Novel KAT6 inhibitor compound, preparation method and application

Abstract

The invention discloses a novel KAT6 inhibitor compound as well as a preparation method and application thereof. Belongs to the field of medicinal chemistry, the sulfonamide compound is a novel KAT6 inhibitor, has very strong inhibitory activity on breast cancer, liver cancer, leukemia, prostatic cancer, lung cancer and the like, and is simple in synthetic route, efficient and high in yield; the method has a good industrialization prospect.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and relates to a novel KAT6 inhibitor compound, a preparation method and use thereof. Background Art

[0002] KAT6 (lysine acetyltransferase 6) is a class of enzymes that plays a central role in epigenetic regulation. It regulates chromatin structure and gene transcriptional activity by catalyzing the acetylation of histone H3 at lysine 23 (H3K23). The KAT6 family comprises two isoforms: KAT6A (MOZ / MYST3) and KAT6B (MORF / MYST4). These two enzymes, through forming multiprotein complexes (for example, by binding to cofactors such as BRPF1 and ING5), participate in key biological processes such as stem cell differentiation, cell cycle regulation, and DNA damage repair. Studies have shown that KAT6A and KAT6B are significantly overexpressed in various malignancies, including breast, lung, ovarian, prostate, and acute myeloid leukemia (AML). Their overexpression is closely associated with increased tumor aggressiveness, chemotherapy resistance, and poor patient prognosis. For example, in breast cancer, KAT6A promotes cancer stem cell properties by activating the Wnt / β-catenin signaling pathway, while KAT6B impairs cell apoptosis by inhibiting the p53 pathway. In addition, KAT6 also regulates the migration and metastasis ability of tumor cells by acetylation of non-histone targets (such as transcription factors RUNX1 and FOXO3a).

[0003] The development of KAT6 inhibitors began with a systematic exploration of epigenetic targets. Patent WO 2016 / 198507A1, filed by Monash University, first reported the use of arylsulfonylhydrazides as novel KAT6A / B selective inhibitors. These compounds, by targeting the histone acetyltransferase (HAT) domain of MYST family proteins, block histone H3K9 acetylation, revealing the potential for overcoming drug resistance by inhibiting KAT6-mediated senescence escape mechanisms. Subsequently developed pyridothiazolesulfonylhydrazide derivatives, through pharmacokinetic optimization, achieved significant tumor suppression in animal models without exhibiting myelotoxicity, providing a new strategy for the treatment of solid tumors.

[0004] In recent years, Pfizer has been continuously developing new anticancer drugs around the MYST family lysine acetyltransferase (KAT) inhibitors. Based on the patents published in 2020 (WO 2020 / 254946 A1, WO 2020 / 254989 A1), the research team significantly improved the oral bioavailability, target selectivity and inhibition activity of KAT enzymes of the compounds through structure-activity relationship modification. In vitro and in vivo experiments have confirmed that tumor proliferation can be inhibited by regulating histone acetylation, but the selectivity of KAT family subtypes still needs to be improved. In 2022, Pfizer further proposed the combination therapy of KAT6 inhibitors with CDK4 inhibitors or anti-estrogens in the patent WO 2022 / 013369 A1, breaking through the clinical resistance limit of endocrine therapy and providing new strategies and hopes for cancer treatment. In the same year, Bayer developed a new type of acyl sulfonamide compound through the patent WO 2022 / 081807 A1, which showed high inhibition activity and broad-spectrum antitumor potential for KAT6A / B enzymes in in vitro experiments. These studies have jointly promoted the development of KAT inhibitors in multi-target combination therapy and overcoming drug resistance. Jiangsu Hengrui Medicine Co., Ltd. disclosed a new type of sulfonamide derivative and its application in cancer treatment through the patent WO 2023 / 016484 A1. The sulfonamide derivative involved in this patent is designed as a lysine acetyltransferase (KAT) inhibitor, which can effectively inhibit the growth of tumor cells such as breast cancer. In addition, other research institutions are also developing KAT6A / B inhibitors for related diseases. SUMMARY

[0005] The purpose of the present application is to provide a new KAT6 inhibitor compound with superior KAT6A / B inhibition activity, which can effectively inhibit KAT6 enzyme activity and has strong antitumor proliferation activity. Another purpose of the present application is to provide a preparation method of a new KAT6 inhibitor compound with simple synthesis route and high yield. The present application also provides the use of a new KAT6 inhibitor compound in the preparation of a treatment for KAT6 related disorders.

[0006] The technical solution of the present application is: the new KAT6 inhibitor compound of the present application has a chemical structural formula as shown in formula (I):

[0007]

[0008] wherein: m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3, 4 or 5;

[0009] Ring A is selected from phenyl, pyridyl, quinolinyl, morpholinyl, imidazolyl, heteroaryl, phenylthio, 5- or 6-membered monocyclic heteroaryl, cycloalkyl, or 7-, 8-, 9- or 10-membered bicyclic heterocyclyl;

[0010] Ring B is selected from phenyl, pyridyl, quinolinyl, morpholinyl, imidazolyl, heteroaryl, phenylthio, 5- or 6-membered monocyclic heteroaryl, cycloalkyl, or 7-, 8-, 9- or 10-membered bicyclic heterocyclyl;

[0011] Ring C is selected from phenyl, pyridyl, quinolinyl, morpholinyl, imidazolyl, heteroaryl, phenylthio, 5- or 6-membered monocyclic heteroaryl, cycloalkyl, or 7-, 8-, 9- or 10-membered bicyclic heterocyclyl;

[0012] R1is selected from one or more of -H, -OCH3, -SO2CH3, -COOCH3, -CN, -CF3, -OCF3, -NO2, halogen, alkyl, alkoxy, or haloalkyl;

[0013] R2is selected from one or more of -H, -OCH3, -SO2CH3, -COOCH3, -CN, -CF3, -OCF3, -NO2, halogen, alkyl, alkoxy, or haloalkyl;

[0014] R3is selected from a hydrogen atom, methyl, halomethyl, or halogen.

[0015] Further, said m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, or 3; p is 0.

[0016] Further, said R1is selected from -H, -F, -OCH3, -CF3, -COOCH3, -CH3;

[0017] R2is selected from -H, -F, -OCH3, -CF3, -CH3, -NO2;

[0018] R3is selected from a hydrogen atom.

[0019] Further, said ring A is selected from phenyl, quinolinyl, pyridyl, morpholinyl;

[0020] said ring B is selected from imidazolyl; and said ring C is selected from pyridyl or imidazolyl.

[0021] Further, said compound is any one of:

[0022]

[0023] Further, a method for preparing a KAT6 inhibitor compound, the synthetic route of which is as follows:

[0024] Synthetic Route 1:

[0025]

[0026] Synthetic route 2:

[0027]

[0028] Synthetic route 3:

[0029]

[0030] Further, a pharmaceutical composition comprising a racemate thereof or a single isomer thereof, and one or a combination of several, containing a therapeutically effective amount of the KAT6 inhibitor compound as described and a pharmaceutically acceptable carrier.

[0031] Further, the KAT6 inhibitor compound is used for the preparation of a KAT6 related disorder disease.

[0032] Further, in the use, the KAT6 related disorder disease is breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, etc., or drug-resistant cancer that has metastasized.

[0033] Further, the KAT6 related disorder disease also includes inflammatory diseases, endocrine diseases and cardiovascular and cerebrovascular diseases.

[0034] Beneficial effects: compared with the prior art, the present application has the following significant features: the sulfonamide KAT6 inhibitor of the present application has superior KAT6A / B inhibitory activity, can strongly inhibit KAT6 enzyme activity, has strong anti-tumor proliferation activity on breast cancer, liver cancer, leukemia and other tumors, and the synthetic route of the compound of the present application is simple, the yield is high, and the compound has good industrialization prospect. DETAILED DESCRIPTION

[0035] In order to more clearly illustrate the technical solutions of the present application, the technical solutions of the present application are further described in detail as follows:

[0036] The following table is the compound type synthesized by the reaction route:

[0037]

[0038]

[0039] The following table is the compound type synthesized by the reaction route:

[0040]

[0041]

[0042]

[0043] The following table shows the types of compounds synthesized by the reaction route:

[0044]

[0045]

[0046] The following table shows the types of compounds synthesized by the reaction route:

[0047]

[0048]

[0049] An object of the present invention is to provide a synthetic route; the specific steps are as follows:

[0050] Synthesis Route 1 Step 1:

[0051]

[0052] 1 (4.0 g, 20.6 mmol) was placed in a 100 mL eggplant-shaped flask, followed by the addition of benzenesulfonyl chloride (6.0 g, 30.8 mmol), 15 mL of dichloromethane, and 0.2 mL of triethylamine. The mixture was allowed to react at 40°C for 12 h. The reaction endpoint was determined by TLC. After the reaction, the reaction mixture was cooled and extracted 2-3 times with water and dichloromethane. The organic phase was dried over anhydrous sodium sulfate, then an appropriate amount of silica gel was added and dried under reduced pressure. After separation by silica gel column chromatography, the mixture was dried under reduced pressure to obtain intermediate 2 as a white solid.

[0053] Synthesis Route 1 Step 2:

[0054]

[0055] Compound 2 (1.0 g, 3.0 mmol) was placed in a 50 mL eggplant-shaped flask. A m-dibromobenzene derivative (3.6 mmol), Pd(PhP3)4 (173.3 mg, 0.15 mmol), K2CO3 (829.3 mg, 6.0 mmol), and 5 mL of solvent (1,4-dioxane:H2O = 4:1) were added, respectively. The reaction was allowed to proceed under nitrogen protection at 100°C for 12 h. The reaction endpoint was determined by TLC. After the reaction, the reaction solution was cooled and extracted 2-3 times with H2O and DCM. The organic phase was dried over anhydrous sodium sulfate, then an appropriate amount of silica gel was added and dried under reduced pressure. The mixture was separated by silica gel column chromatography and dried under reduced pressure to obtain a white or light yellow solid.

