR(400MHz,Chloroform-d)δ7.69(d,J＝7.2Hz,2H),7.39(s,1H),7.30(d,J＝8.4Hz,2H),7.03(s,1H),1.53(s,9H)。

Intermediate F-16: referring to the procedure for the synthesis of intermediate F-3, compound F-16 (410 mg,83% yield) was synthesized. ¹ HNMR(300MHz,Chloroform-d)δ7.59-7.54(m,2H),7.37-7.32(m,2H),7.28(q,J＝1.2Hz,1H),3.74(s,3H),3.27(s,3H),1.45(s,9H)。

Intermediate L-6: the F-16 obtained above was dissolved in 10mL of methylene chloride, 3mL of TFA was added, and the reaction was carried out at room temperature for 2 hours. At the end of the reaction, a large amount of solvent was removed in vacuo, diluted by adding dichloromethane, and ph=9-10 was adjusted by dropwise addition of saturated aqueous sodium bicarbonate. The mixture was extracted 3 times with methylene chloride, and the organic phases were combined and purified by silica gel column chromatography to give compound L-6 (251 mg,85% yield). ¹ H NMR(300MHz,Chloroform-d)δ7.48-7.41(m,2H),7.24(d,J＝1.1Hz,1H),6.67-6.62(m,2H),3.73(s,3H),2.88(s,3H)。

Intermediate synthesis scheme 6:

intermediate F-17: referring to the procedure for the synthesis of intermediate F-2, compound F-17 (1.1 g,64% yield) was obtained. ¹ H NMR(500MHz,Chloroform-d)δ11.13(s,1H),8.27-8.23(m,2H),8.06-8.01(m,2H),7.53(d,J＝1.7Hz,1H)。

Intermediate F-18: referring to the procedure for the synthesis of intermediate F-3, compound F-18 (770 mg,66% yield) was obtained. ¹ H NMR(300MHz,Chloroform-d)δ8.38-8.29(m,2H),7.90-7.82(m,2H),7.39(q,J＝1.2Hz,1H),3.86(s,3H)。

Intermediate L-7: the compound F-18 obtained above was dissolved in 10mL of chloroform, zinc powder (1.09 g,4 eq) was added thereto, and 0.5-1mL of acetic acid was added dropwise. The reaction was carried out at room temperature, and the spot plate was followed until the reaction was completed. The organic phase was filtered, dried by spin, and purified by silica gel column chromatography to give L-7 (551 mg,53% yield). ¹ H NMR(400MHz,Chloroform-d)δ7.45-7.40(m,2H),7.25(d,J＝1.5Hz,1H),6.77-6.71(m,2H),3.72(s,3H)。

Example 1:

example 1 was synthesized with reference to the procedure of general synthesis 1: (30 mg,73% yield). ¹ H NMR (500 mhz, chloroform-d) delta 9.41 (s, 1H), 8.23 (s, 1H), 7.81 (dd, j=7.7, 1.4hz, 1H), 7.72-7.68 (m, 2H), 7.66 (d, j=8.6 hz, 2H), 7.51 (dd, j=8.0, 1.4hz, 1H), 7.46 (td, j=7.5, 1.5hz, 1H), 7.35-7.31 (m, 2H), 3.81 (s, 3H), 3.68 (dt, j=13.4, 6.7hz, 1H), 1.35 (d, j=6.9 hz, 6H); high resolution Mass Spectrometry C ₂₈ H ₂₂ F ₃ N ₄ S[M+H] ⁺ Calculated value 503.15173, found: 503.15073.

example 2:

example 2 was synthesized with reference to the procedure of general synthesis 1: (12 mg,61% yield). ¹ H NMR (500 mhz, chloroform-d) delta 9.35 (s, 1H), 7.74 (dd, j=7.7, 1.5hz, 1H), 7.54 (dd, j=6.4, 1.8hz, 3H), 7.50 (dd, j=8.0, 1.3hz, 1H), 7.45 (td, j=7.5, 1.5hz, 1H), 7.34-7.31 (m, 1H), 7.31-7.27 (m, 3H), 3.75 (s, 3H), 3.66 (q, j=6.8 hz, 1H), 3.34 (dd, j=8.6, 6.7hz, 2H), 1.30 (d, j=6.9, 6H); high resolution Mass Spectrometry C ₂₈ H ₂₆ F ₃ N ₄ S[M+H] ⁺ Calculated value 507.18303, found: 507.18259.

example 3:

example 3 (24 mg,53% yield) was synthesized with reference to the procedure of general synthesis 1. Structural characterization: ¹ h NMR (400 mhz, chloroform-d) delta 9.39 (s, 1H), 8.22 (s, 1H), 7.80 (dd, j=7.7, 1.5hz, 1H), 7.71-7.66 (m, 2H), 7.58-7.53 (m, 2H), 7.51-7.46 (m, 1H), 7.44 (td, j=4.0, 3.0,1.6hz, 2H), 7.31 (td, j=7.4, 1.5hz, 1H), 4.58 (p, j=6.7 hz, 1H), 3.70-3.63 (m, 1H), 1.47 (d, j=6.6 hz, 6H), 1.34 (d, j=6.9 hz, 6H). Mass spectrum C ₃₀ H ₂₆ F ₃ N ₄ S[M+H] ⁺ Calculated 531.2, found: 531.3.

example 4:

example 4 (9 mg,65% yield) was synthesized with reference to the procedure of general synthesis 1. Structural characterization: ¹ h NMR (400 mhz, chloroform-d) delta 9.35 (s, 1H), 7.74 (dd, j=7.7, 1.4hz, 1H), 7.53 (d, j=3.6 hz, 1H), 7.51-7.48 (m, 1H), 7.46-7.43 (m, 3H), 7.40 (d, j=1.3 hz, 1H), 7.35-7.30 (m, 1H), 7.28 (s, 2H), 4.54 (p, j=6.6 hz, 1H), 3.68-3.61 (m, 1H), 3.33 (dd, j=8.7, 6.5hz, 2H), 3.17 (dd, j=8.7, 6.6hz, 2H), 1.44 (d, j=6.7 hz, 6H), 1.29 (d, j=6.9 hz, 6H). Mass spectrum C ₃₀ H ₃₀ F ₃ N ₄ S[M+H] ⁺ Calculated 535.2, found: 535.3.

example 5:

example 5 (20 mg,46% yield) was synthesized with reference to the procedure of general synthesis 1. Structural characterization: ¹ h NMR (300 mhz, chloro-d) delta 9.40 (s, 1H), 8.23 (s, 1H), 7.80 (dd, j=7.7, 1.5hz, 1H), 7.73-7.68 (m, 2H), 7.52-7.44 (m, 4H), 7.32 (td, j=7.4, 1.6hz, 1H), 6.48 (s, 1H), 3.70-3.61 (m, 1H), 2.38 (s, 3H), 1.34 (d, j=6.8 hz, 6H); mass spectrum C ₂₈ H ₂₁ F ₃ N ₄ SNa[M+Na] ⁺ Calculated 525.1, found: 525.2.

example 6:

example 6 (6 mg,52% yield) was synthesized with reference to the procedure of general synthesis 1. Structural characterization: ¹ h NMR (500 mhz, chloroform-d) delta 9.36 (s, 1H), 7.77-7.70 (m, 1H), 7.57 (s, 1H), 7.51 (d, j=7.8 hz, 1H), 7.48-7.43 (m, 1H), 7.37-7.32 (m, 3H), 7.30 (d, j=8.1 hz, 2H), 6.45 (s, 1H), 3.65 (p, j=6.9 hz, 1H), 3.34 (t, j=7.7 hz, 2H), 3.19 (dd, j=8.8, 6.6hz, 2H), 2.32 (s, 3H), 1.30 (d, j=6.8 hz, 6H); mass spectrum C ₂₈ H ₂₆ F ₃ N ₄ S[M+H] ⁺ Calculated value 507.2, found: 507.1.

example 7:

example 7 (19 mg,51% yield) was synthesized with reference to the procedure of general synthesis 1. Structural characterization: ¹ h NMR (500 mhz, chloroform-d) delta 9.40 (s, 1H), 8.21 (s, 1H), 7.81 (dd, j=7.7, 1.4hz, 1H), 7.69-7.64 (m, 2H), 7.51 (dd, j=7.8, 1.4hz, 1H), 7.48-7.43 (m, 3H), 7.32 (td, j=7.5, 1.4hz, 1H), 6.02 (s, 1H), 3.70-3.65 (m, 1H), 2.35 (d, j=0.8 hz, 3H), 2.31 (s, 3H), 1.34 (d, j=6.8 hz, 6H); mass spectrum C ₂₈ H ₂₅ N ₄ S[M+H] ⁺ Calculated value 449.2, found: 449.2.

example 8

Example 8 (6 mg,49% yield) was synthesized with reference to the procedure of general synthesis 1. Structural characterization: ¹ h NMR (300 mhz, chloroform-d) delta 9.34 (s, 1H), 7.73 (dd, j=7.7, 1.5hz, 1H), 7.54-7.48 (m, 2H), 7.43 (dd, j=7.8, 1.5hz, 1H), 7.36-7.29 (m, 3H), 7.23 (d, j=8.4 hz, 2H), 5.97 (s, 1H), 3.65 (H, j=7.1 hz, 1H), 3.32 (t, j=7.6 hz, 2H), 3.15 (dd, j=8.6, 6.5hz, 2H), 2.28 (d, j=7.3 hz, 6H), 1.29 (d, j=6.8 hz, 6H); mass spectrum C ₂₈ H ₂₉ N ₄ S[M+H] ⁺ Calculated 453.2, found: 453.2.

example 9

Example 9 (33 mg,84% yield) was synthesized with reference to the procedure of general synthesis 1. Structural characterization: ¹ H NMR(400MHz,Chloroform-d)δ9.38(s,1H),8.18(s,1H),7.82(dd,J＝7.7,1.5Hz,1H),7.64-7.56(m,2H),7.51(dd,J＝7.9,1.4Hz,1H),7.45(td,J＝7.5,1.5Hz,1H),7.39-7.29 (m, 4H), 3.69 (hept, j=6.8 hz, 1H), 1.35 (d, j=6.9 hz, 6H); mass spectrum C ₂₃ H ₁₉ N ₂ S[M+H] ⁺ Calculated value 355.1, found: 355.1.

example 10

Example 10 (10 mg,66% yield) was synthesized with reference to the procedure of general synthesis 1. Structural characterization: ¹ h NMR (300 mhz, chloro-d) δ9.34 (d, j=3.4 hz, 1H), 7.74 (dd, j=7.7, 1.5hz, 1H), 7.56-7.41 (m, 3H), 7.39-7.27 (m, 3H), 7.23-7.16 (m, 3H), 3.63 (tt, j=13.7, 6.8hz, 1H), 3.31 (dd, j=8.9, 6.5hz, 2H), 3.11 (dd, j=8.9, 6.5hz, 2H), 1.30 (d, j=6.9 hz, 6H); mass spectrum C ₂₃ H ₂₃ N ₂ S[M+H] ⁺ Calculated value 359.2, found: 359.0.

