Compounds and use in the treatment of hdhodh-mediated diseases

Abstract

The present application belongs to the field of medicine, and particularly relates to a kind of compounds and purposes in treating hDHODH-mediated diseases.The present application relates to a kind of novel small molecule compounds as shown in formula I, which has outstanding hDHODH enzyme inhibitory activity, and can be used for treating various diseases mediated by hDHODH, including but not limited to tumors, autoimmune diseases and viral infections and the like.

Description

Technical Field

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

[0002] Pyrimidines are essential components for the synthesis of DNA and RNA in organisms. In human cells, there are two pyrimidine synthesis pathways: the de novo synthesis pathway and the rescue pathway. Human dihydroorotated ehydrogenase (hDHODH) is the fourth-step catalytic enzyme in the cellular de novo pyrimidine synthesis pathway and is also the key rate-limiting enzyme in this pathway. In rapidly proliferating cells, such as malignant tumor cells, activated T lymphocytes, and B lymphocytes, the rescue pathway cannot provide sufficient pyrimidines, thus requiring a high dependence on the hDHODH-mediated de novo synthesis pathway.

[0003] Inhibition of hDHODH can effectively block DNA synthesis in activated T and B lymphocytes, inhibiting their proliferation and showing potential for treating autoimmune diseases. In tumor cells, hDHODH also participates in the regulation of ferroptosis and the mitochondrial oxidative phosphorylation pathway. Inhibition of hDHODH can effectively suppress pyrimidine synthesis in tumor cells, leading to cell cycle arrest, inducing cell differentiation, and inhibiting cell proliferation, indicating that hDHODH is a potential target for anti-tumor drug development. Furthermore, the rapid replication of RNA and DNA viruses after infection depends on pyrimidine synthesis in host cells; inhibition of hDHODH can effectively slow down viral replication, making it a potential host-targeted antiviral target. Summary of the Invention

[0004] A class of small molecule compounds, characterized in that the compound is as shown in Formula I:

[0005]

[0006] Q is independently selected from the following structures:

[0007]

[0008] In each formula, R 6 ~R 23 Independently selected from hydrogen, halogen, C1-C8 substituted alkyl, cycloalkyl, alkenyl, alkoxy, substituted alkyl, substituted alkoxy.

[0009] R 1 Independently selected from alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, arylalkyl, substituted alkyl, substituted cycloalkyl; R 2 R 3 R 4Independently selected from hydrogen, halogen, methyl; R 5 Independently selected from alkyl and substituted alkyl groups.

[0010] Preferred compound R 5 It is a methyl group.

[0011] Further R 2 It is fluorine, R 3 R 4 The hydrogen is present, and the compound is shown in Formula I-1;

[0012]

[0013] Q is independently selected from the following structures:

[0014]

[0015] In each formula, R 6 ~R 23 Independently selected from hydrogen, halogen, C1-C8 substituted alkyl, cycloalkyl, alkenyl, alkoxy, substituted alkyl, substituted alkoxy.

[0016] Among them, R 1 Independently selected from alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, arylalkyl, substituted alkyl, and substituted cycloalkyl.

[0017] Further R 1 Selected from the following group: methyl, ethyl, n-propyl, n-butyl, isopropyl, cyclopropyl, sec-butyl, isobutyl, 2-methylpentyl, allyl, 2-methylallyl, cyclopentylmethyl, cyclohexylmethyl, 2-fluorobenzyl, 2-chloro-6-fluorobenzyl, (S)-trifluoroisopropyl, (R)-trifluoroisopropyl, hexafluoro-2-propyl.

[0018] Further Q is selected from the following group:

[0019]

[0020] The further preferred compound structure is as follows:

[0021]

[0022] This invention provides a method for synthesizing this type of molecule.

[0023] Preparation method, synthetic route 1 is as follows:

[0024]

[0025] (a) Starting material a1 was synthesized from Williamson ether to obtain intermediate b1;

[0026] (b) Intermediate b1 is reduced to intermediate c1 by nitro reduction;

[0027] (c) Intermediate c1 is obtained as intermediate d1 via a one-step suzuki reaction;

[0028] (d) Intermediate d1 is obtained by amide condensation to obtain intermediate e1;

[0029] (e) Intermediate e1 is obtained as the final product by ring-opening with basic isoxazole.