[0056] Synthesis Route 1 Step 3:

[0057]

[0058] 3 (3.6 mmol) was placed in a 50 mL eggplant-shaped flask, and diboronic acid pinacol ester (1.1 g, 4.32 mmol), PdCl2(dppf) (131.7 mg, 0.18 mmol) and KOAc (706.5 mg, 2.4 mmol) were added respectively; solvent 1,4-dioxane was added. 5mL, react under N2 protection and 100°C for 12h, TLC detection of the reaction end point, after the reaction solution is cooled, DCM and H2O are added and extracted 2-3 times, the organic phase is dried over anhydrous sodium sulfate, silica gel is added and evaporated under reduced pressure, and the crude boric acid pinacol ester derivative is separated by silica gel column chromatography; the corresponding boric acid pinacol ester derivative is placed in a 50mL eggplant-shaped flask, and then 1.5eq of 2-bromopyridine, 0.05eq of Pd(PPh3)4 and 2.0eq of cesium carbonate are added according to the amount of the corresponding derivative; 5mL of solvent (1,4-dioxane:H2O=4:1) is added, and then under N2 protection and 100°C for 12h, TLC detection of the reaction end point; after the reaction, the reaction solution is cooled, DCM and H2O are added and extracted 2-3 times, the organic phases are combined and dried over anhydrous sodium sulfate, an appropriate amount of silica gel is added and dried under reduced pressure, silica gel column chromatography is separated and dried under reduced pressure to obtain 4.

[0059] Synthesis Route 1 Step 4:

[0060]

[0061] 4 (0.9 mmol) was placed in a 50 mL eggplant-shaped flask, and 5 mL of a solvent (THF:H₂O = 1:1) was added. NaOH (40.0 mg, 1.0 mmol) was slowly added in an ice bath. The mixture was stirred for 10 minutes and then reacted at 60°C for 6 hours. The reaction endpoint was detected by TLC. After the reaction was completed, the reaction solution was cooled and extracted 2-3 times with EA and H₂O. The organic phases were combined, dried over anhydrous sodium sulfate, and then dried under reduced pressure by adding silica gel. After separation by column chromatography, intermediate 5 was obtained after reduced pressure.

[0062] Synthesis Route 1 Step 5:

[0063]

[0064] Intermediate 5 (0.2 mmol) was placed in a 50 mL eggplant-shaped flask, 3 mL of DCM solvent was added, and various substituted benzenesulfonyl chloride derivatives (0.4 mmol) and triethylamine (0.1 mL) were slowly added dropwise while stirring. The reaction was allowed to proceed at room temperature for 6 h, and the reaction endpoint was detected by TLC. After the reaction, silica gel was added and the mixture was dried under reduced pressure. After separation by silica gel column chromatography, the mixture was dried under reduced pressure to obtain 6.

[0065] Synthesis Route 2 Step 1:

[0066]

[0067] Into a 100 mL pear-shaped flask, 1-bromo-3-fluorobenzene derivative 7 (25.0 mmol) was added, followed by pyrazole (2.55 g, 37.5 mmol) and Cs2CO3(8.15 g, 25.0 mmol); then 15 mL of solvent DMF was added, and the reaction was carried out at 100 °C for 12 h. The reaction was terminated by TLC detection. After the reaction was completed, the reaction solution was cooled, extracted with DCM and H2O for 2-3 times, and the organic phase was combined and dried over anhydrous sodium sulfate. Appropriate silica gel was added, and the mixture was rotary evaporated under reduced pressure. The product was separated by column chromatography and rotary evaporated under reduced pressure to obtain intermediate 8.

[0068] Step 2 of synthesis route 2:

[0069]

[0070] Into a 100 mL pear-shaped flask, 1-bromo-3-fluorobenzene derivative 7 (25.0 mmol) was added, followed by pyrazole (2.55 g, 37.5 mmol) and Cs2CO3(8.15 g, 25.0 mmol); then 15 mL of solvent DMF was added, and the reaction was carried out at 100 °C for 12 h. The reaction was terminated by TLC detection. After the reaction was completed, the reaction solution was cooled, extracted with DCM and H2O for 2-3 times, and the organic phase was combined and dried over anhydrous sodium sulfate. Appropriate silica gel was added, and the mixture was rotary evaporated under reduced pressure. The product was separated by column chromatography and rotary evaporated under reduced pressure to obtain intermediate 8.

[0071] Step 3 of synthesis route 2:

[0072]

[0073] Into a 50 mL pear-shaped flask, 9 (3.0 mmol) was added, followed by 5 mL of solvent (THF:H2O = 1:1), and NaOH (120.0 mg, 3.0 mmol) was slowly added under ice bath conditions. After stirring for 10 min, the reaction was carried out at 60 °C for 6 h. The reaction was terminated by TLC detection. After the reaction was completed, the reaction solution was cooled, extracted with EA and H2O for 2-3 times, and the organic phase was combined and dried over anhydrous sodium sulfate. Appropriate silica gel was added, and the mixture was rotary evaporated under reduced pressure. The product was separated by column chromatography and rotary evaporated under reduced pressure to obtain intermediate 10.

[0074] Step 4 of synthesis route 2:

[0075]

[0076] The intermediate 10 (0.2 mmol) was placed in a 50 mL vial, 3 mL of solvent DCM was added, and various substituted benzene sulfonyl chloride derivatives (0.4 mmol) were slowly added dropwise with stirring, triethylamine (0.1 mL); the reaction was allowed to proceed at room temperature for 6 h, and the reaction was monitored by TLC. After the reaction was completed, silica gel was added and dried under reduced pressure. The product was isolated by column chromatography and dried under reduced pressure to obtain 11.

[0077] Synthesis route 3, step 1:

[0078]

[0079] The 1,3-dibromo benzene derivative 12 (25.0 mmol) was placed in a 100 mL vial, and inter-bromopyridine (3.95 g, 25.0 mmol), Pd(PhP3)4(1.45 g, 1.25 mmol), and Cs2CO3(8.15 g, 25.0 mmol) were added, and 25 mL of solvent (1,4-dioxane:H2O = 4:1) was added. The reaction was allowed to proceed under N2protection at 100°C for 12 h, and the reaction was monitored by TLC. After the reaction was completed, the reaction solution was cooled, and DCM and H2O were added to extract the reaction mixture 2-3 times. The organic phase was combined and dried over anhydrous sodium sulfate. Silica gel was added and dried under reduced pressure. The product was isolated by column chromatography and dried under reduced pressure to obtain the intermediate 13.

[0080] Synthesis route 3, step 2:

[0081]

[0082] The intermediate 13 (8.0 mmol) was placed in a 100 mL vial, and compound 2 (4.01 g, 12 mmol), Pd(PhP3)4(462.2 mg, 0.4 mmol), and Cs2CO3(2.61 g, 8.0 mmol) were added, and 15 mL of solvent (1,4-dioxane:H2O = 4:1) was added. The reaction was allowed to proceed under N2protection at 110°C for 12 h, and the reaction was monitored by TLC. After the reaction was completed, the reaction solution was cooled, and DCM and H2O were added to extract the reaction mixture 2-3 times. The organic phase was combined and dried over anhydrous sodium sulfate. Silica gel was added and dried under reduced pressure. The product was isolated by column chromatography and dried under reduced pressure to obtain compound 14.

[0083] Synthesis route 3, step 3:

[0084]

[0085] Put 14 (3.0 mmol) in a 50 mL tomato bottle, add 5 mL of solvent (THF:H2O = 1:1), slowly add NaOH (120.0 mg, 3.0 mmol) under the condition of ice bath, stir for 10 min, then react at 60°C for 6 h; TLC detects the end point of the reaction, after the reaction is completed, wait for the reaction solution to cool, then extract with EA and H2O for 2-3 times, combine the organic phase, dry with anhydrous sodium sulfate, add silica gel and rotary evaporate under reduced pressure, column chromatography separation, then rotary evaporate under reduced pressure to obtain intermediate 15.

[0086] Synthesis route 3 step 4:

[0087]

[0088] Put intermediate 15 (0.2 mmol) in a 50 mL tomato bottle, add 3 mL of solvent DCM, slowly drop the phenylsulfonyl chloride derivative (0.4 mmol) of various substituents and triethylamine (0.1 mL) during stirring. React at room temperature for 6 h, TLC detects the end point of the reaction, after the reaction is completed, add silica gel and rotary evaporate under reduced pressure, column chromatography separation, then rotary evaporate under reduced pressure to obtain 16.

[0089] The compounds synthesized in this experiment are prepared by a similar process to the above steps.

[0090] Compound 1a: 2-(3-(1-(phenylsulfonyl)-1H-pyrazol-4-yl)phenyl)pyridine

[0091] 1 H NMR (500 MHz, Chloroform-d) δ 8.67 (d, J = 4.8 Hz, 1H), 8.41 (s, 1H), 8.14 (s, 1H), 8.08 - 8.01 (m, 3H), 7.84 (d, J = 7.7 Hz, 1H), 7.72 (d, J = 6.8 Hz, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.54 - 7.47 (m, 3H), 7.44 (t, J = 7.7 Hz, 1H), 7.22 (t, J = 5.8 Hz, 1H). 13C C NMR (126 MHz, Chloroform-d) δ 156.94, 149.98, 143.76, 140.48, 137.23, 134.95, 131.02, 129.77, 128.37, 127.59, 126.78, 126.58, 126.12, 124.92, 122.80, 120.93. ESI-MS (+) [m / z]: 362.15 [M+H]+. Purity >95% by HPLC.