Example 11

Example 11 (35 mg,78% yield) was synthesized with reference to the procedure of general synthesis 1. Structural characterization: ¹ h NMR (500 mhz, chloro-d) delta 9.40 (s, 1H), 8.24 (s, 1H), 8.02 (s, 1H), 7.86 (s, 1H), 7.80 (d, j=7.7 hz, 1H), 7.75 (q, j=8.4 hz, 4H), 7.51 (d, j=7.9 hz, 1H), 7.46 (t, j=7.5 hz, 1H), 7.32 (t, j=7.4 hz, 1H), 3.65 (H, j=6.9 hz, 1H), 1.34 (d, j=6.8 hz, 6H); mass spectrum C ₂₅ H ₂₀ N ₅ S[M+H] ⁺ Calculated value 422.1, found: 422.1.

example 12

Example 12 was synthesized (5 mg,27% yield) with reference to the procedure of general synthesis 1. Structural characterization: ¹ H NMR(300MHz,Chloroform-d)δ9.35(s,1H),7.95(d,J＝1.1Hz,1H),7.84(d,J＝1.1Hz,1H),7.78-7.70(m,1h) 7.69-7.60 (m, 2H), 7.56 (d, j=0.9 hz, 1H), 7.55-7.41 (m, 2H), 7.37-7.29 (m, 3H), 3.62 (H, j=6.8 hz, 1H), 3.34 (dd, j=8.8, 6.4hz, 2H), 3.19 (dd, j=8.7, 6.4hz, 2H), 1.29 (d, j=6.9 hz, 6H); mass spectrum C ₂₅ H ₂₄ N ₅ S[M+H] ⁺ Calculated value 426.2, found: 426.1.

example 13

/>

Example 13 (25 mg,56% yield) was synthesized with reference to the procedure of general synthesis 1. Structural characterization: ¹ h NMR (400 mhz, chloro-d) delta 9.39 (s, 1H), 8.23 (s, 1H), 8.17 (dd, j=7.6, 1.9hz, 1H), 7.71 (d, j=8.4 hz, 2H), 7.65 (d, j=8.3 hz, 2H), 7.62 (d, j=1.6 hz, 1H), 7.52 (td, j=7.7, 1.9hz, 1H), 7.46-7.42 (m, 1H), 7.31 (d, j=1.5 hz, 1H), 3.78 (s, 3H); mass spectrum C ₂₆ H ₁₅ F ₆ N ₄ OS[M+H] ⁺ Calculated value 545.1, found: 545.

example 14

Example 14 (11 mg,81% yield) was synthesized with reference to the procedure of general synthesis method 1. Structural characterization: ¹ h NMR (300 mhz, chloro-d) delta 9.35 (s, 1H), 8.10 (dd, j=7.4, 2.1hz, 1H), 7.55-7.41 (m, 7H), 7.29 (s, 2H), 3.74 (s, 3H), 3.34 (t, j=7.5 hz, 2H), 3.18 (dd, j=8.6, 6.4hz, 2H); mass spectrum C ₂₆ H ₁₈ F ₆ N ₄ OSNa[M+Na] ⁺ Calculated value 571.1, found: 571.2.

example 15

Example 15 (25 mg,40% yield) was synthesized with reference to the procedure of general synthesis 1. Structural characterization: ¹ H NMR(400MHz,Chloroform-d)δ9.40(s,1H),8.24 (s, 1H), 8.18 (dd, j=7.6, 1.9hz, 1H), 7.72 (d, j=8.2 hz, 2H), 7.57 (d, j=8.2 hz, 2H), 7.54-7.49 (m, 1H), 7.47 (dd, j=7.5, 1.5hz, 1H), 7.45-7.42 (m, 2H), 4.60 (p, j=6.7 hz, 1H), 1.47 (d, j=6.7 hz, 6H). Mass spectrum C ₂₈ H ₁₉ F ₆ N ₄ OS[M+H] ⁺ Calculated value 573.1, found: 573.1.

example 16

Example 16 (10 mg,73% yield) was synthesized with reference to the procedure of general synthesis 1. Structural characterization: ¹ h NMR (500 mhz, chloroform-d) delta 9.36 (s, 1H), 8.12 (dd, j=7.6, 1.9hz, 1H), 7.54 (q, j=1.1 hz, 1H), 7.52 (dd, j=7.7, 2.1hz, 1H), 7.48 (dd, j=7.5, 1.5hz, 1H), 7.47-7.43 (m, 3H), 7.41 (q, j=1.2 hz, 1H), 7.29 (d, j=8.1 hz, 2H), 4.56 (H, j=6.6 hz, 1H), 3.40-3.32 (m, 2H), 3.20 (dd, j=8.6, 6.7hz, 2H), 1.44 (d, j=6.7 hz, 6H); mass spectrum C ₂₈ H ₂₃ F ₆ N ₄ OS[M+H] ⁺ Calculated value 577.1, found: 577.2.

example 17

Example 17 (22 mg,56% yield) was synthesized with reference to the procedure of general synthesis method 1. Structural characterization: ¹ h NMR (300 mhz, chloro-d) delta 9.40 (s, 1H), 8.24 (s, 1H), 8.17 (dd, j=7.4, 2.0hz, 1H), 7.77-7.71 (m, 2H), 7.52-7.42 (m, 5H), 6.47 (s, 1H), 2.38 (s, 3H); mass spectrum C ₂₆ H ₁₅ F ₆ N ₄ OS[M+H] ⁺ Calculated value 545.1, found: 545.1.

example 18

Synthesis example 18 (12 mg,87% yield) was synthesized with reference to the procedure of general Synthesis method 1Rate). Structural characterization: ¹ h NMR (300 mhz, chloro-d) delta 9.36 (s, 1H), 8.11 (dd, j=7.4, 2.0hz, 1H), 7.56 (s, 1H), 7.53-7.42 (m, 3H), 7.36-7.28 (m, 4H), 6.44 (s, 1H), 3.35 (dd, j=8.8, 6.3hz, 2H), 3.20 (dd, j=8.6, 6.4hz, 2H), 2.32 (s, 3H); mass spectrum C ₂₆ H ₁₈ F ₆ N ₄ OSNa[M+Na] ⁺ Calculated value 571.1, found: 571.1.

example 19

Example 19 (18 mg,48% yield) was synthesized with reference to the procedure of general synthesis 1. Structural characterization: ¹ h NMR (400 mhz, chloro-d) delta 9.39 (s, 1H), 8.22 (s, 1H), 8.18 (dd, j=7.7, 1.9hz, 1H), 7.75-7.66 (m, 2H), 7.52 (td, j=7.7, 1.9hz, 1H), 7.48-7.40 (m, 4H), 6.01 (s, 1H), 2.34 (s, 3H), 2.30 (s, 3H); mass spectrum C ₂₆ H ₁₇ F ₃ N ₄ OSNa[M+Na] ⁺ Calculated 513.1, found: 513.1.

example 20

Example 20 (10 mg,75% yield) was synthesized with reference to the procedure of general synthesis 1. Structural characterization: ¹ H NMR (300 mhz, chloro-d) delta 9.35 (s, 1H), 8.11 (dd, j=7.3, 2.1hz, 1H), 7.56-7.41 (m, 5H), 7.32 (d, j=8.4 hz, 2H), 7.23 (d, j=2.0 hz, 1H), 5.98 (s, 1H), 3.34 (t, j=7.5 hz, 2H), 3.17 (dd, j=8.6, 6.5hz, 2H), 2.28 (d, j=7.3 hz, 6H); mass spectrum C ₂₆ H ₂₂ F ₃ N ₄ OS[M+H] ⁺ Calculated value 495.1, found: 495.1.

example 21:

synthesis example 21 (25 mg, 74)% yield). Structural characterization: ¹ h NMR (300 mhz, chloro-d) δ9.40 (s, 1H), 8.25 (s, 1H), 8.18 (dd, j=7.5, 2.0hz, 1H), 8.03 (d, j=1.2 hz, 1H), 7.86 (d, j=1.2 hz, 1H), 7.77 (s, 4H), 7.53-7.42 (m, 3H); mass spectrum C ₂₃ H ₁₃ F ₃ N ₅ OS[M+H] ⁺ Calculated value 464.1, measured value: 464.0.

example 22:

example 22 (10 mg,82% yield) was synthesized with reference to the procedure of general synthesis 1. Structural characterization: ¹ h NMR (300 mhz, chloro-d) delta 9.36 (s, 1H), 8.10 (d, j=7.4 hz, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.64 (d, j=8.0 hz, 2H), 7.57 (s, 1H), 7.55-7.41 (m, 3H), 7.33 (d, j=8.0 hz, 2H), 3.36 (t, j=7.5 hz, 2H), 3.21 (t, j=7.7 hz, 2H); mass spectrum C ₂₃ H ₁₆ F ₃ N ₅ OSNa[M+Na] ⁺ Calculated 490.1, found: 490.1.

example 23:

example 23 (17 mg,31% yield) was synthesized with reference to the procedure of general synthesis 1. Structural characterization: ¹ h NMR (300 mhz, chloro-d) delta 7.96 (s, 1H), 7.81 (dd, j=7.7, 1.5hz, 1H), 7.64 (q, j=8.4 hz, 4H), 7.47-7.35 (m, 2H), 7.33-7.29 (m, 1H), 7.23 (d, j=1.5 hz, 1H), 3.83 (q, j=6.8 hz, 1H), 3.77 (s, 3H), 3.48 (s, 6H), 1.33 (d, j=6.8 hz, 6H); mass spectrum C ₃₀ H ₂₇ F ₃ N ₅ S[M+H] ⁺ Calculated 546.2, found: 546.2.

example 24

Synthesis example 24 (10 mg,88% yield) was synthesized with reference to the procedure of general Synthesis method 1Rate). Structural characterization: ¹ h NMR (300 mhz, chloro-d) delta 7.76 (dd, j=7.6, 1.5hz, 1H), 7.57-7.48 (m, 2H), 7.47-7.34 (m, 2H), 7.28 (d, j=1.7 hz, 3H), 7.23 (s, 2H), 3.81 (p, j=6.8 hz, 1H), 3.74 (s, 3H), 3.45 (s, 6H), 3.25 (t, j=7.5 hz, 2H), 3.14 (dd, j=8.3, 6.1hz, 2H), 1.29 (d, j=6.9 hz, 6H); mass spectrum C ₃₀ H ₃₁ F ₃ N ₅ S[M+H] ⁺ Calculated value 550.2, found: 550.3.