[0030] The preparation method, synthetic route 2, is as follows:

[0031]

[0032] (f) Intermediate f1 was synthesized from boric acid via palladium acetate catalysis to form benzophenone intermediate g1;

[0033] (g) Intermediate g1 is obtained by amide condensation to obtain intermediate h1;

[0034] (h) Intermediate h1 is obtained as the final product by ring-opening with basic isoxazole.

[0035] The novel small molecule compounds described in this invention contain isotopic substitutions of any one or more atoms, preferably, the isotope is deuterium.

[0036] The present invention describes a class of novel small molecule compounds that are pharmaceutically acceptable hydrates, solvates, crystal forms, or salts.

[0037] The use of a novel class of small molecule compounds described in this invention in the preparation of drugs for treating hDHODH-mediated diseases.

[0038] The hDHODH-mediated diseases described in this invention are selected from tumors, autoimmune diseases, and viral infections. Detailed Implementation

[0039] The present invention will be further illustrated below with reference to embodiments. These embodiments are for illustrative purposes only and are not intended to limit the invention in any way.

[0040] Table 1. Structures of novel small molecule compounds:

[0041]

[0042]

[0043]

[0044]

[0045]

[0046] Example 1: Preparation of representative intermediate b1

[0047]

[0048] The starting compound 2-bromo-4-fluoro-5-nitrophenol (2.0 g, 8.5 mmol, 1 equiv) was added to a 150 mL round-bottom flask, followed by 40 mL of analytical grade acetonitrile, then potassium carbonate (3.5 g, 25.3 mmol, 3 equiv) and methyl iodoform (3.6 g, 25.3 mmol, 3 equiv). After the addition was complete, the mixture was heated to 80 °C in an oil bath. After the reaction was completed by TLC monitoring, the reaction solution was cooled to room temperature, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography. The mobile phase was petroleum ether. The purified product was concentrated to give 1.9 g of a yellow solid, with a yield of 90%. 1 H NMR (400MHz, DMSO-d6) δ 8.06 (d, J = 10.5 Hz, 1H), 7.77 (d, J = 6.6 Hz, 1H), 3.95 (s, 3H).

[0049] Example 2: Preparation of representative intermediate c1

[0050]

[0051] Intermediate b1 (1.9 g, 7.6 mmol, 1 equiv) was added to a 150 mL round-bottom flask, followed by 20 mL of ethanol and 20 mL of water. Then, reduced iron powder (1.3 g, 22.8 mmol, 3 equiv) and NH4Cl (2.1 g, 38.0 mmol, 5 equiv) were added. After the addition was complete, the mixture was heated in an oil bath to 85 °C for 5 h, and the reaction solution turned black. After the reaction was complete as monitored by TLC, the solution was cooled to room temperature, filtered through diatomaceous earth, washed with water, extracted with EA, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.4 g of a brown oily substance. No further purification was required; the yield was 85%. 1 H NMR (400MHz, DMSO-d6) δ7.16 (d, J = 10.5 Hz, 1H), 6.73 (d, J = 6.6 Hz, 1H), 5.28 (s, 2H), 3.95 (s, 3H).

[0052] Example 3: Preparation of representative intermediate d1

[0053]

[0054] Intermediate C1 (150 mg, 0.7 mmol, 1 equiv) was added to a 25 mL two-necked flask, followed by 15 mL of a dioxane / H2O (v / v, 3 / 1) mixed solvent. Then, 3-methoxyphenylboronic acid (154 mg, 1.0 mmol, 1.5 equiv) and Cs2CO3 (660 mg, 2.1 mmol, 3 equiv) were added. After the addition was complete, the mixture was purged twice under N2 conditions. Then, PdCl2(dppf)2 (75 mg, 0.09 mmol, 0.15 equiv) was added, and the mixture was purged three more times under N2 protection. The mixture was then heated in an oil bath at 80 °C for 5 h under N2 protection. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, extracted with EA, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography. The mobile phase was PE / EA = 80:20, yielding 140 mg of a yellowish-brown solid, with a yield of 81%. 1 H NMR (400MHz, DMSO-d6) δ7.24 (t, J=7.9Hz, 1H), 7.06–6.92 (m, 3H), 6.80 (dd, J= 8.2, 2.5Hz, 1H), 6.50 (d, J = 7.9Hz, 1H), 5.28 (s, 2H), 3.76 (s, 3H), 3.67 (s, 3H).