[0092] Compound 2a: 2-(3-fluoro-5-(1-(phenylsulfonyl)-1H-pyrazol-4-yl)phenyl)pyridine

[0093] 1 H NMR(500MHz,Chloroform-d)δ8.72(dd,J=4.9,1.7Hz,1H),8.44(s,1H),8.09–8.04(m,3H),7.97(d,J=1.5Hz,1H),7.81(td,J=7.8,1 .8Hz,1H),7.74(d,J=7.9Hz,1H),7.67(t,J=7.5Hz,1H),7.63–7.50(m,3H),7.31(dd,J=7.5,4.9Hz,1H),7.22(dt,J=9.1,2.0Hz,1H). 13C NMR(126MHz,Chloroform-d)δ155.62,149.97,143.39,142.58,137.19,134.90,129.67(d,J =4.1Hz),128.34(d,J=3.8Hz),127.76,125.00,123.19,120.78,120.41,113.72–112.98(m). 19F NMR(471MHz, CDCl3)δ-112.17(dd,J=19.4,9.7Hz).ESI-MS(+)[m / z]:380.14[M+H]+.Purity>95% by HPLC.

[0094] Compound 3a: 2-(3-(1-(phenylsulfonyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)pyridine

[0095] 1 H NMR(500MHz,Chloroform-d)δ8.73(d,J=4.8Hz,1H),8.48(s,1H),8.34(s,1H),8.14(s,1H),8.12–8.05(m,3H), 7.81(dt,J=13.3,7.8Hz,2H),7.74(s,1H),7.67(t,J=7.5Hz,1H),7.57(t,J=7.8Hz,2H),7.32(t,J=6.1Hz,1H). 13CNMR(126MHz,Chloroform-d)δ160.73,158.66,155.58,150.34,143.75,141.50,137.90(d,J=8.8Hz),137.60,132.65,132.39,1 32.17,131.77,128.98(d,J=2.2Hz),128.19,125.51–125.33(m),124.70,123.62,123.45(d,J=3.7Hz),121.13,118.11,117.94. 19F NMR(471MHz, CDCl3)δ-62.70.ESI-MS(+)[m / z]:430.15[M+H]+.Purity>95% by HPLC.

[0096] Compound 4a: 2-(3-(1-((2-fluorophenyl)sulfonyl)-1H-pyrazol-4-yl)phenyl)pyridine

[0097] 1 H NMR(500MHz,Chloroform-d)δ8.73(d,J=4.9Hz,1H),8.55(s,1H),8.21–8.13(m,2H),8.11(s,1H),7.90(d,J=7.7Hz,1H),7.79(h,J=7.7Hz,2 H),7.68(q,J=7.2Hz,1H),7.57(d,J=7.7Hz,1H),7.52(t,J=7.6Hz,1H),7.38(t,J=7.9Hz,1H),7.29(t,J=6.1Hz,1H),7.19(t,J=9.3Hz,1H). 13C NMR(126MHz,Chloroform-d)δ160.21,158.13,156.68,149.65,143.61,140.21,137.19(d,J=8.6Hz),136.78,131.18,130.63 ,129.37,127.94(d,J=2.2Hz),126.48,126.28,125.46,124.83(t,J=3.4Hz),124.65,122.38,120.56,117.48(d,J=20.7Hz). 19F NMR(471MHz, CDCl3)δ-107.41(dt,J=11.1,6.2Hz).ESI-MS(+)[m / z]:380.16[M+H]+.Purity>95% by HPLC.

[0098] Compound 5a: 2-(3-fluoro-5-(1-((2-fluorophenyl)sulfonyl)-1H-pyrazol-4-yl)phenyl)pyridine

[0099] 1 H NMR (500 MHz, Chloroform-d) δ 8.72 (d, J = 4.8 Hz, 1H), 8.55 (s, 1H), 8.20 - 8.14 (m, 1H), 8.08 (s, 1H), 7.98 (s, 1H), 7.81 (td, J = 7.7, 1.8 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.68 (dt, J = 7.9, 4.6 Hz, 1H), 7.63 (dt, J = 9.6, 1.9 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.31 (dd, J = 7.5, 4.8 Hz, 1H), 7.26 - 7.16 (m, 2H). 13C C NMR (126 MHz, Chloroform-d) δ 164.97, 163.01, 160.73, 158.66, 155.89, 150.24, 143.87, 142.87 (d, J = 7.7 Hz), 137.83 (d, J = 8.7 Hz), 137.44, 133.06 (d, J = 8.4 Hz), 131.75, 128.81, 125.38 (d, J = 4.2 Hz), 123.43, 121.05, 120.73 (d, J = 2.6 Hz), 118.10, 117.93, 113.69 (dd, J = 22.9, 20.3 Hz). 19 F NMR (471 MHz, CDCl3) δ -107.42 (dt, J = 10.5, 6.5 Hz), -112.11 (q, J = 9.3 Hz). ESI-MS (+) [m / z]: 398.15 [M+H]+. Purity >95% by HPLC.

[0100] Compound 6a: 2-(3-(1-((2,6-dimethoxyphenyl)sulfonyl)-1H-pyrazol-4-yl)-5-fluorophenyl)pyridine

[0101] 1 H NMR (500 MHz, Chloroform-d) δ 8.73 (d, J = 4.9 Hz, 1H), 8.54 (s, 1H), 8.01 (d, J = 14.8 Hz, 2H), 7.85 - 7.73 (m, 2H), 7.61 (d, J = 9.7 Hz, 1H), 7.48 (t, J = 8.5 Hz, 1H), 7.35 - 7.26 (m, 2H), 6.59 (d, J = 8.5 Hz, 2H), 3.82 (s, 6H).13C NMR (126 MHz, DMSO-d6) δ 164.71, 162.78, 159.75, 154.81 (d, J = 2.9 Hz), 150.05, 142.52, 142.31 (d, J = 8.4 Hz), 137.84, 137.48, 134.00 (d, J = 9.4 Hz), 130.91, 123.91, 122.53 (d, J = 2.5 Hz), 121.46, 120.20, 114.33 - 112.94 (m), 112.21 (d, J = 23.2 Hz), 105.95, 57.29. 19 F NMR (471 MHz, DMSO) δ -112.48 (t, J = 10.2 Hz). ESI-MS (+) [m / z]: 440.14 [M+H]+. Purity >95% by HPLC.

[0102] Compound 7a: 2-(3-fluoro-5-(1-(2-methoxyphenyl)sulfonyl)-1H-pyrazol-4-yl)phenyl)pyridine

[0103] 1 H NMR (500 MHz, Chloroform-d) δ 8.72 (d, J = 4.8 Hz, 1H), 8.57 (s, 1H), 8.19 - 8.13 (m, 1H), 8.02 (s, 1H), 7.98 (s, 1H), 7.82 - 7.77 (m, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.65 - 7.57 (m, 2H), 7.30 (dd, J = 7.4, 4.8 Hz, 1H), 7.26 - 7.22 (m, 1H), 7.14 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 3.80 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ 164.61, 162.66, 157.59, 155.54 (d, J = 2.9 Hz), 149.81, 142.51, 137.00, 133.19 (d, J = 8.6 Hz), 131.68, 129.81, 129.24, 124.31, 123.39 (d, J = 2.6 Hz), 123.04, 120.85, 120.69, 120.33 - 120.12 (m), 113.27 (d, J = 4.4 Hz), 113.06 (d, J = 9.5 Hz), 112.66, 56.33. 19F NMR(471MHz, CDCl3)δ-112.20(t,J=9.4Hz).ESI-MS(+)[m / z]:410.19[M+H]+.Purity>95% by HPLC.

[0104] Compound 8a: 2-(3-(1-((2-fluorophenyl)sulfonyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)pyridine

[0105] 1 H NMR(500MHz,Chloroform-d)δ8.77–8.72(m,1H),8.60(s,1H),8.37(d,J=2.2Hz,1H),8.18–8.15(m,2H ),7.87–7.80(m,2H),7.78(s,1H),7.73–7.64(m,J=7.4,1H),7.43–7.33(m,2H),7.20(t,J=9.2Hz,1H). 13C NMR (126MHz, Chloroform-d) δ 160.23, 158.16, 155.08, 149.83, 143.25, 140.99, 137.39 (d, J = 8.8Hz), 137.09, 132.14, 131.89, 131. 66,131.26,128.47(d,J=2.2Hz),127.68,125.00–124.82(m),124.19,123.12,122.89(dd,J=12.9,3.8Hz),120.62,117.60,117.44. 19 F NMR(471MHz, CDCl3)δ-62.69,-107.42(dt,J=10.9,5.7Hz).ESI-MS(+)[m / z]:448.11[M+H]+.Purity>95% by HPLC.

[0106] Compound 9a: 4-(3-fluoro-5-(1H-pyrazol-1-yl)phenyl)-1-(phenylsulfonyl)-1H-pyrazole

[0107] 1H NMR(500MHz,Chloroform-d)δ8.41(s,1H),8.07(dt,J=7.3,1.3Hz,2H),8.03(s,1H),7.94(d,J=2.6Hz,1H),7.75(d,J=1.8Hz ,1H),7.71–7.65(m,2H),7.61–7.47(m,2H),7.33(dt,J=9.6,2.2Hz,1H),7.09(dt,J=9.0,1.9Hz,1H),6.51(t,J=2.2Hz,1H). 13C NMR(126MHz,Chloroform-d)δ164.92,162.95,143.41,142.14,137.14,135.25,133.84,129.96,128.6 5,128.16,127.25,124.70(d,J=2.8Hz),112.59(d,J=2.9Hz),111.12,110.93,108.81,106.11,105.90. 19 F NMR(471MHz, CDCl3)δ-110.07(t,J=9.3Hz).ESI-MS(+)[m / z]:369.15[M+H]+.Purity>95% by HPLC.