example 25:

example 25 (16 mg,28% yield) was synthesized with reference to the procedure of general synthesis 1. Structural characterization: ¹ h NMR (300 mhz, chloroform-d) delta 7.97 (s, 1H), 7.81 (dd, j=7.7, 1.5hz, 1H), 7.71-7.66 (m, 2H), 7.55-7.50 (m, 2H), 7.47-7.42 (m, 2H), 7.39 (td, j=7.5, 1.5hz, 1H), 7.23 (d, j=1.5 hz, 1H), 4.57 (H, j=6.7 hz, 1H), 3.79 (H, j=6.9 hz, 1H), 3.48 (s, 6H), 1.46 (d, j=6.7 hz, 6H), 1.33 (d, j=6.8 hz, 6H); mass spectrum C ₃₂ H ₃₁ F ₃ N ₅ S[M+H] ⁺ Calculated value: 574.2, found: 574.2.

example 26:

example 26 was synthesized (5 mg,44% yield) with reference to the procedure of general synthesis 1. Structural characterization: ¹ h NMR (500 mhz, chloro form-d) delta 7.76 (dd, j=7.7, 1.5hz, 1H), 7.47-7.38 (m, 5H), 7.30-7.27 (m, 2H), 7.26 (d, j=5.3 hz, 2H), 4.55 (p, j=6.7 hz, 1H), 3.82 (p, j=6.8 hz, 1H), 3.46 (s, 6H), 3.27 (t, j=7.5 hz, 2H), 3.16 (dd, j=8.5, 6.5hz, 2H), 1.44 (d, j=6.7 hz, 6H), 1.30 (d, j=6.8 hz, 6H); mass spectrum C ₃₂ H ₃₅ F ₃ N ₅ S[M+H] ⁺ Calculated value 578.3, found: 578.3.

example 27

Example 27 (15 mg,29% yield) was synthesized with reference to the procedure of general synthesis 1. Structural characterization: ¹ h NMR (300 mhz, chloro-d) delta 7.95 (s, 1H), 7.83 (dd, j=7.7, 1.5hz, 1H), 7.67-7.63 (m, 2H), 7.41 (dq, j=7.9, 6.7hz, 4H), 7.28 (d, j=1.6 hz, 1H), 6.00 (s, 1H), 3.88-3.76 (m, 1H), 3.48 (s, 6H), 2.33 (d, j=0.8 hz, 3H), 2.30 (s, 3H), 1.33 (d, j=6.9 hz, 6H); mass spectrum C ₃₀ H ₃₀ N ₅ S[M+H] ⁺ Calculated value 492.2, found: 492.3.

example 28

Example 28 was synthesized (5 mg,35% yield) with reference to the procedure of general synthesis 1. Structural characterization: ¹ h NMR (300 mhz, chloro-d) delta 7.76 (d, j=7.6 hz, 1H), 7.47-7.35 (m, 2H), 7.30 (d, j=7.9 hz, 4H), 7.23 (d, j=7.5 hz, 3H), 5.97 (s, 1H), 3.82 (d, j=8.5 hz, 1H), 3.46 (s, 6H), 3.24 (d, j=7.6 hz, 2H), 3.13 (t, j=7.5 hz, 2H), 2.28 (d, j=7.8 hz, 6H), 1.29 (d, j=6.9 hz, 6H); mass spectrum C ₃₀ H ₃₄ N ₅ S[M+H] ⁺ Calculated 496.3, found: 496.3.

example 29

Example 29 (12 mg,21% yield) was synthesized with reference to the procedure of general synthesis 1. Structural characterization: ¹ h NMR (300 mhz, chloro form-d) delta 7.98 (s, 1H), 7.82 (dd, j=7.7, 1.5hz, 1H), 7.73-7.68 (m, 2H), 7.47-7.41 (m, 3H), 7.40-7.35 (m, 1H), 7.28 (d, j=1.5 hz, 1H), 6.47 (s, 1H), 3.82 (p, j=6.9 hz, 1H), 3.49 (s, 6H), 2.37 (s, 3H), 1.33 (d, j=6.8 hz, 6H); mass spectrum C ₃₀ H ₂₇ F ₃ N ₅ S[M+H] ⁺ Calculated 546.2, found: 546.2.

example 30

Example 30 (3.6 mg,47% yield) was synthesized with reference to the procedure of general synthesis 1. Structural characterization: ¹ h NMR (300 mhz, chloro-d) delta 7.75 (dd, j=7.7, 1.5hz, 1H), 7.42 (ddd, j=13.7, 7.5,1.6hz, 2H), 7.37-7.27 (m, 6H), 6.44 (s, 1H), 3.81 (dt, j=13.7, 6.8hz, 1H), 3.46 (s, 6H), 3.24 (d, j=7.3 hz, 2H), 3.16 (dd, j=8.1, 5.7hz, 2H), 2.31 (s, 3H), 1.29 (d, j=6.8 hz, 6H); mass spectrum C ₃₀ H ₃₁ F ₃ N ₅ S[M+H] ⁺ Calculated value 550.2, found: 550.3.

example 31

/>

Example 31 (21 mg,44% yield) was synthesized with reference to the procedure of general synthesis 1. Structural characterization: ¹ h NMR (300 mhz, chloro-d) delta 7.99 (d, j=10.0 hz, 2H), 7.88-7.78 (m, 2H), 7.72 (s, 4H), 7.49-7.35 (m, 2H), 7.28 (s, 1H), 3.81 (p, j=6.8 hz, 1H), 3.48 (s, 6H), 1.33 (d, j=6.9 hz, 6H); mass spectrum C ₂₇ H ₂₅ N ₆ S[M+H] ⁺ Calculated value: 465.2, found: 465.3.

example 32

Example 32 (11 mg,86% yield) was synthesized with reference to the procedure of general synthesis 1. Structural characterization: ¹ h NMR (500 mhz, chloro-d) delta 7.90 (d, j=57.6 hz, 2H), 7.76 (d, j=7.6 hz, 1H), 7.62 (d, j=8.0 hz, 2H), 7.46 (d, j=7.8 hz, 1H), 7.40 (t, j=7.5 hz, 1H), 7.33 (d, j=8.1 hz, 2H), 7.29 (s, 2H), 3.88-3.78 (m, 1H), 3.47 (s, 6H), 3.27 (t, j=7.5 hz, 2H), 3.17 (t, j=7.5 hz, 2H), 1.30 (d, j=6.9 hz, 6H); mass spectrum C ₂₇ H ₂₉ N ₆ S[M+H] ⁺ Calculated value 469.2, found: 469.3.

example 33

Example 33 (21 mg,23% yield) was synthesized with reference to general synthetic method 2 procedure. Structural characterization: ¹ h NMR (300 mhz, chloro-d) δ11.48 (s, 1H), 8.77 (s, 1H), 7.57 (dd, j=18.0, 7.6hz, 3H), 7.49-7.33 (m, 6H), 7.23 (d, j=7.4 hz, 1H), 4.53 (p, j=6.7 hz, 1H), 3.44-3.31 (m, 1H), 1.44 (d, j=6.7 hz, 6H), 1.21 (d, j=6.8 hz, 6H); mass spectrum C ₃₀ H ₂₇ F ₃ N ₅ [M+H] ⁺ Calculated 514.2, found: 514.3.

example 34

Example 34 was synthesized (5 mg,40% yield) with reference to general synthetic method 2 procedure. Structural characterization: ¹ h NMR (400 mhz, chloro-d) delta 10.07 (s, 1H), 8.67 (s, 1H), 7.62 (d, j=7.5 hz, 1H), 7.42 (q, j=6.3, 4.8hz, 5H), 7.29 (d, j=7.6 hz, 3H), 7.04 (s, 1H), 4.53 (p, j=6.7 hz, 1H), 3.52 (q, j=6.8 hz, 1H), 3.18 (dd, j=14.7, 6.1hz, 4H), 1.44 (d, j=6.8 hz, 6H), 1.25 (d, j=6.8 hz, 6H); mass spectrum C ₃₀ H ₃₁ F ₃ N ₅ [M+H] ⁺ Calculated 518.2, found: 518.4.

example 35

Example 35 (9 mg,84% yield) was synthesized with reference to general synthetic method 2 procedure. Structural characterization: ¹ h NMR (500 mhz, chloroform-d) delta 10.03 (s, 1H), 8.65 (s, 1H), 7.63 (dd, j=7.6, 1.5hz, 1H), 7.51 (d, j=7.9 hz, 2H), 7.48-7.45 (m, 1H), 7.43-7.38 (m, 1H), 7.34-7.31 (m, 1H), 7.30-7.27 (m, 3H), 7.09 (s, 1H), 3.74 (s, 3H), 3.55-3.49 (m, 1H), 3.22 (t, j=7.2 hz, 2H), 3.15 (t, j=7.2 hz, 2H), 1.25 (d, j=6.8 hz, 6H); mass spectrum C ₂₈ H ₂₇ F ₃ N ₅ [M+H] ⁺ Calculated value 490.2, found: 490.3.

example 36

Example 36 (30 mg,59% yield) was synthesized with reference to general synthetic method 2 procedure. Structural characterization: ¹ h NMR (300 mhz, chloro-d) δ12.03 (s, 1H), 8.54 (s, 1H), 7.64-7.50 (m, 2H), 7.44 (d, j=4.3 hz, 2H), 7.23 (d, j=10.5 hz, 6H), 3.25 (p, j=7.0 hz, 1H), 1.14 (d, j=7.0 hz, 6H); mass spectrum C ₂₃ H ₂₀ N ₃ [M+H] ⁺ Calculated value 338.2, found: 338.1.

example 37

Example 37 was synthesized (5 mg,53% yield) with reference to general synthetic method 2 procedure. Structural characterization: ¹ h NMR (400 mhz, chloro-d) delta 9.06 (s, 1H), 8.90 (s, 1H), 7.62 (d, j=7.7 hz, 1H), 7.44 (dd, j=18.0, 7.7hz, 2H), 7.30 (s, 1H), 7.24 (s, 2H), 7.22-7.09 (m, 4H), 3.52 (q, j=7.0 hz, 1H), 3.17 (t, j=7.4 hz, 2H), 3.09 (t, j=7.7 hz, 2H), 1.24 (d, j=7.4 hz, 6H); mass spectrum C ₂₃ H ₂₄ N ₃ [M+H] ⁺ Calculated 342.2, found: 342.2.

example 38

Example 38 (21 mg,30% yield) was synthesized with reference to general synthetic method 2 procedure. Structural characterization: ¹ H NMR(300MHz,DMSO-d ₆ ) δ9.07 (d, j=1.2 hz, 1H), 8.87 (d, j=1.3 hz, 1H), 8.34 (s, 1H), 8.02-7.90 (m, 3H), 7.75-7.65 (m, 2H), 7.54 (dd, j=7.6, 1.5hz, 1H), 7.48-7.36 (m, 2H), 7.31-7.22 (m, 1H), 3.47 (d, j=6.7 hz, 1H), 1.19 (d, j=6.9 hz, 6H); mass spectrum C ₂₅ H ₂₁ N ₆ [M+H] ⁺ Calculated 405.2, found: 405.1.