[0055] Example 4: Preparation of representative end product A1

[0056]

[0057] Biphenyl intermediate d1 (90 mg, 0.4 mmol, 1 equiv) was added to a 25 mL round-bottom flask, followed by 15 mL of analytical grade THF. The mixture was then stirred at -10 °C for 10 min in a cold trap. Subsequently, 5-methyl-4-isoxazole carbonyl chloride (66 mg, 0.5 mmol, 1.25 equiv) was slowly added dropwise, and finally triethylamine (55 mg, 0.6 mmol, 1.5 equiv) was added dropwise. After stirring for 30 min, the mixture was reacted at room temperature for 2 h. The reaction was monitored by TLC until it was complete. After concentration under reduced pressure, crude intermediate e1 was obtained. The unpurified intermediate e1 was directly dissolved in 10 mL of isopropanol / H2O (v / v, 2 / 1) mixed solvent. 1 M NaOH solution was added dropwise until the pH of the reaction system reached 12. The mixture was then reacted at room temperature for 2 h. The reaction was monitored by TLC until it was complete. The pH was adjusted to 4 with dilute hydrochloric acid, and a white solid precipitated from the solution. The solid was filtered and dried to obtain the final product A1, with a yield of 65%. 1H NMR (400MHz, CDCl3) δ15.34(s,1H),7.84(s,1H),7.79(d,J=6.6Hz,1H),7.32(t,J=7.9Hz,1H),7.13(d, J=11.2Hz,1H),7.08–7.05(m,2H),6.89(dd,J=8.0,2.1Hz,1H),3.83(s,3H),3.80(s,3H),2.37(s,3H). 13 C NMR (100MHz, CDCl3) δ188.64, 167.19, 159.35, 152.64 (d, J = 1.8Hz), 147.37 (d, J = 238.8Hz), 138.09 (d, J = 1.0Hz), 129.19, 127.94 (d ,J=6.7Hz),123.63(d,J=11.6Hz),121.79,116.91(d,J=20.9Hz),115.91,115.20,112.99,105.76,80.94,56.30,55.30,22.02.HRMS m / z(ESI)calculatedfor C 19 H 17 FN₂O₄357.1272[M+H] + ,found:357.1239.

[0058] Example 5: Preparation of representative intermediate g1

[0059]

[0060] Intermediate f1 (260 mg, 1.9 mmol, 1 equiv) and 20 mL of TFA / H2O (v / v, 1 / 3) mixed solvent were added to a 50 mL two-necked flask. Then phenylboronic acid (280 mg, 2.4 mmol, 1.2 equiv) and CsF (887 mg, 5.9 mmol, 3 equiv) were added. The mixture was substituted twice under N2 conditions. Then Pd(OAc)2 (44 mg, 0.2 mmol, 0.1 equiv) and ligand 2-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine (L1, 34 mg, 0.2 mmol, 0.1 equiv) were added. After the addition was completed, the mixture was substituted three more times under N2 protection and the reaction was carried out in an oil bath at 95 °C for 10 h. The reaction was monitored by TLC until it was complete. The reaction solution was cooled to room temperature, the pH was adjusted to alkaline with NaOH aqueous solution, extracted with EA, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography. The mobile phase system was PE / EA = 50:50, yielding 260 mg of pale yellow solid, with a yield of 70%. 1H NMR (400MHz, CDCl3) δ7.77–7.69(m,2H),7.55–7.47(m,1H),7.44–7.36(m,2H ),7.17(d,J=11.1Hz,1H),6.33(d,J=7.1Hz,1H),4.13(brs,2H),3.62(s,3H).

[0061] Compounds A2-A51 were prepared according to the preparation method described above.