[0108] Compound 10a: 4-(3-fluoro-5-(1H-pyrazol-1-yl)phenyl)-1-((2-fluorophenyl)sulfonyl)-1H-pyrazole

[0109] 1 H NMR (500MHz, DMSO) δ9.32 (s, 1H), 8.68 (d, J = 2.5Hz, 1H), 8.60 (s, 1H), 8.16–8.08 (m, 2H), 7.91 (td, J=8.0,3.9Hz,1H),7.80(d,J=1.6Hz,1H),7.70–7.62(m,2H),7.59–7.50(m,2H),6.67–6.59(m,1H). 13C NMR(126MHz,DMSO-d6)δ159.91,144.65,142.03,139.19,131.37,130.57,128.88, 126.38,124.25,118.57,118.41,111.69,110.76,110.57,108.82,105.28,105.07. 19F NMR (471 MHz, DMSO) δ -109.03 (dt, J = 11.8, 6.4 Hz), -110.79 (t, J = 10.1 Hz). ESI-MS (+) [m / z]: 409.11 [M+Na]+. Purity >95% by HPLC.

[0110] Compound 11a: 4-(3-fluoro-5-(lH-pyrazol-l-yl)phenyl)-l-((3- fluorophenyl)sulfonyl)-lH-pyrazole

[0111] 1 H NMR (500 MHz, Chloroform-d) δ 8.40 (s, 1H), 8.05 (s, 1H), 7.94 (d, J = 2.5 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.79 - 7.73 (m, 2H), 7.68 (s, 1H), 7.58 - 7.54 (m, 1H), 7.41 - 7.31 (m, 2H), 7.09 (d, J = 8.9 Hz, 1H), 6.51 (s, 1H). 13C F NMR (471 MHz, CDCl3) δ -107.96 (td, J = 7.9, 4.6 Hz), -109.95 (t, J = 9.2 Hz). ESI-MS (+) [m / z]: 387.18 [M+H]+. Purity >95% by HPLC. 19 F NMR (471 MHz, CDCl3) δ -107.96 (td, J = 7.9, 4.6 Hz), -109.95 (t, J = 9.2 Hz). ESI-MS (+) [m / z]: 387.18 [M+H]+. Purity >95% by HPLC.

[0112] Compound 12a: l-((3,5-difluorophenyl)sulfonyl)-4-(3-fluoro-5-(lH-pyrazol-l- yl)phenyl)-lH-pyrazole

[0113] 1H NMR (500 MHz, Chloroform-d) δ 8.38 (s, 1H), 8.08 (s, 1H), 7.94 (d, J = 2.6 Hz, 1H), 7.75 (s, 1H), 7.69 (s, 1H), 7.63 - 7.59 (m, 2H), 7.35 (dd, J = 8.3, 3.5 Hz, 1H), 7.14 - 7.06 (m, 2H), 6.52 (t, J = 2.1 Hz, 1H). 13C F NMR (471 MHz, CDC13) δ -103.59 (dd, J = 8.5, 4.8 Hz), -109.86 (t, J = 9.3 Hz). ESI-MS (+) [m / z]: 405.18 [M+H]+. Purity >95% by HPLC. 19 F NMR (471 MHz, CDC13) δ -103.59 (dd, J = 8.5, 4.8 Hz), -109.86 (t, J = 9.3 Hz). ESI-MS (+) [m / z]: 405.18 [M+H]+. Purity >95% by HPLC.

[0114] Compound 13a: l-((2,6-difluorophenyl)sulfonyl)-4-(3-fluoro-5-(lH-pyrazol-l- yl)phenyl)-lH-pyrazole

[0115] 1 H NMR (500 MHz, Chloroform-d) δ 8.38 (s, 1H), 8.08 (s, 1H), 7.94 (d, J = 2.6 Hz, 1H), 7.75 (s, 1H), 7.69 (s, 1H), 7.63 - 7.59 (m, 2H), 7.35 (dd, J = 8.3, 3.5 Hz, 1H), 7.14 - 7.06 (m, 2H), 6.52 (t, J = 2.1 Hz, 1H). 13CNMR (126 MHz, CDC13) δ 164.95, 162.98, 161.49, 159.39, 143.81, 142.18, 137.61, 128.82, 127.28, 114.10, 113.89, 112.69 (d, J = 2.9 Hz), 111.25, 111.07, 108.85, 106.30, 106.09. 19 FNMR (471 MHz, CDC13) δ -104.44 - -104.54 (m), -109.96 (t, J = 9.2 Hz). ESI-MS (+) [m / z]: 405.17 [M+H]+. Purity >95% by HPLC.

[0116] Compound 14a: 4-(3-fluoro-5-(lH-pyrazol-l-yl)phenyl)-l-((2- methoxyphenyl)sulfonyl)-lH-pyrazole

[0117] 1 H NMR (500 MHz, Chloroform-d) δ 8.56 (s, 1H), 8.20 - 8.12 (m, 1H), 8.00 (s, 1H), 7.97 (s, 1H), 7.75 (d, J = 1.7 Hz, 1H), 7.71 (t, J = 1.7 Hz, 1H), 7.65 - 7.60 (m, 1H), 7.34 (dt, J = 9.6, 2.2 Hz, 1H), 7.19 - 7.10 (m, 2H), 7.04 - 6.91 (m, 1H), 6.52 (t, J = 2.1 Hz, 1H), 3.80 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ 164.45, 162.49, 157.46, 142.00, 141.61, 136.95, 133.76, 131.62, 129.26, 126.76, 124.06, 122.75 (d, J = 2.7 Hz), 120.77, 112.54, 111.98 (d, J = 2.8 Hz), 110.29, 108.27, 105.43, 56.21. 19 F NMR (471 MHz, CDC13) δ -110.16 (t, J = 9.3 Hz). ESI-MS (+) [m / z]: 399.18 [M+H]+. Purity >95% by HPLC.

[0118] Compound 15a: l-((2,6-dimethoxyphenyl)sulfonyl)-4-(3-fluoro-5-(lH-pyrazol-l- yl)phenyl)-lH-pyrazole

[0119] 1 H NMR (500 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.72 (d, J = 2.6 Hz, 1H), 8.43 (s, 1H), 8.13 (s, 1H), 7.80 (d, J = 1.7 Hz, 1H), 7.65 - 7.60 (m, 3H), 7.55 (td, J = 7.6, 2.9 Hz, 1H), 6.81 (d, J = 8.6 Hz, 2H), 6.62 (s, 1H), 3.75 (s, 6H). 13C C NMR (126 MHz, DMSO-d6) δ 164.61, 162.68, 159.73, 158.72, 142.46, 141.97, 137.50, 133.99, 132.48, 131.95 (d, J = 9.7 Hz), 131.15, 129.22 (d, J = 11.7 Hz), 128.90, 122.14 (d, J = 2.6 Hz), 113.20, 111.33, 108.75, 105.88 (d, J = 8.1 Hz), 43.08, 15.55. 19 F NMR (471 MHz, DMSO) δ -110.87 (t, J = 10.1 Hz). ESI-MS (+) [m / z]: 429.22 [M+H]+. Purity > 95% by HPLC.

[0120] Compound 16a: 4-(3-fluoro-5-(1H-pyrazol-1-yl)phenyl)-1-((2- (trifluoromethyl)phenyl)sulfonyl)-1H-pyrazole

[0121] 1 H NMR (500 MHz, CDCl3) δ 8.54 - 8.44 (m, 2H), 8.02 (s, 1H), 7.93 (dd, J = 18.2, 3.2 Hz, 2H), 7.84 (dd, J = 6.5, 3.0 Hz, 2H), 7.75 (d, J = 1.8 Hz, 1H), 7.69 - 7.65 (m, 1H), 7.39 - 7.32 (m, 1H), 7.13 - 7.07 (m, 1H), 6.53 - 6.49 (m, 1H). 13CNMR (126 MHz, CDC13) δ 164.91, 162.95, 143.49, 142.14, 135.52, 135.34, 134.38, 133.75, 133.27, 129.14 - 128.99 (m), 128.86 (d, J = 5.3 Hz), 127.27, 124.19 (d, J = 2.8 Hz), 112.61 (d, J = 2.9 Hz), 111.21, 111.02, 108.81, 106.24, 106.03. 19 F NMR (471 MHz, CDC13) δ -62.89, -109.91 (t, J = 9.2 Hz). ESI-MS (+) [m / z]: 437.11 [M+H]+. Purity >95% by HPLC.

[0122] Compound 17a: 4-(3-fluoro-5-(lH-pyrazol-l-yl)phenyl)-l-((3- (trifluoromethyl)phenyl)sulfonyl)-lH-pyrazole

[0123] 1 H NMR (500 MHz, Chloroform-d) δ 8.52 - 8.47 (m, 1H), 8.46 (s, 1H), 8.02 (s, 1H), 7.95 (d, J = 2.5 Hz, 1H), 7.91 (q, J = 7.2, 6.0 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.74 (d, J = 7.2 Hz, 1H), 7.67 (s, 1H), 7.37 (d, J = 2.2 Hz, OH), 7.10 (d, J = 8.9 Hz, 1H), 6.51 (t, J = 2.2 Hz, 1H). 13 C NMR (126 MHz, Chloroform-d) δ 164.41, 162.45, 142.99, 141.94 (d, J = 11.1 Hz), 141.65, 134.84, 133.89, 133.21 (d, J = 9.7 Hz), 132.77, 128.53 (d, J = 6.3 Hz), 128.36 (d, J = 5.0 Hz), 126.77, 123.68 (d, J = 2.8 Hz), 112.11 (d, J = 2.8 Hz), 110.71, 110.53, 108.31, 105.75, 105.54. ESI-MS (+) [m / z]: 437.30 [M+H]+. Purity >95% by HPLC.