Example 39

Example 39 (7 mg,55% yield) was synthesized with reference to general synthetic method 2 procedure. Structural characterization: ¹ h NMR (500 mhz, chloro-d) delta 9.60 (s, 1H), 8.83 (s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.61 (t, j=8.5 hz, 3H), 7.44 (dd, j=23.2, 7.8hz, 2H), 7.30 (d, j=7.9 hz, 3H), 7.15 (s, 1H), 3.51 (q, j=6.9 hz, 1H), 3.19 (dp, j=11.0, 5.6,4.8hz, 4H), 1.25 (d, j=7.3 hz, 6H); mass spectrum C ₂₅ H ₂₅ N ₆ [M+H] ⁺ Calculated 409.2, found: 409.4.

example 40

Example 40 (33 mg,45% yield) was synthesized with reference to general synthetic method 2 procedure. Structural characterization: ¹ h NMR (500 mhz, chloro-d) delta 12.16 (s, 1H), 8.54 (s, 1H), 7.55 (d, j=8.6 hz, 2H), 7.49-7.37 (m, 4H), 7.31 (d, j=8.2 hz, 2H), 7.23 (td, j=7.3, 1.7hz, 1H), 5.99 (s, 1H), 3.34 (hept, j=6.8 hz, 1H), 2.31 (s, 3H), 2.25 (s, 3H), 1.16 (d, j=6.8 hz, 6H); mass spectrum C ₂₈ H ₂₆ N ₅ [M+H] ⁺ Calculated 432.2, found: 432.3.

example 41

Example 41 (6 mg,48% yield) was synthesized with reference to general synthetic method 2 procedure. Structural characterization: ¹ H NMR(300MHz,Chloroform-d)δ10.23(s,1H),8.69(s,1H),7.61(dd,J＝7.6,1.4Hz,1H),7.53-7.36(m,2H),7.33-7.27(m,3H),7.21(d,J＝8.3Hz,2H),7.03(s,1H),5.99(s,1H),3.58-3.40(m,1H),3.15(dq,J＝11.7,6.3Hz,4H) 2.31 (s, 3H), 2.26 (s, 3H), 1.23 (d, j=6.8 hz, 6H); mass spectrum C ₂₈ H ₃₀ N ₅ [M+H] ⁺ Calculated value 436.2, found: 436.3.

example 42

Example 42 (22 mg,25% yield) was synthesized with reference to general synthetic method 2 procedure. Structural characterization: ¹ H NMR (300 mhz, chloro-d) delta 12.08 (s, 1H), 8.59 (s, 1H), 7.73-7.66 (m, 1H), 7.62 (s, 1H), 7.57-7.49 (m, 2H), 7.44-7.41 (m, 2H), 7.33 (d, j=8.4 hz, 2H), 7.25-7.20 (m, 1H), 6.42 (s, 1H), 3.34 (p, j=6.8 hz, 1H), 2.29 (s, 3H), 1.17 (d, j=6.8 hz, 6H); mass spectrum C ₂₈ H ₂₁ F ₃ N ₅ [M-H] ^- Calculated value 484.2, found: 484.1.

example 43

Example 43 (9 mg,69% yield) was synthesized according to the procedure of general synthesis method 2. Structural characterization: ¹ h NMR (400 mhz, chloro-d) delta 9.57 (s, 1H), 8.80 (s, 1H), 7.62 (dd, j=7.7, 1.5hz, 1H), 7.46 (dd, j=8.0, 1.5hz, 1H), 7.41 (td, j=7.5, 1.5hz, 1H), 7.33-7.26 (m, 5H), 7.08 (s, 1H), 6.45 (s, 1H), 3.55-3.44 (m, 1H), 3.23-3.12 (m, 4H), 2.31 (s, 3H), 1.24 (d, j=6.9 hz, 6H); mass spectrum C ₂₈ H ₂₇ F ₃ N ₅ [M+H] ⁺ Calculated value 490.2, found: 490.3.

example 44:

synthesis of example 44 with reference to general Synthesis method 2 procedure. ¹ H NMR(300MHz,CDCl ₃ )δ8.95(s,1H),8.07(dd,J＝7.4,2.0Hz,1H),7.88(s,1H),7.48(ddd,J＝9.4,7.3,2.8Hz,4H),7.40(d, J=8.1 Hz, 1H), 7.35-7.30 (M, 3H) mass spectrometry: C21H12F3N3O [ M+H ]] ⁺ Calculated 380.3, found 380.1.

Example 45

Example 45 was synthesized with reference to general synthesis method 2 procedure. ¹ H NMR(400MHz,CDCl ₃ ) Delta 8.96 (s, 1H), 8.01 (dd, J=7.4, 2.0Hz, 1H), 7.52-7.38 (M, 2H), 7.27 (d, J=1.5 Hz, 1H), 7.24 (s, 1H), 7.19 (dd, J=7.6, 3.6Hz, 2H), 3.23-3.17 (M, 2H), 3.14-3.08 (M, 2H) mass spectrometry: C21H16F3N3O [ M+H ] ] ⁺ Calculated 386.1, found: 386.1.

example 46

Example 46 was synthesized with reference to general synthesis method 2 procedure. ¹ H NMR(300MHz,CDCl ₃ ) δ10.46 (s, 1H), 9.01 (s, 1H), 8.15-7.99 (M, 2H), 7.90 (d, j=18.3 hz, 2H), 7.68 (dd, j=29.3, 8.2hz, 4H), 7.46 (dd, j=15.9, 7.8hz, 3H). Mass spectrometry: C23H13F3N6O [ m+h)] ⁺ Calculated value 447.1, found: 447.1.

example 47

Example 47 was synthesized with reference to general synthesis procedure 2 procedure. ¹ H NMR(400MHz,CDCl ₃ ) Delta 9.16 (s, 1H), 8.90 (s, 1H), 8.00 (dd, J=7.3, 1.9Hz, 1H), 7.94 (s, 1H), 7.84 (s, 1H), 7.59 (d, J=8.3 Hz, 2H), 7.48-7.37 (M, 3H), 7.29 (d, J=8.3 Hz, 2H), 3.21 (s, 4H) mass spectrometry: C23H17F3N6O [ M+H ]] ⁺ Calculated value 451.1, found: 451.1.

example 48

Example 48 was synthesized with reference to general synthesis procedure 2 procedure. ¹ H NMR(400MHz,CDCl ₃ ) Delta 9.06 (s, 1H), 8.07 (dd, J=7.4, 1.8Hz, 1H), 7.86 (s, 1H), 7.65 (d, J=8.6 Hz, 2H), 7.50-7.36 (M, 5H), 6.47 (s, 1H), 2.37 (s, 3H). Mass Spectrometry: C26H15N5OF6[ M+H ]] ⁺ Calculated 528.4, found: 528.1.

example 49

Example 49 was synthesized with reference to general synthesis method 2 procedure. ¹ H NMR(300MHz,CDCl ₃ ) δ9.19 (s, 1H), 8.92 (s, 1H), 8.03 (dd, J=7.1, 2.1Hz, 1H), 7.51-7.39 (M, 3H), 7.33 (dd, J=9.8, 3.5Hz, 4H), 7.22 (s, 1H), 6.47 (s, 1H), 3.22 (s, 4H), 2.33 (s, 3H) mass spectrometry: C6H26N5O [ M+H ] ] ⁺ Calculated 532.1, found: 532.1.

example 50

Example 50 was synthesized with reference to general synthesis method 2 procedure. ¹ H NMR(400MHz,CDCl ₃ ) Delta 8.95 (s, 1H), 8.07 (d, J=6.6 Hz, 1H), 7.72 (s, 1H), 7.63 (d, J=8.1 Hz, 2H), 7.57 (d, J=8.2 Hz, 2H), 7.47-7.36 (M, 3H), 7.32 (s, 1H), 3.78 (s, 3H) mass spectrometry: C26H15F6N5O [ M-1 ]] ^- Calculated 526.1, found 526.1.

Example 51

Example 51 was synthesized with reference to general synthesis method 2 procedure. ¹ H NMR(400MHz,CDCl ₃ ) Delta 8.86 (s, 1H), 8.03-7.96 (m, 1H), 7.47-7.37 (m, 6H), 7.24 (s, 2H), 7.12 (s, 1H), 3.48 (s, 3H), 3.23-3.15 (m, 4H); mass spectrum C26H19N5OF6[ M+H ]] ⁺ Calculated value 532.45, actualMeasured 532.1.

Example 52

Example 52 was synthesized with reference to general synthesis method 2 procedure. ¹ H NMR(300MHz,CDCl ₃ ) Delta 8.86 (s, 1H), 8.02 (d, J=6.1 Hz, 1H), 7.67 (s, 1H), 7.56-7.7 (M, 8H), 6.04 (s, 1H), 2.35 (s, 3H), 2.31 (s, 3H) mass spectrum: C26H18N5OF3[ M+H)] ⁺ Calculated value 474.45, found: 473.9.

example 53

Example 53 was synthesized with reference to general synthesis procedure 2 procedure. ¹ H NMR(500MHz,CDCl ₃ ) δ10.35 (s, 1H), 8.71 (s, 1H), 8.01 (d, j=6.5 hz, 1H), 7.43 (dt, j=23.7, 8.2hz, 4H), 7.29 (d, j=8.0 hz, 2H), 7.21 (d, j=7.9 hz, 2H), 7.07 (s, 1H), 6.00 (s, 1H), 3.18 (dd, j=19.9, 6.2hz, 4H), 2.33 (s, 3H), 2.26 (s, 4H) mass spectrometry: c26H22F3N5O [ m+h) ] ⁺ Calculated 478.2, found 478.1.

Example 54

Example 54 was synthesized with reference to general synthesis method 2 procedure. ¹ H NMR(300MHz,CDCl ₃ ) δ9.19 (s, 1H), 8.92 (s, 1H), 8.03 (dd, J=7.1, 2.1Hz, 1H), 7.51-7.39 (M, 3H), 7.33 (dd, J=9.8, 3.5Hz, 4H), 7.22 (s, 1H), 6.47 (s, 1H), 3.22 (s, 4H), 2.33 (s, 3H) mass spectrometry: C28H22F3N5O [ M+H ]] ⁺ Calculated 556.47, found 556.0.

Example 55

Reference is led toExample 55 was synthesized using the procedure of synthesis 2. ¹ H NMR (300 mhz, meod) delta 8.91 (s, 1H), 7.89 (dd, j=7.1, 1.5hz, 2H), 7.66-7.54 (m, 3H), 7.50-7.35 (m, 5H), 4.53 (dt, j=13.3, 6.7hz, 1H), 3.22 (dd, j=9.2, 5.2hz, 4H), 1.46 (s, 3H), 1.44 (s, 3H); mass spectrum C28H26F3N5O [ M+H ]] ⁺ Calculated 560.5, measured 560.2.