[0062] Compound A2

[0063]

[0064] 1 H NMR (400MHz, CDCl3) δ15.35(s,1H),7.83(s,1H),7.78(d,J=6.7Hz,1H),7.31(t,J=7.9Hz,1H),7.14(d,J=11.3Hz,1H), 7.13–7.10(m,2H),6.88(dd,J=8.2,2.2Hz,1H),4.02(q,J=7.0Hz,2H),3.83(s,3H),2.36(s,3H),1.36(t,J=7.0Hz,3H). 13 C NMR (100MHz, CDCl3) δ188.61,167.16,159.28,152.00(d,J=1.9Hz),147.40(d,J=238.8Hz),138.17,129.08,128.07(d,J=6.6Hz) ,123.55(d,J=11.5Hz),121.75,116.81(d,J=20.8Hz),115.91,114.93,113.21,107.09,80.93,64.97,55.26,22.00,14.71.HRMS m / z(ESI)calculated for C 20 H 19 FN₂O₄ 371.1329[M+H] + ,found:371.1396.

[0065] Compound A3

[0066]

[0067] 11H NMR (400 MHz, CDCl3) δ 15.36 (s, 1H), 7.83 (s, 1H), 7.77 (d, J = 6.7 Hz, 1H), 7.30 (t, J = 8.1 Hz, 1H), 7.14 (d, J = 11.3 Hz, 1H), 7.10–7.08 (m, 2H), 6.91–6.84 (m, 1H), 3.91 (t, J = 6.4 Hz, 2H), 3.83 (s, 3H), 2.37 (s, 3H), 1.86–1.66 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 188.60, 167.16, 159.26, 152.18 (d, J = 1.9 Hz), 147.36 (d, J = 238.8 Hz), 138.21, 129.01, 128.13 (d, J = 6.6 Hz), 123.52 (d, J =​​​​​​​​​​​​​​​​​13C NMR (100 MHz, DMSO-d6) δ 186.07, 165.96, 159.38, 151.40, 148.60 (d, J = 238.1 Hz), 138.47, 133.82, 129.48, 126.49 (d, J = 6.8 Hz), 125.81 (d, J = 12.6 Hz), 121.99, 119.17, 117.57, 116.91 (d, J = 21.4 Hz), 115.17, 113.35, 109.25, 82.10, 69.68, 55.46, 23.63. HRMS m / z (ESI) calculated for C 21 H 19 FN2O4 383.1329 [M+H] + , found: 383.1396。

[0071] Compound A5

[0072] [[ID=十四]]

[0073] 1 1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 7.74 (d, J = 6.8 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.25 (d, J = 11.5 Hz, 1H), 7.13–7.10 (m, 2H), 6.89 (dd, J = 8.2, 2.1 Hz, 1H), 4.46–4.40 (m, 1H), 3.79 (s, 3H), 2.28 (s, 3H), 1.22 (d, J = 6.0 Hz, 6H). 13 13C NMR (100 MHz, DMSO-d6) δ 186.25, 166.10, 159.31, 150.61, 148.61 (d, J = 238.6 Hz), 138.74, 129.44, 127.37, 125.70 (d, J = 12.6 Hz), 121.89, 119.20, 116.96 (d, J = 21.2 Hz), 114.98, 113.40, 111.08, 81.93, 71.43, 55.44, 23.65, 22.18 (2C). HRMS m / z (ESI) calculated for C 21 H 21 FN2O4 407.1385 [M+Na] + , found: 407.1374。

[0074] Compound A6

[0075]

[0076] 1 1H NMR (400 MHz, CDCl3) δ 15.39 (s, 1H), 7.82 (s, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 7.14 (d, J = 11.3 Hz, 1H), 7.13–7.10 (m, 2H), 6.87 (dd, J = 8.2, 1.7 Hz, 1H), 4.24–4.19 (m, 1H), 3.83 (s, 3H), 2.38 (s, 3H), 1.67–1.65 (m, 1H), 1.60–1.52 (m, 1H), 1.21 (d, J = 6.1 Hz, 3H), 0.90 (t, J = 7.5 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 188.59, 167.16, 159.17, 151.10 (d, J = 2.0 Hz), 147.39 (d, J = 239.1 Hz), 138.51, 129.33 (d, J = 6.6 Hz), 128.94, 123.46 (d, J = 11.7 Hz), 121.86, 116.89 (d, J = 20.6 Hz), 115.94, 114.95, 113.15, 109.25, 80.91, 76.79, 55.25, 28.97, 22.01, 18.89, 9.61. HRMS m / z (ESI) calculated for C 22 H 23 FN2O4 421.1542 [M+Na] + , found: 421.1528。