[0124] Compound 18a: 4-(3-fluoro-5-(lH-pyrazol-l-yl)phenyl)-l-((4- (trifluoromethyl)phenyl)sulfonyl)-lH-pyrazole

[0125] 1 H NMR(500MHz,Chloroform-d)δ8.41(s,1H),8.20(d,J=8.2Hz,2H),8.05(s,1H),7.94(d,J=2.5Hz,1H),7.83(d,J= 8.1Hz,2H),7.74(s,1H),7.67(s,1H),7.33(dd,J=7.2,4.9Hz,1H),7.08(d,J=8.9Hz,1H),6.50(d,J=2.3Hz,1H). 13C NMR(126MHz,Chloroform-d)δ164.87,162.90,144.04,142.16,140.52,133.47(d,J=9.6Hz),129.24,128.30,127.24,1 27.09(q,J=3.7Hz),125.19(d,J=2.7Hz),124.29,122.12,112.62(d,J=2.9Hz),110.93,108.85,106.10(d,J=26.2Hz). 19 F NMR(471MHz, CDCl3)δ-63.40,-109.90(t,J=9.3Hz).ESI-MS(+)[m / z]:437.15[M+H]+.Purity>95% by HPLC.

[0126] Compound 19a: Methyl 2-((4-(3-fluoro-5-(1H-pyrazol-1-yl)phenyl)-1H-pyrazol-1-yl)sulfonyl)benzoate

[0127] 1 H NMR(500MHz,Chloroform-d)δ8.48(s,1H),8.26(d,J=7.7Hz,1H),8.04(s,1H),7.95(d,J=2.6Hz,1H),7.75–7.70( m,4H),7.66(d,J=7.2Hz,1H),7.35(d,J=9.5Hz,1H),7.13(d,J=8.9Hz,1H),6.51(s,1H),5.30(s,1H),3.98(s,3H). 13CNMR (126 MHz, DMSO-d6) δ 166.49, 164.43, 162.50, 144.15, 141.97 (d, J = 15.0 Hz), 135.97, 133.65, 132.75, 132.26, 130.77, 130.48, 130.12, 128.74, 123.54, 111.49, 110.38, 108.71, 104.97 (d, J = 26.7 Hz), 53.66. 19 F NMR (471 MHz, CDC13) δ -110.16 (t, J = 9.3 Hz). ESI-MS (+) [m / z]: 427.18 [M+H]+. Purity >95% by HPLC.

[0128] Compound 20a: l-((2-fluorophenyl)sulfonyl)-4-(3-methyl-5-(lH-pyrazol-l- yl)phenyl)-lH-pyrazole

[0129] 1 H NMR (500 MHz, Chloroform-d) δ 8.51 (s, 1H), 8.20 - 8.09 (m, 1H), 8.06 (s, 1H), 7.98 - 7.94 (m, 1H), 7.74 (s, 1H), 7.68 (s, 2H), 7.44 (s, 1H), 7.38 (q, J = 10.1, 8.9 Hz, 1H), 7.19 (t, J = 9.3 Hz, 1H), 6.49 (t, J = 2.0 Hz, 1H), 2.46 (s, 3H). 13 C NMR (126 MHz, Chloroform-d) δ 160.71, 158.64, 143.96, 141.61, 141.22, 140.76, 137.76 (d, J = 8.7 Hz), 131.83, 131.71, 128.58 (d, J = 2.2 Hz), 127.23, 125.44, 125.27 (d, J = 4.7 Hz), 119.55, 118.07, 117.91, 114.62, 108.17, 21.89. 19 F NMR (471 MHz, CDC13) δ -106.50 - -108.98 (m). ESI-MS (+) [m / z]: 383.14 [M+H]+. Purity >95% by HPLC.

[0130] Compound 21a: l-((3-fluorophenyl)sulfonyl)-4-(3-methyl-5-(lH-pyrazol-l- yl)phenyl)-lH-pyrazole

[0131] 1H NMR (500 MHz, Chloroform-d) δ 8.38 (s, 1H), 8.07 (s, 1H), 7.95 (d, J = 2.5 Hz, 1H), 7.92 - 7.83 (m, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 7.56 (td, J = 8.4, 5.1 Hz, 2H), 7.42 (s, 1H), 7.36 (td, J = 8.4, 2.6 Hz, 1H), 7.22 (s, 1H), 6.48 (s, 1H), 2.44 (s, 3H). 13C F NMR (471 MHz, CDC13) δ -108.10 (td, J = 7.9, 5.1 Hz). ESI-MS (+) [m / z]: 383.16 [M+H]+. Purity >95% by HPLC. 19 F NMR (471 MHz, CDC13) δ -108.10 (td, J = 7.9, 5.1 Hz). ESI-MS (+) [m / z]: 383.16 [M+H]+. Purity >95% by HPLC.

[0132] Compound 22a: 3-(3-(l-(phenylsulfonyl)-lH-pyrazol-4-yl)-5- (trifluoromethyl)phenyl)pyridine

[0133] 1 H NMR (500 MHz, Chloroform-d) δ 8.38 (s, 1H), 8.07 (s, 1H), 7.95 (d, J = 2.5 Hz, 1H), 7.92 - 7.83 (m, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 7.56 (td, J = 8.4, 5.1 Hz, 2H), 7.42 (s, 1H), 7.36 (td, J = 8.4, 2.6 Hz, 1H), 7.22 (s, 1H), 6.48 (s, 1H), 2.44 (s, 3H). 13CNMR (126 MHz, Chloroform-d) δ 149.70, 148.36, 143.31, 140.12, 137.08, 135.29, 135.19, 133.06, 132.80, 132.70, 129.96, 128.67, 128.36, 128.14, 124.54, 124.28, 123.62 (d, J = 3.8 Hz), 122.96, 122.78 (d, J = 3.8 Hz). 19 F NMR (471 MHz, CDC13) δ -62.78. ESI-MS (+) [m / z]: 430.15 [M+H]+. Purity >95% by HPLC.

[0134] Compound 23a: 3-(3-fluoro-5-(l-((2-fluorophenyl)sulfonyl)-lH-pyrazol-4-yl)phenyl)pyridine

[0135] 1 H NMR (500 MHz, Chloroform-d) δ 8.85 (d, J = 2.5 Hz, 1H), 8.65 (d, J = 4.9 Hz, 1H), 8.52 (s, 1H), 8.20 - 8.13 (m, 1H), 8.03 (s, 1H), 7.90 (dt, J = 7.9, 2.0 Hz, 1H), 7.48 (d, J = 1.7 Hz, 1H), 7.45 - 7.33 (m, 2H), 7.26 - 7.15 (m, 3H). 13C NMR (126 MHz, Chloroform-d) δ 164.97, 163.00, 160.73, 158.66, 149.83, 148.61, 143.68, 141.41, 137.91 (d, J = 8.7 Hz), 135.48 (d, J = 2.3 Hz), 134.82, 133.59, 131.80, 128.81 (d, J = 2.1 Hz), 125.42 (d, J = 3.8 Hz), 124.09, 121.07 (d, J = 2.6 Hz), 1 18.02 (d, J = 20.5 Hz), 1 13.98 (d, J = 22.5 Hz), 1 13.07 (d, J = 22.7 Hz). 19 F NMR (471 MHz, CDC13) δ -107.51 (dt, J = 1 1.2, 5.9 Hz), -1 1 1.29 (t, J = 9.1 Hz). ESI-MS (+) [m / z]: 398.16 [M+H]+. Purity >95% by HPLC.

[0136] Compound 24a: 3-(3-Fluoro-5-(1-((2-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazol-4-yl)phenyl)pyridine

[0137] 1 H NMR(500MHz,Chloroform-d)δ8.85(s,1H),8.65(d,J=4.8Hz,1H),8.52–8.44(m,2H),8.01(s,1H) ,7.90(d,J=8.0Hz,2H),7.85–7.82(m,2H),7.46(s,1H),7.44–7.40(m,1H),7.22(d,J=9.3Hz,2H). 13C NMR (126MHz, Chloroform-d) δ164.93,162.96,149.51,148.31,143.50,141.26(d,J=8.5Hz),135.69–135.31(m),135.05,134.38,133.50(d,J=8. 8Hz),133.25,128.99(q,J=6.1,5.5Hz),128.76(d,J=7.3Hz),124.35(d, J=2.7Hz),124.18,121.04(d,J=2.7Hz),114.04,113.86,113.20,113.02. 19 FNMR(471MHz, CDCl3)δ-57.57,-111.23(t,J=9.2Hz).ESI-MS(+)[m / z]:448.15[M+H]+.Purity>95% by HPLC.

[0138] Compound 25a: Methyl 2-((4-(3-fluoro-5-(pyridin-3-yl)phenyl)-1H-pyrazol-1-yl)sulfonyl)benzoate

[0139] 1 H NMR(500MHz,Chloroform-d)δ8.85(s,1H),8.65(s,1H),8.47(s,1H),8.29–8.24(m,1H),8.03(s,1H),7.88(d,J=7.8 Hz,1H),7.76–7.62(m,3H),7.48(s,1H),7.42–7.39(m,1H),7.25(d,J=10.1Hz,1H),7.23–7.19(m,1H),3.98(s,3H). 13CNMR(126MHz,Chloroform-d)δ166.96,164.92,162.96,149.68,148.52,143.29,135.03,134.93,134.85,133.78(d,J=8.8Hz),1 33.34, 131.68 (d, J = 7.3Hz), 129.99, 129.28, 124.12 (d, J = 2.8Hz), 121.02 (d, J = 2.6Hz), 113.89, 113.71, 113.14, 112.96, 53.77. 19 F NMR(471MHz, CDCl3)δ-111.40.ESI-MS(+)[m / z]:438.18[M+H]+.Purity>95% by HPLC.

[0140] Compound 26a: 8-((4-(3-fluoro-5-(pyridin-3-yl)phenyl)-1H-pyrazol-1-yl)sulfonyl)quinoline

[0141] 1 H NMR (500MHz, DMSO-d6) δ9.55(s,1H),9.10(s,1H),8.97(d,J=4.3Hz,1H),8.63(d,J=4.8Hz,1H),8.55(dd,J=15.5,7.9Hz,2H),8.46(d,J=8. 3Hz,2H),8.27(d,J=8.0Hz,1H),8.12(s,1H),7.88(t,J=7.9Hz,1H),7.77(d,J=9.9Hz,1H),7.65(dd,J=8.4,4.1Hz,1H),7.62–7.51(m,2H). 13C NMR (126MHz, DMSO-d6) δ164.55,162.62,152.44,149.42,148.28,143.52,143.05,140.33(d,J=8.7Hz),137.43,136.95,134.92,134.32,1 33.94(d,J=9.3Hz),133.58,132.80,132.21,128.89,126.22,124.17,123.43,122.79(d,J=2.5Hz),120.69,112.60(dd,J=23.0,19.0Hz). 19 F NMR(471MHz, DMSO)δ-112.06.ESI-MS(+)[m / z]:431.22[M+H]+.Purity>95% by HPLC.