Example 56

Example 56 (21 mg,80% yield) was synthesized with reference to general synthesis procedure 1 procedure. ¹ H NMR(500MHz,CDCl ₃ ) Delta 9.06 (s, 1H), 8.24 (s, 1H), 7.69 (d, j=6.8 hz, 1H), 7.61-7.56 (m, 2H), 7.50-7.46 (m, 1H), 7.44 (t, j=7.5 hz, 1H), 7.39-7.35 (m, 3H), 7.30 (td, j=7.5, 1.3hz, 1H), 3.51 (dt, j=13.7, 6.9hz, 1H), 1.30 (s, 3H), 1.29 (s, 3H) ppm; high resolution mass spectrum C23H18N2O [ M+H ]] ⁺ Calculated value 339.14919, found: 339.14926.

example 57

Example 57 (7.5 mg,65% yield) was synthesized with reference to general synthetic method 1 procedure. ¹ H NMR(500MHz,CDCl ₃ ) Delta 8.97 (s, 1H), 7.65 (t, j=3.2 hz, 2H), 7.51-7.46 (m, 1H), 7.46-7.39 (m, 1H), 7.34-7.27 (m, 3H), 7.23-7.15 (m, 3H), 3.51 (dq, j=13.7, 6.8hz, 1H), 3.17-3.06 (m, 4H), 1.29 (s, 3H), 1.27 (s, 3H) ppm; high resolution mass spectrum C23H22N2O [ M+H ]] ⁺ Calculated value 343.18049, found: 343.18051.

example 58

Example 58 (38 mg,70% yield) was synthesized with reference to general synthesis procedure 1. ¹ H NMR(500MHz,CDCl ₃ )δ9.06(s,1H),8.06(d,J＝2.2hz, 1H), 7.82 (d, j=1.8 hz, 1H), 7.65-7.58 (m, 5H), 7.47 (d, j=8.1 hz, 1H), 7.33 (s, 1H), 7.07 (dd, j=2.2, 0.7hz, 1H), 3.80 (s, 3H), 3.50 (dt, j=13.7, 6.8hz, 1H), 1.24 (s, 3H), 1.23 (s, 3H) ppm; mass spectrum C28H21F3N4O [ M+H ]] ⁺ Calculated value 487.2, found: 487.2.

example 59

Example 59 (10.5 mg,62% yield) was synthesized according to the procedure of general synthesis 1. ¹ H NMR(500MHz,CDCl ₃ ) δ8.96 (s, 1H), 7.96 (d, j=2.1 hz, 1H), 7.47 (d, j=8.1 hz, 2H), 7.37 (d, j=1.4 hz, 1H), 7.29 (d, j=8.0 hz, 1H), 7.23 (d, j=8.1 hz, 3H), 7.16 (dd, j=8.0, 1.5hz, 1H), 6.98 (d, j=1.9 hz, 1H), 3.68 (s, 3H), 3.34 (dq, j=13.7, 6.8hz, 1H), 2.99-2.83 (m, 4H), 1.13 (d, j=6.9 hz, 6H) ppm; mass spectrum C28H25F3N4O [ M+H ]] ⁺ Calculated value 491.2, found: 491.2.

example 60

Example 60 (37 mg,70% yield) was synthesized with reference to general synthesis method 1 procedure. ¹ H NMR(500MHz,CDCl ₃ ) δ9.07 (s, 1H), 8.06 (d, j=2.2 hz, 1H), 8.02 (s, 1H), 7.88 (s, 1H), 7.83 (s, 1H), 7.78-7.72 (m, 2H), 7.70-7.64 (m, 2H), 7.61 (dd, j=8.1, 1.4hz, 1H), 7.47 (d, j=8.2 hz, 1H), 7.08 (d, j=1.9 hz, 1H), 3.55-3.44 (m, 1H), 1.25 (s, 3H), 1.23 (s, 3H) ppm; mass spectrum C25H19N5O [ M+H ]] ⁺ Calculated 406.2, found: 404.2.

example 61

Example 61 (14.5 mg,68% yield) was synthesized according to the procedure of general synthesis 1. ¹ H NMR(500MHz,CDCl ₃ )δ9.05(s,1H),8.05(d,J＝2.2hz, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.65 (d, j=8.4 hz, 2H), 7.45 (d, j=1.7 hz, 1H), 7.37 (dd, j=14.4, 8.2hz, 3H), 7.24 (d, j=8.1 hz, 1H), 7.06 (d, j=1.9 hz, 1H), 3.47-3.36 (m, 1H), 3.01 (dq, j=9.6, 6.1hz, 4H), 1.21 (d, j=6.9 hz, 6H) ppm; mass spectrum C25H24N5OM+H] ⁺ Calculated value 410.2, measured value: 410.2.

example 62

Example 62 (36 mg,76% yield) was synthesized with reference to general synthesis procedure 1 procedure. ¹ H NMR(500MHz,CDCl ₃ ) δ9.05 (d, j=0.6 hz, 1H), 8.05 (d, j=2.2 hz, 1H), 7.82 (t, j=2.4 hz, 1H), 7.61-7.57 (m, 3H), 7.45 (dd, j=10.0, 8.4hz, 3H), 7.07 (dd, j=2.2, 0.7hz, 1H), 6.04 (s, 1H), 3.50 (dt, j=13.7, 6.8hz, 1H), 2.34 (s, 6H), 1.24 (s, 3H), 1.23 (s, 3H) ppm; mass spectrum C28H24N4O [ M+H ]] ⁺ Calculated value 433.2, found: 433.2.

example 63

Example 63 (9 mg,50% yield) was synthesized according to the procedure of general synthesis method 1. ¹ H NMR(400MHz,CDCl ₃ ) Delta 8.95 (s, 1H), 7.95 (d, j=2.1 hz, 1H), 7.37 (s, 1H), 7.27 (dd, j=17.7, 8.2hz, 3H), 7.21-7.14 (m, 4H), 6.97 (d, j=1.5 hz, 1H), 5.90 (s, 1H), 3.33 (dt, j=13.5, 6.8hz, 1H), 2.94-2.85 (m, 4H), 2.22 (s, 3H), 2.19 (s, 3H), 1.14 (s, 3H), 1.12 (s, 3H) ppm; mass spectrum C28H28N4O [ M+H ]] ⁺ Calculated value 437.2, found: 437.2.

example 64

Example 64 (30 mg,58% yield) was synthesized with reference to general synthesis procedure 1 procedure. ¹ H NMR(400MHz,CDCl ₃ )δ8.97(s,1H),7.97(d,J＝22hz, 1H), 7.74 (d, j=1.7 hz, 1H), 7.53 (td, j=6.3, 3.2hz, 3H), 7.45 (d, j=8.4 hz, 2H), 7.38 (d, j=8.2 hz, 1H), 7.36 (d, j=1.0 hz, 1H), 7.02-6.94 (m, 1H), 4.51 (hept, j=6.7 hz, 1H), 3.42 (hept, j=6.8 hz, 1H), 1.40 (s, 3H), 1.39 (s, 3H), 1.16 (s, 3H), 1.14 (s, 3H) ppm; mass spectrum C30H23N4OM+H] ⁺ Calculated 515.2, found: 515.2.

example 65

Example 65 (3 mg,30% yield) was synthesized with reference to general synthesis method 1 procedure. ¹ H NMR(500MHz,CDCl ₃ ) δ8.29 (s, 1H), 7.46 (d, j=8.0 hz, 2H), 7.40 (d, j=12.4 hz, 2H), 7.34 (d, j=8.0 hz, 1H), 7.31 (d, j=8.0 hz, 2H), 7.21 (d, j=8.0 hz, 1H), 4.77 (t, j=8.9 hz, 2H), 4.58 (dt, j=13.3, 6.7hz, 1H), 3.44 (t, j=9.0 hz, 2H), 3.38 (dd, j=13.8, 6.8hz, 1H), 2.98 (dq, j=9.8, 5.9hz, 4H), 1.46 (d, j=6.7 hz, 6H), 1.20 (d, j=6.9 hz, 6H) ppm; mass spectrum C30H24OM+H ] ⁺ Calculated 519.3, found: 519.3.

example 66

Example 66 (32 mg,62% yield) was synthesized with reference to general synthesis method 1 procedure. ¹ H NMR(500MHz,CDCl ₃ ) δ9.07 (s, 1H), 8.07 (d, j=2.2 hz, 1H), 7.82 (s, 1H), 7.62 (dd, j=12.4, 8.4hz, 3H), 7.46 (dd, j=12.9, 8.4hz, 3H), 7.08 (d, j=2.0 hz, 1H), 6.48 (s, 1H), 3.54-3.45 (m, 1H), 2.39 (d, j=0.5 hz, 3H), 1.24 (d, j=6.8 hz, 6H) ppm; mass spectrum C28H21F3N4O [ M+H ]] ⁺ Calculated value 487.17412, found: 487.17416.

example 67

Synthesis example 6 with reference to general Synthesis method 1 procedure7 (3 mg,28% yield). ¹ H NMR(400MHz,CDCl ₃ ) Delta 8.97 (s, 1H), 7.96 (d, j=2.2 hz, 1H), 7.36 (d, j=1.5 hz, 1H), 7.30 (d, j=8.0 hz, 1H), 7.27-7.22 (m, 4H), 7.16 (d, j=8.1 hz, 1H), 6.98 (d, j=1.6 hz, 1H), 6.36 (s, 1H), 3.32 (dt, j=13.7, 6.9hz, 1H), 2.97-2.86 (m, 4H), 2.24 (s, 3H), 1.13 (d, j=6.9 hz, 6H) ppm; high resolution mass spectrum C28H25F3N4O [ M+H ]] ⁺ Calculated value 491.2, found: 491.2.

example 68

Example 68 (22 mg,50% yield) was synthesized with reference to general synthesis procedure 1. ¹ H NMR(400MHz,CDCl ₃ ) δ9.02 (s, 1H), 8.20 (s, 1H), 8.03 (dd, j=7.6, 1.9hz, 1H), 7.65-7.59 (m, 4H), 7.47-7.33 (m, 3H), 7.27 (d, j=0.9 hz, 1H), 3.75 (s, 3H) ppm; mass spectrum C26H14F6N4O2[ M+H ]] ⁺ Calculated value 529.1, found: 529.1.