[0077] Compound A7

[0078]

[0079] 11H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 7.74 (d, J = 6.8 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 11.4 Hz, 1H), 7.11 (d, J = 2.2 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.89 (dd, J = 8.2, 2.1 Hz, 1H), 4.41–4.28 (m, 1H), 3.79 (s, 3H), 2.29 (s, 3H), 1.64–1.53 (m, 1H), 1.52–1.42 (m, 1H), 1.40–1.24 (m, 2H), 1.18 (d, J = 6.0 Hz, 3H), 0.85 (t, J = 7.3 Hz, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ 186.14, 166.07, 159.28, 150.80 (d, J = 1.6 Hz), 148.53 (d, J = 238.2 Hz), 138.76, 129.39, 127.41 (d, J = 6.6 Hz), 125.63 (d, J = 12.5 Hz), 121.93, 119.05, 116.98 (d, J = 21.4 Hz), 115.04, 113.37, 110.74, 82.07, 74.68, 55.40, 38.35, 23.53, 19.61, 18.46, 14.32. HRMS m / z (ESI) calculated for C 23 H 25 FN2O4 435.1698 [M+Na] + , found: 435.1687。

[0080] Compound A8

[0081]

[0082] 1 1H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 7.74 (d, J = 6.8 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 11.4 Hz, 1H), 7.12 (d, J = 2.2 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 6.89 (dd, J = 8.2, 2.0 Hz, 1H), 4.16–4.11 (m, 1H), 3.78 (s, 3H), 2.30 (s, 3H), 1.64–1.46 (m, 4H), 0.83 (t, J = 7.4 Hz, 6H). 1313C NMR (100 MHz, DMSO-d6) δ 186.05, 166.03, 159.25, 151.13, 148.41 (d, J = 238.2 Hz), 138.78, 129.36, 127.31 (d, J = 6.6 Hz), 125.61 (d, J = 12.6 Hz), 121.94, 118.98, 116.96 (d, J = 21.2 Hz), 115.07, 113.30, 110.39, 82.17, 80.81, 55.39, 25.47 (2C), 23.48, 9.66 (2C). HRMS m / z (ESI) calculated for C 23 H 25 FN2O4 435.1698 [M+Na] + , found: 435.1686。

[0083] Compound A9

[0084]

[0085] 1 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 7.77 (d, J = 6.7 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.25 (d, J = 11.4 Hz, 1H), 7.13–7.10 (m, 2H), 6.95–6.85 (m, 1H), 3.79 (s, 3H), 3.71 (d, J = 6.4 Hz, 2H), 2.29 (s, 3H), 2.00–1.91 (m, 1H), 0.92 (d, J = 6.7 Hz, 6H). 13 13C NMR (100 MHz, DMSO-d6) δ 185.98, 165.94, 159.33, 151.99 (d, J = 1.4 Hz), 148.35 (d, J = 237.6 Hz), 138.53, 129.36, 126.21 (d, J = 6.5 Hz), 125.82 (d, J = 12.8 Hz), 122.02, 119.19, 116.82 (d, J = 21.2 Hz), 115.14, 113.32, 108.63, 82.14, 75.33, 55.45, 28.27, 23.63, 19.52 (2C). HRMS m / z (ESI) calculated for C 22 H 23 FN2O4 399.1642 [M+H] + , found: 399.1702。

[0086] Compound A10

[0087]