[0142] Compound 27a: 3-(3-(1-((2-fluorophenyl)sulfonyl)-1H-pyrazol-4-yl)-5- methoxyphenyl)pyridine

[0143] 1 H NMR (500 MHz, Chloroform-d) δ 8.85 (s, 1H), 8.63 (d, J = 4.8 Hz, 1H), 8.52-8.47 (m, 1H), 8.43 (s, 1H), 8.02 (s, 1H), 7.94-7.88 (m, 2H), 7.67 (dd, J = 12.1, 7.6 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.47-7.44 (m, 1H), 7.40 (dd, J = 8.0, 5.0 Hz, 1H), 7.05 (s, 2H), 3.91 (s, 3H). 13C C NMR (126 MHz, Chloroform-d) δ 161.06, 160.65, 158.58, 149.20, 148.53, 143.92, 140.55, 137.77 (d, J = 8.7 Hz), 136.53, 134.92, 132.62, 131.71 (d, J = 9.1 Hz), 129.14, 128.52 (d, J = 2.1 Hz), 125.57, 125.47-125.24 (m), 123.99, 118.03, 112.74, 111.74, 55.91. 19 F NMR (471 MHz, Chloroform-d) δ -107.50 (dt, J = 11.0, 6.0 Hz). ESI-MS (+) [m / z]: 410.20 [M+H]+. Purity >95% by HPLC.

[0144] Compound 28a: 3-(3-methoxy-5-(1-((2-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazol-4- yl)phenyl)pyridine

[0145] 1 H NMR (500 MHz, Chloroform-d) δ 8.85 (s, 1H), 8.63 (d, J = 4.8 Hz, 1H), 8.52-8.47 (m, 1H), 8.43 (s, 1H), 8.02 (s, 1H), 7.94-7.88 (m, 2H), 7.67 (dd, J = 12.1, 7.6 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.47-7.44 (m, 1H), 7.40 (dd, J = 8.0, 5.0 Hz, 1H), 7.05 (s, 2H), 3.91 (s, 3H). 13CNMR(126MHz,Chloroform-d)δ161.12,149.39,148.72,143.82,140.70,136.55,135.20,134.88,134.29,133.23,132.63, 132.50(d,J=10.0Hz),132.33(d,J=2.7Hz),129.06–128.83(m),128.51,125.37,123.99,118.01,112.81,111.85,55.96. 19 F NMR(471MHz, CDCl3)δ-57.57.ESI-MS(+)[m / z]:460.22[M+H]+.Purity>95% by HPLC.

[0146] Compound 29a: 3-(3-(1-((2-fluorophenyl)sulfonyl)-1H-pyrazol-4-yl)-5-nitrophenyl)pyridine

[0147] 1 H NMR (500MHz, CDCl3) δ8.92(s,1H),8.72(d,J=4.8Hz,1H),8.64(s,1H),8.38(d,J=8.0Hz,2H),8.19(t,J=7.5Hz,1H),8.12(s,1 H),8.01(s,1H),7.97(d,J=8.2Hz,1H),7.74–7.68(m,1H),7.47(dd,J=7.9,5.0Hz,1H),7.43–7.39(m,1H),7.24–7.18(m,1H). 13C NMR (126MHz, CDCl3) δ160.75,158.68,150.48,149.86,148.61,143.42,141.06,138.11(d,J=8.8Hz),137.58,134.97,13 3.46,131.88,130.69,129.31(d,J=2.3Hz),125.50(d,J=3.8Hz),124.30,123.58,121.51,120.60,118.06(d,J=20.5Hz). 19 F NMR(471MHz, CDCl3)δ-107.47(dt,J=11.0,6.2Hz).ESI-MS(+)[m / z]:425.17[M+H]+.Purity>95% by HPLC.

[0148] Compound 30a: 3-(3-(1-((2-fluorophenyl)sulfonyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)pyridine

[0149] 1 H NMR(500MHz,Chloroform-d)δ8.89(s,1H),8.69(d,J=4.9Hz,1H),8.58(s,1H),8.18(t,J=7.5Hz,1H),8.09(s,1H),7. 94(d,J=7.9Hz,1H),7.87(s,1H),7.77(d,J=11.6Hz,2H),7.74–7.67(m,1H),7.48–7.34(m,2H),7.20(t,J=9.2Hz,1H). 19 F NMR (471MHz, CDCl3) δ-62.76,-107.50 (dt, J=10.7, 6.0Hz). 13C NMR (126MHz, Chloroform-d) δ 160.45, 158.38, 149.57, 148.22, 143.31, 139.94, 137.73 (d, J = 9.0Hz), 135.09, 134.86, 132.80, 132.54, 132. 35,131.55,128.74,128.19,125.20,124.87,124.75,123.44,122.57,117.76(d,J=21.3Hz).ESI-MS(+)[m / z]:448.17[M+H]+.Purity>95%by HPLC.

[0150] Compound 31a: 3-(3-(1-((3-fluorophenyl)sulfonyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)pyridine

[0151] 1 H NMR(500MHz,Chloroform-d)δ8.88–8.84(m,1H),8.67(d,J=4.8Hz,1H),8.45(s,1H),8.10(s,1H),7.90(dd,J=12.7,8.0Hz,2H),7.8 3(s,1H),7.78(d,J=8.0Hz,1H),7.75(s,2H),7.66(dd,J=12.1,7.7Hz,1H),7.60–7.51(m,1H),7.49–7.41(m,2H),7.42–7.34(m,1H). 13CNMR(126MHz,Chloroform-d)δ163.73,161.71,149.94,148.54,143.71,140.27,135.26,135.01,132.33(d,J=2.7Hz),131.83(d,J=7.8Hz),12 8.89(d,J=12.2Hz),128.40,128.22,124.89,124.53(d,J=3.5Hz),124 .20,123.77(d,J=3.8Hz),122.91–122.69(m),122.58,116.17,115.97. 19 F NMR(471MHz, CDCl3)δ-62.78,-107.92(d,J=5.3Hz).ESI-MS(+)[m / z]:448.30[M+H]+.Purity>95% by HPLC.

[0152] Compound 32a: 3-(3-(1-((2,6-difluorophenyl)sulfonyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)pyridine

[0153] 1 H NMR(500MHz,Chloroform-d)δ8.89(d,J=2.4Hz,1H),8.69(d,J=4.8Hz,1H),8.56(s,1H),8.12(s,1H),7.97–7.92( m,1H),7.87(s,1H),7.78(d,J=9.4Hz,2H),7.70–7.60(m,1H),7.46(dd,J=7.9,4.8Hz,1H),7.08(t,J=8.7Hz,2H). 13C NMR (126MHz, Chloroform-d) δ 161.11, 159.00 (d, J = 2.7Hz), 149.44, 148.07, 143.33, 139.86, 137.28 (t, J = 11.1Hz), 134.98, 134. 78,132.12,128.43,128.10,123.98,123.87,123.41(d,J=4.2Hz),122.63–122.39(m),113.70(d,J=4.3Hz),113.52(d,J=4.5Hz). 19 F NMR(471MHz, CDCl3)δ-62.77,-104.50(dd,J=8.7,6.0Hz).ESI-MS(+)[m / z]:466.16[M+H]+.Purity>95% by HPLC.

[0154] Compound 33a: 3-(3-(1-((2-methoxyphenyl)sulfonyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)pyridine

[0155] 1 H NMR(500MHz,Chloroform-d)δ8.91–8.87(m,1H),8.69(d,J=4.8Hz,1H),8.60(s,1H),8.18(dd,J=7.9,1.7Hz,1H),8.04(s,1H),7.98–7.92(m,1H), 7.87(s,1H),7.78(s,1H),7.75(s,1H),7.67–7.62(m,1H),7.46(dd,J=7. 9,4.8Hz,1H),7.16(t,J=7.7Hz,1H),6.98(d,J=8.4Hz,1H),3.81(s,3H). 13C NMR (126MHz, CDCl3) δ157.41,148.72,147.42,142.05,139.36,137.00,135.12,132.58(d,J=12.6Hz),131.96,131.88,131.77(d,J=2.7Hz),1 31.57,129.21,128.34(d,J=12.1Hz),127.74,123.92(d,J=6.8Hz),122 .84(d,J=4.1Hz),122.53,122.17(d,J=4.0Hz),120.75,112.54,56.19. 19 F NMR(471MHz, CDCl3)δ-62.73.ESI-MS(+)[m / z]:460.15[M+H]+.Purity>95% by HPLC.

[0156] Compound 34a: 3-(3-(1-((2,6-dimethoxyphenyl)sulfonyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)pyridine

[0157] 1 H NMR(500MHz,Chloroform-d)δ8.88(s,1H),8.67(s,1H),8.56(s,1H),8.02(s,1H),7.94(d,J=7.8Hz ,1H),7.88(s,1H),7.78(s,1H),7.73(s,1H),7.53–7.43(m,2H),6.59(d,J=8.6Hz,2H),3.81(s,6H).13C NMR (126 MHz, Chloroform-d) δ 160.38, 149.73, 148.41, 141.67, 140.12, 136.91, 135.42, 135.08, 133.28 (d, J = 10.8 Hz), 132.98, 132.72, 132.50 - 132.11 (m), 129.33, 128.85 (d, J = 12.2 Hz), 128.12, 125.17, 124.22, 123.19 (d, J = 4.1 Hz), 122.64 - 122.25 (m), 113.64, 105.39, 57.14. 19 F NMR (471 MHz, CDC13) δ -62.74. ESI-MS (+) [m / z]: 490.23 [M+H]+. Purity >95% by HPLC.