Example 69

Synthesis of Compound 7- (phenylethynyl) -2- (2- (trifluoromethoxy) phenyl) furan [3,2-d ] by reference to the operating method of general Synthesis method 1]Pyrimidine. (14 mg,37% yield). ¹ H NMR (400 mhz, chloroform-d) delta 9.10 (s, 1H), 8.26 (s, 1H), 8.06 (dd, j=7.7, 1.8hz, 1H), 7.64-7.58 (m, 2H), 7.52 (ddd, j=8.1, 7.5,1.9hz, 1H), 7.48-7.40 (m, 2H), 7.40-7.34 (m, 3H). The compound obtained above was dissolved in ethyl acetate, 2mg of lindera catalyst was added, hydrogen was replaced 3 times, and the reaction was carried out at room temperature for 4 hours. After the reaction, the organic phase was dried by spin-drying, and the target molecule example 69 (3 mg,28% yield) was obtained by separation and purification by preparative thin layer chromatography. ¹ H NMR (400 mhz, chloro-d) delta 9.04 (s, 1H), 8.14 (d, j=16.3 hz, 1H), 8.11-8.08 (m, 1H), 8.07 (s, 1H), 7.56 (ddd, j=7.9, 4.6,1.7hz, 2H), 7.52 (dd, j=7.7, 2.0hz, 1H), 7.50-7.43 (m, 2H), 7.38 (dd, j=8.3, 6.8hz, 2H), 7.32-7.28 (m, 1H), 7.15 (d, j=16.3 hz, 1H); mass spectrum C ₂₁ H ₁₄ F ₃ N ₂ O ₂ [M+H] ⁺ Calculated value 383.1, found: 383.1.

example 70

Example 70 (9.8 mg,67% yield) was synthesized according to the procedure of example 69. ¹ H NMR(500MHz,CDCl ₃ ) δ9.00 (s, 1H), 7.93 (dd, j=7.6, 1.8hz, 1H), 7.75 (s, 1H), 7.65 (d, j=8.2 hz, 2H), 7.49 (d, j=8.0 hz, 3H), 7.46-7.37 (m, 2H), 7.33 (s, 1H), 6.95 (d, j=12.1 hz, 1H), 6.86 (d, j=12.1 hz, 1H), 3.78 (s, 3H) ppm; high resolution mass spectrum C26H16F6N4O2[ M+H ] ] ⁺ Calculated value 531.12502, found: 531.12531.

example 71

/>

Example 71 (35 mg,72% yield) was synthesized with reference to general synthesis procedure 1 procedure. ¹ H NMR(500MHz,CDCl ₃ ) δ9.11 (s, 1H), 8.30 (s, 1H), 8.12 (dd, j=7.7, 1.8hz, 1H), 8.05 (d, j=1.0 hz, 1H), 7.89 (d, j=0.9 hz, 1H), 7.82-7.76 (m, 4H), 7.55-7.52 (m, 1H), 7.49-7.45 (m, 1H), 7.44 (d, j=8.0 hz, 1H) ppm; high resolution mass spectrum C23H12F3N5O2[ M+H ]] ⁺ Calculated value 48.10169, found: 448.10172.

example 72

Example 72 (35 mg,71% yield) was synthesized with reference to general synthesis procedure 1 procedure. ¹ H NMR(400MHz,CDCl ₃ ) δ9.01 (s, 1H), 8.19 (s, 1H), 8.03 (dd, j=7.6, 1.8hz, 1H), 7.62 (d, j=8.6 hz, 2H), 7.41 (dd, j=7.3, 1.7hz, 4H), 7.36-7.33 (m, 1H), 5.97 (s, 1H), 2.29 (s, 3H), 2.26 (s, 3H) ppm; mass spectrum C26H17F3N4O2[ M+H] ⁺ Calculated value 475.1, found: 475.1.

example 73

Example 73 (8 mg,40% yield) was synthesized according to the procedure of example 69. ¹ H NMR(500MHz,CDCl ₃ ) Delta 8.99 (s, 1H), 8.02-7.90 (m, 1H), 7.77 (s, 1H), 7.50-7.41 (m, 7H), 6.94 (d, j=12.0 hz, 1H), 6.84 (d, j=12.0 hz, 1H), 6.03 (s, 1H), 2.33 (s, 6H) ppm; mass spectrum C26H19F3N4O2[ M+H] ⁺ Calculated 477.2, found: 477.2.

example 74

Example 74 (3 mg,15% yield) was synthesized with reference to general synthesis method 1 procedure. ¹ H NMR(500MHz,CDCl ₃ ) Delta 8.99 (s, 1H), 8.04 (dd, j=7.6, 1.7hz, 1H), 7.65 (s, 1H), 7.54-7.49 (m, 1H), 7.46 (d, j=7.5 hz, 1H), 7.43 (d, j=8.0 hz, 1H), 7.34 (d, j=8.2 hz, 2H), 7.25 (s, 2H), 5.99 (s, 1H), 3.17 (dd, j=16.2, 6.3hz, 4H), 2.31 (s, 3H), 2.28 (s, 3H) ppm; mass spectrum C26H21F3N4O2[ M+H] ⁺ Calculated value 479.2, found: 479.2.

example 75

Example 75 (11 mg,29% yield) was synthesized with reference to general synthesis procedure 3 procedure. Structural characterization: ¹ h NMR (300 mhz, chloro-d) delta 9.37 (s, 1H), 8.21 (s, 1H), 7.93-7.80 (m, 1H), 7.68 (q, j=8.1 hz, 4H), 7.40 (t, j=8.1 hz, 1H), 7.33 (s, 1H), 7.09 (dd, j=8.1, 5.5hz, 2H), 4.60 (p, j=6.1 hz, 1H), 3.80 (s, 3H), 1.32 (d, j=6.0 hz, 6H); mass spectrum C ₂₈ H ₂₂ F ₃ N ₄ OS[M+H] ⁺ Calculated 519.1, found: 519.2.

example 76

Example 76 (6 mg,47% yield) was synthesized with reference to the procedure of general synthesis 3. Structural characterization: ¹ h NMR (500 mhz, chloro form-d) delta 9.33 (s, 1H), 7.78 (dd, j=7.7, 1.9hz, 1H), 7.54 (d, j=8.0 hz, 2H), 7.49 (s, 1H), 7.40 (td, j=7.8, 1.9hz, 1H), 7.31-7.27 (m, 3H), 7.09 (dd, j=8.1, 5.2hz, 2H), 4.56 (p, j=6.1 hz, 1H), 3.75 (s, 3H), 3.36 (t, j=7.6 hz, 2H), 3.22 (t, j=7.6 hz, 2H), 1.28 (d, j=6.1 hz, 6H); mass spectrum C ₂₈ H ₂₅ F ₃ N ₄ OSNa[M+Na] ⁺ Calculated value 545.2, found: 545.3.

Example 77

Taking compound intermediate a-5 (x=s, R ₂ =2-isopropylphenyl, 100mg,0.26 mmol), (BPin) ₂ (134mg,2.0eq)，Pd(dppf) ₂ Cl ₂ (10 mg,0.05 eq) and AcOK (51 mg,2.0 eq) were added sequentially to a 10mL reaction tube, 1mL1, 4-dioxane solvent was added, and the reaction was carried out at 100℃for 12h. And after the reaction is finished, cooling to room temperature, and washing by silica gel column chromatography to obtain a crude product of the borate. Weighing compound L-5, pd (dppf) ₂ Cl ₂ ，K ₂ CO ₃ The crude product-containing 25 reaction tube was then added, followed by 1,4-dioxane/water (v/v, 5:1) and reacted at 90℃for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered and dried by spin-drying, and the desired product example 77 (5 mg,6% yield) was obtained by separation and purification through preparative silica gel thin chromatography. ¹ H NMR (400 mhz, chloro-d) delta 9.36 (s, 1H), 7.72 (d, j=7.7 hz, 1H), 7.62-7.51 (m, 3H), 7.45 (t, j=11.1 hz, 3H), 7.31 (d, j=6.6 hz, 3H), 4.37 (s, 2H), 3.75 (s, 3H), 3.66-3.54 (m, 1H), 1.26 (d, j=5.3 hz, 6H); high resolution Mass Spectrometry C ₂₇ H ₂₃ F ₃ N ₄ SNa[M+Na] ⁺ Calculated value 515.14932, found: 515.14880.

example 78:

taking compound intermediate a-5 (x=s, R ₂ =2-isopropylphenyl, 40mg,0.1 mmol), L-6 (40 mg,1.5 eq), pd ₂ (dba) ₃ (10mg,0.1eq)，XantPhos(12mg,0.2eq)，Cs ₂ CO ₃ (103 mg,3.0 eq) was added sequentially to a 10mL reaction tube, 0.5mL anhydrous 1,4-dioxane was added, argon was replaced 3 times, and the reaction was carried out at 110℃overnight. After the reaction, cooling to room temperature, filtering, and spin-drying the organic phase, the target product example 78 (12 mg,22% yield) was obtained by separation and purification by two preparative thin layer chromatography. Structural characterization: ¹ H NMR (400 mhz, chloroform-d) delta 9.37 (s, 1H), 7.74 (s, 1H), 7.66 (dd, j=7.5, 1.2hz, 1H), 7.50-7.44 (m, 2H), 7.43-7.35 (m, 2H), 7.26-7.22 (m, 2H), 6.96-6.88 (m, 2H), 3.71 (s, 3H), 3.53 (s, 4H), 1.13 (d, j=6.9 hz, 6H); mass spectrum C ₂₇ H ₂₅ F ₃ N ₅ S[M+H] ⁺ Calculated 508.2, found: 508.2.

example 79

Example 79 (30 mg,57% yield) was synthesized with reference to the procedure of example 78. Structural characterization: ¹ h NMR (400 mhz, chloro-d) delta 9.33 (s, 1H), 7.70 (dd, j=7.7, 1.4hz, 1H), 7.65-7.59 (m, 2H), 7.54-7.45 (m, 2H), 7.41 (s, 1H), 7.33 (d, j=4.3 hz, 2H), 7.31-7.28 (m, 2H), 3.78 (s, 3H), 3.53 (p, j=6.8 hz, 1H), 1.30 (d, j=6.8 hz, 6H). Mass spectrum C ₂₆ H ₂₂ F ₃ N ₅ SNa[M+Na] ⁺ Calculated value 516.1, found: 516.2.

example 80

Example 80 (9.0 mg,20% yield) was synthesized according to the procedure of example 78. 1H NMR (300 MHz, CDCl 3) δ9.27 (s, 1H), 8.13 (dd, J=7.5, 1.9Hz, 1H), 7.99 (s, 1H), 7.86(d,J＝0.7Hz,1H),7.75(d,J＝8.5Hz,2H),7.59(d,J＝8.4Hz,2H),7.52–7.41(m,3H),6.33(s,1H),5.49–5.47(m,1H),4.60(d,J＝2.7Hz,2H)。C22H15F3N6OSNa[M+Na] ⁺ Calculated values: 491.1, found: 491.1.

example 81

Example 81 (5.1 mg,22% yield) was synthesized according to the procedure described for the preparation of example 78. ¹ H NMR(300MHz,CDCl ₃ )δ9.25(s,1H),7.69–7.57(m,3H),7.51(dd,J＝10.1,4.8Hz,3H),7.48–7.40(m,2H),7.31(s,1H),6.32(s,1H),5.42–5.40(m,1H),4.56(d,J＝3.7Hz,2H),3.77(s,3H),3.48(dt,J＝13.6,6.9Hz,1H),1.27(s,3H),1.24(s,3H).C27H25F3N5S[M+H] ⁺ Calculated 508.2, found 508.2.