[0088] 1 H NMR(400MHz,DMSO-d6)δ10.54(s,1H),7.77(d,J=6.7Hz,1H),7.32(t,J=8.1Hz,1H),7.27(d,J=11.3Hz,1H),7.14–7.08(m,2H),6.91(dd,J=8.2,2.2Hz,1H),4.96(d,J=37.7Hz,1H),4.42(s,2H),3.78(s,3H),2.30(s,3H),1.73(s,3H). 13 C NMR(100MHz,DMSO-d6)δ185.84,165.86,159.37,151.46(d,J=1.3Hz),148.61(d,J=238.0Hz),141.02,138.46,129.43,126.64(d,J=6.8Hz),125.67(d,J=12.6Hz),122.04,118.90,116.92(d,J=21.3Hz),115.23,113.32,112.61,109.13,82.39,72.41,55.44,23.42,19.71.HRMS m / z(ESI)calculated for C 22 H 21 FN2O4 397.1485[M+H] + ,found:397.1554。

[0089] Compound A11

[0090]

[0091] 1 H NMR(400MHz,DMSO-d6)δ11.25(s,1H),7.96(d,J=6.9Hz,1H),7.30(t,J=7.9Hz,1H),7.21(d,J=11.7Hz,1H),7.11–7.07(m,2H),6.87(dd,J=8.2,2.1Hz,1H),3.78(s,3H),3.72(d,J=6.0Hz,2H),2.18(s,3H),1.76–1.59(m,6H),1.26–1.10(m,3H),1.04–0.97(m,2H).HRMS m / z(ESI)calculated for C 25 H27 FN2O4 461.1855 [M+Na] + , found: 461.1842。

[0092] Compound A12

[0093]

[0094] 1 H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 7.94 (d, J = 6.7 Hz, 1H), 7.48 (t, J = 7.3 Hz, 1H), 7.40 (dd, J = 13.6, 6.3 Hz, 1H), 7.32–7.25 (m, 2H), 7.23–7.19 (m, 2H), 7.12 (d, J = 1.4 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 6.87 (dd, J = 8.2, 2.1 Hz, 1H), 5.11 (s, 2H), 3.70 (s, 3H), 2.30 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 186.19, 166.05, 160.71 (d, J = 246.1 Hz), 159.33, 151.36 (d, J = 1.4 Hz), 148.86 (d, J = 238.5 Hz), 138.36, 130.85 (d, J = 4.1 Hz), 130.74, 129.48, 126.73 (d, J = 7.0 Hz), 125.87 (d, J = 12.7 Hz), 124.88 (d, J = 3.4 Hz), 124.05 (d, J = 14.5 Hz), 121.91, 119.17, 117.06 (d, J = 21.3 Hz), 115.77 (d, J = 20.9 Hz), 114.83, 113.79, 109.43, 82.07, 65.15 (d, J = 3.7 Hz), 55.32, 23.63. HRMS m / z (ESI) calculated for C 25 H 20 F2N2O4 451.1391 [M+H] + , found: 451.1458。

[0095] Compound A13

[0096]

[0097] 11H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 7.98 (d, J = 6.6 Hz, 1H), 7.47 (dd, J = 14.4, 8.2 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.32–7.20 (m, 3H), 7.06–7.03 (m, 2H), 6.82 (dd, J = 8.2, 1.7 Hz, 1H), 5.11 (s, 2H), 3.65 (s, 3H), 2.31 (s, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ 186.26, 166.11, 161.85 (d, J = 250.1 Hz), 159.26, 151.45, 149.20 (d, J = 239.1 Hz), 138.20, 135.86 (d, J = 5.1 Hz), 132.24 (d, J = 9.8 Hz), 129.47, 127.06 (d, J = 6.7 Hz), 126.09 (d, J = 3.1 Hz), 125.87 (d, J = 13.0 Hz), 122.20 (d, J = 17.9 Hz), 121.74, 119.09, 117.13 (d, J = 21.8 Hz), 115.17 (d, J = 22.4 Hz), 114.46, 113.96, 110.17, 82.03, 62.68, 55.20, 23.60. HRMS m / z (ESI) calculated for C 25 H 19 ClF2N2O4 485.1001 [M+H] + , found: 485.1071。

[0098] Compound A14

[0099]