[0158] Compound 35a: 3-(3-(trifluoromethyl)-5-(1-((2-(trifluoromethyl)phenyl)sulfonyl)-1H- pyrazol-4-yl)phenyl)pyridine

[0159] 1 H NMR (500 MHz, Chloroform-d) δ 8.89 (s, 1H), 8.70 (d, J = 4.8 Hz, 1H), 8.56 - 8.49 (m, 2H), 8.06 (s, 1H), 7.98 - 7.90 (m, 2H), 7.85 (d, J = 8.4 Hz, 3H), 7.76 (s, 2H), 7.49 - 7.45 (m, 1H). 13C NMR (126 MHz, Chloroform-d) δ 149.61, 148.25, 143.16, 139.99, 135.16, 134.88, 134.27, 132.95 (d, J = 25.1 Hz), 132.59, 132.32, 128.81, 128.63, 128.21, 124.01, 123.79, 123.49, 122.59. 19 F NMR (471 MHz, CDC13) δ -57.59, -62.78. ESI-MS (+) [m / z]: 498.13 [M+H]+. Purity >95% by HPLC.

[0160] Compound 36a: 3-(3-(trifluoromethyl)-5-(1-((3-(trifluoromethyl)phenyl)sulfonyl)-1H- pyrazol-4-yl)phenyl)pyridine

[0161] 1H NMR(500MHz,Chloroform-d)δ8.86(d,J=2.4Hz,1H),8.68(dd,J=4.9,1.6Hz,1H),8.46(s,1H),8.35(s,1H),8.30(d,J= 8.0Hz,1H),8.11(s,1H),7.97–7.88(m,2H),7.83(d,J=1.7Hz,1H),7.76(d,J=7.6Hz,3H),7.44(dd,J=7.9,4.8Hz,1H). 13C NMR(126MHz,Chloroform-d)δ149.45,148.02,143.46,139.79,137.80,134. 74,134.53,132.61,132.37(d,J=5.6Hz),132.12,131.84,131.51,131.42(d ,J=3.7Hz),130.34,127.92,127.71,125.23(d,J=3.9Hz),124.56(d,J=10.3 Hz), 123.73 (d, J = 7.4Hz), 123.34 (d, J = 3.8Hz), 122.30 (d, J = 3.9Hz), 121.59. 19 F NMR(471MHz, CDCl3)δ-62.90.ESI-MS(+)[m / z]:498.14[M+H]+.Purity>95% by HPLC.

[0162] Compound 37a: 3-(3-(trifluoromethyl)-5-(1-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-pyrazol-4-yl)phenyl)pyridine

[0163] 1 H NMR(500MHz,Chloroform-d)δ8.87(s,1H),8.69(s,1H),8.45(s,1H),8.23(d,J=8.1Hz,2H),8.10(s ,1H),7.91(d,J=7.9Hz,1H),7.87–7.81(m,3H),7.75(d,J=5.6Hz,2H),7.44(dd,J=7.9,4.8Hz,1H). 13CNMR(126MHz,Chloroform-d)δ149.38,147.95,143.47,139.94,139.72,136.36,136.10,134.73,134.56,132.55,132.29,13 1.78, 128.77, 127.89, 127.76, 126.61 (q, J = 3.8Hz), 124.56, 123.75 (d, J = 4.8Hz), 123.32 (d, J = 4.1Hz), 122.28 (d, J = 3.8Hz). 19 F NMR(471MHz, CDCl3)δ-62.80,-63.43.ESI-MS(+)[m / z]:498.15[M+H]+.Purity>95% by HPLC.

[0164] Compound 38a: 3-(3-(1-(o-toluenesulfonyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)pyridine

[0165] 1 H NMR (500MHz, CDCl3) δ8.88(s,1H),8.68(s,1H),8.52(s,1H),8.17(d,J=8.0Hz,1H),8.06(s,1H),7.93(s,1H),7 .85(s,1H),7.75(d,J=9.5Hz,2H),7.56(t,J=7.6Hz,1H),7.45–7.39(m,2H),7.33(d,J=8.3Hz,1H),2.65(s,3H). 13C NMR (126MHz, CDCl3) δ149.21,147.86,142.58,142.27,139.61,139.06,134.91(d,J=6.8Hz),134.71(d,J=7.8Hz),132.96,132.51,132 .24,130.63,130.07,128.20,127.86,127.71,126.80,123.80(d,J=11.8Hz),123.45,123.05(d,J=4.0Hz),122.54–121.92(m),20.41. 19 F NMR(471MHz, CDCl3)δ-62.74.ESI-MS(+)[m / z]:444.18[M+H]+.Purity>95% by HPLC.

[0166] Compound 39a: 3-(3-(1-(m-tolylsulfonyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)phenyl)pyridine

[0167] 1 H NMR (500 MHz, Chloroform-d) δ 8.87 (s, 1H), 8.68 (d, J = 4.8 Hz, 1H), 8.46 (s, 1H), 8.07 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.90 - 7.85 (m, 2H), 7.83 (s, 1H), 7.74 (d, J = 6.9 Hz, 2H), 7.50 - 7.41 (m, 3H), 2.44 (s, 3H). 13 C NMR (126 MHz, Chloroform-d) δ 149.84, 148.48, 143.19, 140.43, 140.16, 136.85, 136.15, 135.34, 135.05, 133.02, 132.74 (d, J = 3.6 Hz), 129.80, 128.88, 128.34, 128.09, 125.13, 124.45, 124.21, 123.57 (d, J = 3.9 Hz), 122.73 (d, J = 3.7 Hz), 21.71. 19 F NMR (471 MHz, CDCl3) δ -62.76. ESI-MS (+) [m / z]: 444.17 [M+H]+. Purity >95% by HPLC.

[0168] Compound 40a: 3-((4-(3-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)-1H-pyrazol-1- yl)sulfonyl)pyridine

[0169] 1 H NMR (500 MHz, Chloroform-d) δ 9.27 (d, J = 2.4 Hz, 1H), 8.92 - 8.86 (m, 2H), 8.70 (d, J = 4.8 Hz, 1H), 8.47 (s, 1H), 8.42 - 8.36 (m, 1H), 8.11 (s, 1H), 7.97 - 7.91 (m, 1H), 7.83 (s, 1H), 7.78 - 7.74 (m, 2H), 7.54 (dd, J = 8.2, 4.6 Hz, 2H), 7.49 - 7.43 (m, 2H). 13C NMR (126 MHz, Chloroform-d) δ 155.56, 149.96, 149.23, 148.53, 143.99, 140.29, 136.45, 135.22, 135.01, 134.07, 132.51, 132.31 (d, J = 3.0 Hz), 128.83, 128.43, 128.18, 125.07, 124.38, 124.20, 123.86 (d, J = 3.9 Hz), 122.91. 19 F NMR (471 MHz, CDC13) δ -62.78. ESI-MS (+) [m / z]: 431.16 [M+H]+. Purity >95% by HPLC.

[0170] Compound 41a: 3-(3-(1-(benzylsulfonyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)phenyl)pyridine

[0171] 1 H NMR (500 MHz, Chloroform-d) δ 8.84 (s, 1H), 8.67 (d, J = 4.9 Hz, 1H), 8.18 (s, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.87 (s, 1H), 7.72 (d, J = 13.7 Hz, 2H), 7.61 (s, 1H), 7.46 (dd, J = 7.8, 4.8 Hz, 2H), 7.38 - 7.28 (m, 3H), 7.12 (d, J = 7.4 Hz, 2H), 4.75 (s, 2H). 13 C NMR (126 MHz, Chloroform-d) δ 149.41, 148.05, 143.24, 139.93, 135.51, 132.62, 131.27, 130.95, 130.05, 129.85, 129.44, 128.37, 126.63, 124.42, 123.92, 123.63, 122.91, 60.32. 19 F NMR (471 MHz, CDC13) δ -62.81. ESI-MS (+) [m / z]: 444.16 [M+H]+. Purity >95% by HPLC.

[0172] Compound 42a: 4-((4-(3-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)-1H- pyrazol-1-yl)sulfonyl)morpholine

[0173] 1H NMR(500MHz,Chloroform-d)δ8.94(s,1H),8.72(s,1H),8.34(s,1H),8.12(s,1H),7.98(d,J=7.8Hz,1H) ,7.89(s,1H),7.76(d,J=14.7Hz,2H),7.49(dd,J=8.1,4.2Hz,1H),3.47–3.34(m,4H),3.27–3.16(m,4H). 13 C NMR(126MHz,Chloroform-d)δ149.32,148.06,142.00,139.91,135.64,133.08,132.93,132.82,129.06, 128.37, 124.46, 123.46 (d, J = 3.7Hz), 123.19, 122.99, 122.79 (d, J = 3.8Hz), 66.76, 66.18, 47.30, 46.99. 19 F NMR(471MHz, CDCl3)δ-62.74.ESI-MS(+)[m / z]:439.17[M+H]+.Purity>95% by HPLC.

[0174] Compound 43a: 3-(2,4-difluoro-5-(1-((2-fluorophenyl)sulfonyl)-1H-pyrazol-4-yl)phenyl)pyridine

[0175] 1 H NMR(500MHz,DMSO)δ9.03(s,1H),8.93(s,1H),8.71(d,J=5.1Hz,1H),8.46(s,1H),8.21(dt,J=13.1,6.5Hz,2 H),8.11(t,J=7.6Hz,1H),7.90(q,J=7.1Hz,1H),7.68(dd,J=8.0,5.0Hz,1H),7.55(dq,J=18.4,10.3Hz,3H). 13C NMR (126 MHz, DMSO) δ 159.80, 157.79 (d, J = 11.7 Hz), 148.13, 147.81, 145.06 (d, J = 5.9 Hz), 139.11 (d, J = 9.1 Hz), 138.71, 131.27, 130.87 (d, J = 4.5 Hz), 130.77 - 130.58 (m), 126.22 (d, J = 3.6 Hz), 124.65, 124.09 (d, J = 13.0 Hz), 122.04 (d, J = 13.9 Hz), 118.34 (d, J = 18.4 Hz), 115.41 (d, J = 13.1 Hz), 106.07, 105.85, 105.64. 19 F NMR (471 MHz, DMSO) δ -74.60, -108.66 - -110.76 (m), -114.53 (q, J = 9.4 Hz). ESI-MS (+) [m / z]: 416.17 [M+H]+. Purity > 95% by HPLC.