Example 82

Example 82 (13.1 mg,25% yield) was synthesized according to the procedure described for the preparation of example 78. ¹ H NMR(400MHz,CDCl ₃ )δ9.25(s,1H),7.68–7.62(m,1H),7.55(d,J＝8.3Hz,2H),7.45(qd,J＝8.0,4.5Hz,4H),7.31(td,J＝7.6,1.5Hz,1H),6.46(s,1H),6.32(s,1H),5.43–5.41(m,1H),4.57(d,J＝4.8Hz,2H),3.49(dt,J＝13.7,6.8Hz,1H),2.35(s,3H),1.27(s,3H),1.26(s,3H).C27H25F3N5S[M+H] ⁺ Calculated values: 508.2, found 508.2.

Example 83

Example 83 (12.1 mg,26% yield) was synthesized according to the procedure of example 78. ¹ H NMR(400MHz,CDCl ₃ )δ9.27(s,1H),8.13(dd,J＝7.6,1.9Hz,1H),7.55(t,J＝5.8Hz,2H),7.52–7.39(m,5H),6.46(s,1H),6.32(s,1H),5.47–5.45(m,1H),4.59(d,J＝4.5Hz,2H),2.35(s,3H).C25H18F6N5OS[M+H] ⁺ Calculated 550.1, found: 550.1.

example 84

Example 84 (7.2 mg,24% yield) was synthesized according to the procedure of example 78. ¹ H NMR(400MHz,CDCl ₃ )δ9.26(s,1H),8.16–8.08(m,1H),7.63(d,J＝8.1Hz,2H),7.55–7.48(m,3H),7.44(d,J＝11.4Hz,1H),7.31(s,1H),6.74(d,J＝8.7Hz,1H),6.32(s,1H),5.35(s,1H),4.59–4.57(m,2H),3.77(s,3H).C25H18F6N5OS[M+H] ⁺ Calculated 550.1, found: 550.1.

example 85

/>

Example 85 (10.0 mg,22% yield) was synthesized with reference to the procedure of example 78. ¹ H NMR(300MHz,CDCl ₃ )δ9.25(s,1H),7.68–7.59(m,1H),7.54–7.52(m,4H),7.48–7.39(m,3H),7.32(dd,J＝7.2,1.4Hz,1H),6.34(s,1H),5.40(s,1H),4.57–4.55(m,3H),3.48(dt,J＝13.7,6.8Hz,1H),1.46(s,3H),1.44(s,3H),1.26(s,3H),1.24(s,3H).C29H29F3N5S[M+H] ⁺ Calculated 536.2, found: 536.2.

example 86

Example 86 (13.0 mg,29% yield) was synthesized according to the procedure of example 78. ¹ H NMR(400MHz,CDCl ₃ )δ9.26(s,1H),8.12(dd,J＝7.6,1.9Hz,1H),7.57–7.49(m,5H),7.47(dd,J＝7.5,1.5Hz,1H),7.44–7.40(m,2H),6.33(s,1H),5.45(t,J＝5.3Hz,1H),4.64–4.52(m,3H),1.46(s,3H),1.45(s,3H).C27H22F6N5OS[M+H] ⁺ Calculated value 578.1, measured value: 578.1.

example 87

Example 87 (7.1 mg,23% yield) was synthesized with reference to the procedure of example 78. ¹ H NMR(300MHz,CDCl ₃ )δ9.27(s,1H),8.00(s,1H),7.86(s,1H),7.75(d,J＝8.4Hz,2H),7.67(d,J＝7.6Hz,1H),7.60(d,J＝8.2Hz,2H),7.48(t,J＝8.1Hz,2H),7.33(d,J＝7.8Hz,1H),6.34(s,1H),5.46(s,1H),4.60–4.58(m,2H),3.51(dt,J＝13.6,6.9Hz,1H),1.28(s,3H),1.27(s,3H).C24H23N6S[M+H] ⁺ Calculated value 427.2, measured value: 427.2.

example 88

Example 88 (5.3 mg, yield 21%) was synthesized according to the procedure of example 78. ¹ H NMR(500MHz,CDCl ₃ )δ7.82(dd,J＝31.4,6.4Hz,1H),7.66(d,J＝7.6Hz,1H),7.60(d,J＝8.0Hz,2H),7.52(d,J＝8.0Hz,2H),7.43(d,J＝7.7Hz,1H),7.40–7.36(m,1H),7.30(s,1H),6.08(s,1H),5.42(s,1H),4.52–4.50(s,2H),3.75(s,3H),3.67–3.59(m,1H),3.43(s,6H),1.27(s,3H),1.26(s,3H).C29H30F3N6S[M+H] ⁺ Calculated value 551.2, measured value: 551.2.

example 89

Example 89 was synthesized with reference to the procedure of general synthesis 3, with DME as solvent, (12 mg,23% yield). ¹ H NMR (400 mhz, chloro form-d) delta 7.92 (s, 1H), 7.79 (dd, j=7.7, 1.4hz, 1H), 7.66-7.56 (m, 4H), 7.47-7.42 (m, 1H), 7.38 (td, j=7.6, 1.4hz, 1H), 7.30 (s, 1H), 7.23 (dd, j=7.5, 1.3hz, 1H), 5.35-5.23 (m, 1H), 3.76 (s, 4H), 3.22 (d, j=4.8 hz, 3H), 1.32 (d, j=6.9 hz, 6H). Mass spectrum C ₂₉ H ₂₅ F ₃ N ₅ S[M+H] ⁺ Calculated value 532.18, found: 532.1.

example 90

Example 90 (6 mg, 59% yield) was synthesized with reference to the procedure of general synthesis 3. ¹ H NMR (400 mhz, chloro-d) delta 7.78 (d, j=7.7 hz, 1H), 7.53 (d, j=7.8 hz, 2H), 7.48 (d, j=7.4 hz, 1H), 7.43 (d, j=8.1 hz, 1H), 7.32-7.28 (m, 4H), 7.21 (s, 1H), 5.07-4.92 (m, 1H), 3.80-3.70 (m, 4H), 3.31-3.23 (m, 5H), 3.18 (t, j=7.6 hz, 2H), 1.33 (d, j=6.9 hz, 6H). Mass spectrum C ₂₉ H ₂₉ F ₃ N ₅ S[M+H] ⁺ Calculated value 536.21, found: 536.1.

example 91

Example 91 (3 mg, yield 41%) was synthesized with reference to the procedure of general synthesis 3. ¹ H NMR(400MHz,CDCl ₃ ) Delta 8.07 (s, 1H), 7.87 (dd, j=7.7, 1.2hz, 1H), 7.71-7.60 (m, 4H), 7.46 (dtd, j=9.1, 7.9,1.3hz, 2H), 7.31 (ddd, j=8.6, 5.4,1.5hz, 2H), 4.23 (s, 3H), 3.83-3.70 (m, 4H), 1.36 (s, 3H), 1.34 (s, 3H). Mass spectrometry: C29H24F3N4OS [ M+H ]] ⁺ Theoretical 533.15, found 533.2.

Example 92

Example 92 (6.7 mg, yield 76%) was synthesized according to the procedure of general synthesis 3. ¹ H NMR(400MHz,CDCl ₃ ) Delta 7.79 (dd, j=7.7, 1.3hz, 1H), 7.54-7.47 (m, 3H), 7.46-7.41 (m, 1H), 7.36 (s, 1H), 7.34-7.26 (m, 4H), 4.20 (s, 3H), 3.77-3.71 (m, 4H), 3.30 (t, j=7.6 hz, 2H), 3.16 (t, j=7.6 hz, 2H), 1.33 (s, 3H), 1.31 (s, 3H). Mass spectrometry: C29H28F3N4OS [ M+H ] ] ⁺ Theoretical 537.19, measured 537.2.

Example 93

Example 93 was synthesized with reference to the procedure of general synthesis 3. (3.1 mg, yield 42%) ¹ H NMR(500MHz,CDCl ₃ ) Delta 8.17 (s, 1H), 7.76 (dd, j=7.7, 1.3hz, 1H), 7.71-7.68 (m, 2H), 7.67-7.62 (m, 2H), 7.48 (dd, j=7.3, 6.1hz, 1H), 7.44 (td, j=7.7, 1.4hz, 1H), 7.31 (ddd, j=8.7, 5.8,1.2hz, 2H), 3.80 (s, 3H), 3.59 (dt, j=13.6, 6.8hz, 1H), 2.89 (s, 3H), 1.34 (s, 3H), 1.33 (s, 3H). Mass spectrometry. C29H24F3N4S [ M+H ]] ⁺ Theoretical 517.16, found 517.2.

Example 94

Example 94 (3.1 mg, yield 42%) was synthesized with reference to the procedure of general synthesis method 3. ¹ H NMR(400MHz,CDCl ₃ ) Delta 7.72 (d, j=7.7 hz, 1H), 7.55 (d, j=7.1 hz, 3H), 7.49 (d, j=8.5 hz, 3H), 7.19 (s, 1H), 7.02 (s, 2H), 3.77 (dd, j=8.0, 3.8hz, 4H), 3.33 (d, j=8.1 hz, 2H), 3.20 (d, j=8.6 hz, 2H), 2.87 (s, 3H), 1.32 (s, 3H), 1.30 (s, 3H). Mass spectrometry: C29H28F3N4S [ M+H ]] ⁺ Theoretical 521.19, found 521.2.

Example 95

Example 95 (20 mg, yield 29%) was synthesized with reference to the procedure of general synthesis method 1. ¹ H NMR (400 mhz, chloro-d) delta 9.48 (s, 1H), 8.72 (s, 1H), 8.32 (s, 1H), 7.74 (d, j=8.4 hz, 2H), 7.69 (d, j=8.4 hz, 2H), 7.37 (d, j=1.3 hz, 1H), 3.97 (s, 3H), 3.83 (s, 3H), 1.91-1.84 (m, 1H), 0.99-0.94 (m, 2H), 0.93-0.83 (m, 2H). Mass spectrum C ₂₇ H ₂₀ F ₃ N ₆ OS[M+H] ⁺ Calculated value 533.1, found: 533.0.

example 96

Example 96 (4 mg, yield 23%) was synthesized with reference to the procedure of general synthesis method 1. ¹ H NMR (400 mhz, chloroform-d) delta 9.42 (s, 1H), 8.71 (s, 1H), 7.60 (d, j=1.0 hz, 1H), 7.57-7.52 (m, 2H), 7.33-7.29 (m, 2H), 7.28 (s, 1H), 3.96 (s, 3H), 3.77 (s, 3H), 3.39-3.33 (m, 2H), 3.21 (t, j=7.6 hz, 2H), 1.83-1.77 (m, 1H), 1.27 (dd, j=4.2, 2.3hz, 2H), 0.93-0.90 (m, 2H). Mass spectrum C ₂₇ H ₂₄ F ₃ N ₆ OS[M+H] ⁺ Calculated value 537.2, found: 537.1.