[0176]

[0177] In the present application, lysine acetyltransferase KAT6A inhibition experiment:

[0178] The experiment is based on AlphaScreen technology (Amplified Luminescent Proximity Homogeneous Assay Screen), that is, amplified chemiluminescence affinity homogeneous detection, which is a microbead-based homogeneous affinity detection method; in the experiment, the donor microbeads (Donor beads) are coated with streptavidin protein, which can specifically recognize and combine with the biotin (Biotin) labeled histone polypeptide substrate in the solution, and the acceptor microbeads (Acceptor beads) are coated with Protein A which can recognize the Fc segment of the antibody, and can specifically bind with the histone acetylation antibody; after KAT6A / B transfers the acetyl group on acetyl coenzyme A to the polypeptide lysine, the antibody specifically recognizes the site, and finally causes the Acceptor beads and the Donor beads to approach each other, and when the light at 680 nm wavelength is excited, the photosensitizer benzidine blue on the Donor beads is activated to produce high-energy singlet oxygen, which diffuses to the solution within a half-life of 4 μs, so that the dimethyl thiophene derivative on the Acceptor beads within 200 nm is excited, and the light emission at 520-620 nm produces a light signal; 100 nL of small molecule compound is added to the 384-well plate, and then KAT6A / B enzyme, acetyl coenzyme A and biotinylated polypeptide required for the experiment are added in succession, and incubated at room temperature for 60 min; 4 μL of assay buffer containing AlphaScreen Protein A acceptor beads and Streptavidin donor beads is added in the dark, and incubated for 5 h, and finally the system forms a sandwich structure, and the emission light signal intensity is detected to determine the enzyme activity; for each compound, according to the positive and negative controls, the inhibition percentage is calculated to evaluate the effect of the compound on the KAT6A / B enzyme activity.

[0179] The following table is the inhibition rate of the new KAT6A inhibitor compound on KAT6A enzyme under the condition of 100 nM and the KAT6A enzyme IC of part of the superior compounds 50 Value (unit: nM). Mean ± S.D (n = 3)

[0180]

[0181]

[0182] The following table is the inhibition rate of the new KAT6A inhibitor compound on KAT6A enzyme under the condition of 100 nM and the KAT6A enzyme IC of part of the superior compounds 50 Value (unit: nM). Mean ± S.D (n = 3)

[0183]

[0184]

[0185] Note: " / " means not detected.

[0186] CCK8 detection of new KAT6A inhibitor anti-breast cancer cell proliferation activity:

[0187] This experiment will determine the cell growth inhibition rate of the newly synthesized KAT6A inhibitor, and test the HR+ / HER2- breast cancer cell line T47D; this experiment will use CCK8 method to determine the cell viability after 144h of new inhibitor, cells are seeded in 96-well plates, then the same concentration of different compounds is added, each sample is repeated 3 times, single culture medium treatment as control group, single PBS treatment as blank group; after 144h (during observation of cell state, 2-3 days to replace the culture medium containing compound), add CCK8 reagent to each well, incubate at 37℃ for 4h, use the enzyme label instrument to determine the absorbance at 450nm. Calculate the inhibition rate of drug on tumor cell growth according to the following formula: cell inhibition rate % = (OD blank group-OD experimental group) / (OD blank group-OD control group)*100%.

[0188] The following table is the inhibition rate of new KAT6A inhibitor compounds on T47D cell line under the condition of 1 μM for 144h and the IC 50 value (unit: μM) of part of the dominant compounds in T47D cell line for 144h. Mean±S.D (n=3)

[0189]

[0190]

[0191] The following table is the inhibition rate of new KAT6A inhibitor compounds on T47D cell line under the condition of 1 μM for 144h and the IC 50 value (unit: μM) of part of the dominant compounds in T47D cell line for 144h. Mean±S.D (n=3)

[0192]

[0193] Note: " / " means not detected.

[0194] CCK8 detection of new KAT6A inhibitor anti-hepatocellular carcinoma cell proliferation activity:

[0195] This experiment will determine the cell growth inhibition rate of the newly synthesized KAT6A inhibitor and test it on the liver cancer cell line Huh7; this experiment will use the CCK8 method to determine the cell viability of the new inhibitor after 1 week. The cells were seeded in 96-well plates, and then different compounds at the same concentration were added. Each sample was repeated 3 times. The control group was treated with only culture medium, and the blank group was treated with only PBS. After 144 hours of action (the cell status was observed during this period, and the culture medium containing the compound was replaced every 2-3 days), CCK8 reagent was added to each well, incubated at 37°C for 4 hours, and the absorbance at 450nm was measured using a microplate reader. The drug's inhibition rate on tumor cell growth was calculated according to the following formula: Cell inhibition rate (%) = (OD blank group - OD experimental group) / (OD blank group - OD control group) * 100%.

[0196] The following table shows the inhibition rate IC of some new KAT6A inhibitor compounds on Huh7 cell line 50 Value (unit: μM). Mean ± SD (n = 3)

[0197]

[0198] CCK8 assay for the anti-leukemia cell proliferation activity of novel KAT6A inhibitors:

[0199] This experiment will determine the cell growth inhibition rate of a newly synthesized KAT6A inhibitor, testing it on the leukemia cell lines HL-60 and OCI-AML-3. This experiment will use the CCK8 assay to measure cell viability after one week of treatment with the novel inhibitor. Cells were seeded in 96-well plates and then treated with the same concentrations of different compounds. Each sample was replicated three times. The control group was treated with culture medium alone, while the blank group was treated with PBS alone. After a prolonged treatment period (cell status was observed during this period, and the culture medium containing the compound was replaced every 2-3 days), CCK8 reagent was added to each well. The cells were incubated at 37°C for 4 hours, and the absorbance at 450nm was measured using a microplate reader. The inhibitory rate of the drug on tumor cell growth was calculated using the following formula: Cell inhibition rate (%) = (OD blank group - OD experimental group) / (OD blank group - OD control group) * 100%.

[0200] The following table shows the inhibition rates of some new KAT6A inhibitor compounds on HL-60 and OCI-AML-3 cell lines IC 50 Value (unit: nM). Mean ± SD (n = 3)

[0201]

[0202]

Claims

1. A novel KAT6 inhibitor compound, characterized in that The chemical structural formula of the compound is shown in formula (I): Where: m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, or 5; Ring A is selected from phenyl, pyridyl, quinolinyl, morpholinyl, imidazolyl, heteroaryl, thiophenyl, 5- or 6-membered monocyclic heteroaryl, cycloalkyl, or 7-, 8-, 9- or 10-membered bicyclic heterocyclyl; Ring B is selected from phenyl, pyridyl, quinolinyl, morpholinyl, imidazolyl, heteroaryl, thiophenyl, 5- or 6-membered monocyclic heteroaryl, cycloalkyl, or 7-, 8-, 9- or 10-membered bicyclic heterocyclyl; Ring C is selected from phenyl, pyridyl, quinolinyl, morpholinyl, imidazolyl, heteroaryl, thiophenyl, 5- or 6-membered monocyclic heteroaryl, cycloalkyl or 7-, 8-, 9- or 10-membered bicyclic heterocyclyl; R1 is selected from one or more of -H, -OCH3, -SO2CH3, -COOCH3, -CN, -CF3, -OCF3, -NO2, halogen, alkyl, alkoxy or haloalkyl; R2 is selected from one or more of -H, -OCH3, -SO2CH3, -COOCH3, -CN, -CF3, -OCF3, -NO2, halogen, alkyl, alkoxy or haloalkyl; R3 is selected from a hydrogen atom, a methyl group, a halomethyl group or a halogen group.

2. The KAT6 inhibitor compound according to claim 1, characterized in that Said m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, or 3; p is 0.

3. The KAT6 inhibitor compound according to claim 1, characterized in that The R1 is selected from -H, -F, -OCH3, -CF3, -COOCH3, -CH3; R2 is selected from -H, -F, -OCH3, -CF3, -CH3, -NO2; R3 is selected from hydrogen atom.

4. The KAT6 inhibitor compound according to claim 1, characterized in that The ring A is selected from phenyl, quinolyl, pyridyl, and morpholinyl; The ring B is selected from imidazolyl; The ring C is selected from pyridyl or imidazolyl.

5. The KAT6 inhibitor compound according to claim 1, characterized in that The compound is any one of the following:

6. The method for preparing the KAT6 inhibitor compound according to any one of claims 1 to 5, wherein: Its synthetic route is as follows: Synthesis Route 1: Synthesis route 2: Synthesis route 3:

7. A pharmaceutical composition comprising a racemate or a single isomer thereof, and one or more combinations thereof, comprising a therapeutically effective amount of one or more KAT6 inhibitor compounds according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

8. Use of the KAT6 inhibitor compound according to any one of claims 1 to 5 in the preparation of a method for treating KAT6-related disorders.

9. The use according to claim 8, characterized in that The KAT6-related disorders include breast cancer, liver cancer, leukemia, lung cancer, ovarian cancer, endometrial cancer, prostate cancer or metastatic and drug-resistant cancer.

10. The use according to claim 8, characterized in that The KAT6-related disorders also include inflammatory diseases, endocrine diseases and cardiovascular and cerebrovascular diseases.

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