example 97

Example 97 (17 mg, 14% yield) was synthesized with reference to the procedure of general synthesis 1. ¹ H NMR (500 MHz, chloro form-d) δ9.46 (s, 1H), 8.69 (s, 1H), 8.30 (s, 1H), 7.76-7.70 (m, 2H), 7.51-7.44 (m, 2H), 6.49 (s, 1H), 3.95 (s, 3H), 2.39 (s, 3H), 1.87-1.82 (m, 1H), 0.95-0.91 (m, 2H), 0.90-0.84 (m, 2H). Mass spectrum C ₂₇ H ₂₀ F ₃ N ₆ OS[M+H] ⁺ Calculated value 533.1, found: 533.1.

example 98

Example 98 was synthesized (8 mg, yield 47%) with reference to the procedure of general synthesis method 1. ¹ H NMR (400 mhz, chloro-d) delta 9.42 (s, 1H), 8.71 (s, 1H), 7.63 (s, 1H), 7.36 (d, j=8.5 hz, 2H), 7.31 (d, j=8.2 hz, 2H), 6.47 (s, 1H), 3.96 (s, 3H), 3.36 (t, j=7.6 hz, 2H), 3.22 (t, j= 7.1,2H), 2.34 (s, 3H), 1.8-1.77 (m, 1H), 1.29-1.24 (m, 2H), 0.92 (m, 2H). Mass spectrum C ₂₇ H ₂₄ F ₃ N ₆ OS[M+H] ⁺ Calculated value 537.2, found: 537.2.

example 99

Example 99 (4.5 mg, yield 12%) was synthesized according to the procedure of example 77. 1H NMR (500 MHz, chloroform-d) δ9.42 (s, 1H), 8.69 (s, 1H), 7.59 (s, 1H), 7.50 (d, J=7.9 Hz, 2H), 7.46 (d, J=7.9 Hz, 2H), 7.42 (s, 1H), 4.59-4.52 (m, 1H), 4.38 (s, 2H), 3.95 (s, 3H), 1.73 (dt, J=8.2, 3.7Hz, 1H), 1.46 (d, J=6.7 Hz, 6H), 1.26-1.24 (m, 2H), 0.88-0.86 (m, 2H). Mass spectrum C ₂₈ H ₂₆ F ₃ N ₆ OS[M+H] ⁺ Calculated value 551.2, found: 551.2.

example 100

Example 100 (6.0 mg, yield 18%) was synthesized according to the procedure of example 77. ¹ H NMR (400 MHz, chloroform-d) δ9.43 (s, 1H), 8.71 (s, 1H), 7.64-7.58 (m, 3H), 7.47 (d, J=8.0 Hz, 2H), 7.33 (s, 1H), 4.39 (s, 2H), 3.96 (s, 3H), 3.78 (s, 3H), 1.77-1.71 (m, 1H), 1.28-1.24 (m, 2H), 0.91-0.87 (m, 2H). Mass spectrum C ₂₆ H ₂₂ F ₃ N ₆ OS[M+H] ⁺ Calculated value 523.2, found: 523.1.

example 101: determination of inhibition of USP1/UAF1 by 100. Mu.M Compound

The inhibition of USP1/UAF1 by 100. Mu.M compounds was evaluated by: USPl/UAF1 deubiquitinase activity was determined using Ub-AMC as substrate. The measurement principle is as follows: the cleavage of the amide bond between AMC and C-terminal glycine of ubiquitin by USPl/UAF1 increases the fluorescence signal.

The measurement conditions were as follows: to 35. Mu.l of USP1/UAF1 enzyme solution at a concentration of 2.5nM, 70. Mu.l of buffer (50 mM Tris-HCl pH 7.5,150mM NaCl,1mM DTT,0.05%Tween 20) and 35. Mu.l of small molecule compound solution at a concentration of 500. Mu.M (containing 5% DMSO) were added, and 140. Mu.l of the mixture was gently mixed and incubated at the test temperature for 20min. Mu.l of the mixture was aspirated, 10. Mu.l of a 5. Mu.M substrate solution was added to the mixture to initiate the reaction, and the reaction was rapidly read in a kinetic mode at 25℃under Ex360/Em460 conditions, once every 30 seconds for 10 minutes. The control group was replaced with 35 μl of 5% DMSO-containing buffer without compound and the relative percent activity of USP1/UAF1 was determined from the data. One blank well and three sample wells were set for the assay.

The relative activity of USP1/UAF1 at 100. Mu.M compound was calculated as follows:

note that: where cpd_Time 1 is the average of the starting readings of the test group reaction, cpd_Time 2 is the average of the 10min readings of the test group reaction, ctrl_Time 1 is the average of the starting readings of the 1% DMSO control group, and ctrl_Time 2 is the average of the 10min readings of the 1% DMSO control group reaction.

The inhibition of USP1/UAF1 by 100. Mu.M compound is:

Inhibition(％)＝1-USP1/UAF1 activity(％)

reagent: ub-AMC, hefei KS-V Peptide Biotechnology Co., ltd;5M Nacl,Sango Biotech,B548121;2M Tris-HCl 7.5,Sango Biotech,Cat#B548139; 7.3. Mu.M USP1/UAF1, R & D Systems.

Partial compounds of the present invention (100. Mu.M) showed inhibition of USP1/UAF1 enzyme. Inhibition of USP1/UAF1 enzyme by compounds at a concentration of 100. Mu.M: "+" indicates that the inhibition rate is less than or equal to 25%; "++" indicates 25% < inhibition rate less than or equal to 50%; "+". ++'s representing 50% < the inhibition rate is less than or equal to 75 percent; "+". ++'s represents 75% < the inhibition rate is less than or equal to 100 percent.

/>

Example 102: determination of half maximal inhibitory concentration (IC 50) of Compounds for USP1/UAF1 enzyme

Half maximal Inhibitory Concentration (IC) of the compound against USP1/UAF1 ₅₀ Value) is evaluated by: USPl/UAF1 deubiquitinase activity was determined using Ub-AMC as substrate. The measurement principle is as follows: the cleavage of the amide bond between AMC and C-terminal glycine of ubiquitin by USPl/UAF1 increases the fluorescence signal.

The measurement conditions were as follows: to 35. Mu.l of USP1/UAF1 enzyme solution at a concentration of 2.5nM, 70. Mu.l of buffer (50 mM Tris-HCl pH 7.5,150mM NaCl,1mM DTT,0.05%Tween 20) and 35. Mu.l of a series of small molecule compound solutions (5% DMSO) at different concentrations (500. Mu.M, 150. Mu.M, 50. Mu.M, 15. Mu.M, 5. Mu.M, 1.5. Mu.M, 0.5. Mu.M, 0.15. Mu.M, 0.05. Mu.M, 0.015. Mu.M, 0.005. Mu.M) were added, and the mixture was gently mixed and incubated at the test temperature for 20min. Mu.l of the mixture was aspirated, 10. Mu.l of a 5. Mu.M substrate solution was added to the mixture to initiate the reaction, and the reaction was rapidly read in a kinetic mode at 25℃under Ex360/Em460 conditions, once every 30 seconds for 10 minutes. The control group was replaced with 35 μl of 5% DMSO-containing buffer without compound and the relative percent activity of USP1/UAF1 was determined from the data. One blank well and three sample wells were set for the assay.

The relative activity of USP1/UAF1 at various concentrations of the compound was calculated as follows:

activity data were analyzed and plotted using GraphPad Prism statistical software using a nonlinear regression model ([ Inhibitor ]]vs. response-Variable slope four parameters) to plot S-type dose-activity value curvesAnd calculate IC ₅₀ Values.

Half maximal inhibitory concentration (IC 50) of some compounds of the invention against USP1/UAF1 enzyme. Half inhibition concentration of compound against USP1/UAF1 enzyme (IC 50, μm): "+" indicates IC50> 10. Mu.M; "++" indicates 1. Mu.M < IC 50.ltoreq.10. Mu.M; "+". ++'s represents 0.5 mu M < IC50 is less than or equal to 1 mu M; "+". ++ + "means IC50 is less than or equal to 0.5 mu M.

/>

The foregoing is merely illustrative of the present invention, and the present invention is not limited thereto, and any person skilled in the art will readily recognize that variations or substitutions are within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims

1. A compound of formula (I), or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof:

x is selected from: -S-, -O-, -NH-;

y is selected from: -CH ₂ -、-NR ^ya -、-C≡C-、-CH＝CH-；

R ^ya Selected from: hydrogen, C1-C4 straight chain alkyl;

preferably, R ^ya Selected from: hydrogen gasMethyl;

when Y is selected from-NR ^ya -、-CH ₂ -when n is 0 or 1;

when Y is selected from-C.ident.C-, -CH=CH-, n is 0;

R ₁ selected from: -H, -NR ^1a R ^1b 、-OR ^1c 、-CH ₂ R ^1d ；

preferably, R ₄ Selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trichloromethyl.

2. The compound of claim 1, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof:

wherein: x is selected from: -S-, -O-, -NH-.

3. A compound according to claim 1 or 2, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof:

wherein: r is R ₁ Selected from: -H, -NHCH ₃ 、-NCH ₃ CH ₃ 、-OCH ₃ 、-CH ₃ 。

4. A compound according to any one of claims 1 to 3, or an enantiomer, diastereomer, tautomer, salt, crystal form, solvate, and/or isotopically substituted derivative thereof:

wherein: y is selected from: -CH ₂ -、-NH-、-NCH ₃ -、-C≡C-、-CH＝CH-。

5. A compound according to any one of claims 1 to 4, or an enantiomer, diastereomer, tautomer, salt, crystal form, solvate, and/or isotopically substituted derivative thereof:

wherein: r is R ₂ Selected from: isopropylphenyl, isopropyloxyphenyl, methoxyphenyl, trifluoromethoxyphenyl, and cyclopropylmethoxypyrimidinyl.

6. A compound according to any one of claims 1 to 5, or an enantiomer, diastereomer, tautomer, salt, crystal form, solvate, and/or isotopically substituted derivative thereof:

wherein: r is R ₃ Selected from:

7. a compound according to any one of claims 1 to 6, or an enantiomer, diastereomer, tautomer, salt, crystal form, solvate, and/or isotopically substituted derivative thereof:

wherein: the compound is selected from:

8. a pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or an enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and/or isotopically substituted derivative thereof, and/or optionally a pharmaceutically acceptable carrier, excipient or diluent.

9. Use of a compound according to any one of claims 1 to 7, or an enantiomer, diastereomer, tautomer, salt, crystal form, solvate, and/or isotopically substituted derivative thereof, or a pharmaceutical composition according to claim 8, for the manufacture of a medicament for the treatment and/or prevention of a disease caused by ubiquitin-specific protease 1 (USP 1) activity.

10. Use of a compound according to any one of claims 1 to 7, or an enantiomer, diastereomer, tautomer, salt, crystal form, solvate, and/or isotopically substituted derivative thereof, or a pharmaceutical composition according to claim 8, for the manufacture of a medicament for the treatment and/or prevention of a disease caused by ubiquitin-specific protease 1 (USP 1) activity, wherein the disease is: cancer, or a disease or disorder associated with DNA damage; preferably, the cancer is a BRCA1 or BRCA2 mutation-related cancer.