[0100] 1 1H NMR (400 MHz, CDCl3) δ 15.32 (s, 1H), 7.74 (s, 1H), 7.71 (d, J = 6.8 Hz, 1H), 7.48–7.40 (m, 2H), 7.31 (t, J = 7.4 Hz, 2H), 7.23 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 11.3 Hz, 1H), 4.15–4.10 (m, 1H), 2.30 (s, 3H), 1.63–1.43 (m, 2H), 1.12 (d, J = 6.1 Hz, 3H), 0.80 (t, J = 7.5 Hz, 3H). 1313C NMR(100MHz,CDCl3)δ187.52,166.12,150.08(d,J = 2.0Hz),146.41(d,J = 239.2Hz),136.14,128.55(d,J = 6.6Hz),128.39(2C),126.92(2C),126.20,122.33(d,J = 11.6Hz),115.83(d,J = 20.5Hz),114.90,108.23,79.87,75.78,27.92,20.96,17.80,8.51.HRMS m / z(ESI)calculated for C 21 H 21 FN2O3 368.1536[M + H] + ,found:368.1523。

[0101] Compound A15

[0102]

[0103] 1 1H NMR(400MHz,CDCl3)δ15.42(s,1H),7.80(s,1H),7.75(d,J = 6.9Hz,1H),7,46(d,J = 8.7Hz,2H),7.10(d,J = 11.4Hz,1H),6.92(d,J = 8.7Hz,2H),4.29–4.14(m,1H),3.84(s,3H),2.37(s,3H),1.70–1.52(m,2H),1.20(d,J = 6.1Hz,3H),0.89(t,J = 7.4Hz,3H). 13 13C NMR(100MHz,CDCl3)δ188.53,167.13,158.89,151.00,147.54(d,J = 239.0Hz),130.55(2C),129.59(d,J = 0.8Hz),129.35(d,J = 6.6Hz),122.84(d,J = 11.7Hz),116.​​​​​​​​Compound A16

[0105]

[0106] 1 H NMR (400MHz, DMSO-d6) δ10.48(s,1H),7.68(d,J=6.2Hz,1H),7.19(d,J=11.3Hz,1H),7.10(s,1H),7.01(d,J=7.8Hz,1H),6.94( d,J=7.8Hz,1H),6.05(s,2H),4.32–4.17(m,1H),2.30(s,3H),1.69–1.48(m,2H),1.18(d,J=5.6Hz,3H),0.87(t,J=7.1Hz,3H). 13 C NMR (100MHz, DMSO-d6) δ186.08, 166.06, 150.64 (d, J = 0.4Hz), 148.65 (d, J = 238.1Hz), 147.35, 146.78, 131.21, 127.58 (d, J = 6.3Hz), 125. 05(d,J=12.4Hz),123.19,118.78,116.84(d,J=21.1Hz),111.04,110.09,108.37,101.44,82.17,76.12,28.89,23.35,19.07,9.80.HRMS m / z(ESI)calculated for C 22 H 21 FN₂O₅ 412.1434[M+H] + ,found:412.1409.

[0107] Compound A17

[0108]

[0109] 1 H NMR (400MHz, DMSO-d6) δ12.29(s,1H),8.32(d,J=7.1Hz,1H),7.29–7.15(m,3H),7.10(d,J=6.9Hz,1H),6.88(d,J=11.4 Hz,1H),4.10–4.00(m,1H),2.12(s,3H),2.05(s,3H),1.52–1.35(m,2H),1.07(d,J=4.9Hz,3H),0.72(t,J=7.0Hz,3H). 1313C NMR(100MHz,DMSO-d6)δ188.79,167.19,150.92,145.94(d,J=235.3Hz),138.24,136.75,130.54,129.82,128.99(d,J=11.6Hz),127.46,125.69,125.27,124.05(d,J=6.5Hz),116.42(d,J=20.0Hz),107.82,77.69,76.05,29.02,27.52,20.29,19.21,9.65.HRMS m / z(ESI)calculated for C 22 H 23 FN2O3383.1693[M+H] + ,found:383.1754。

[0110] Compound A18

[0111]

[0112] 1 1H NMR(400MHz,CDCl3)δ15.38(s,1H),7.85(s,1H),7.80(d,J=6.8Hz,1H),7.34–7.25(m,2H),7.16(t,J=7.0Hz,1H),7.10(t,J=9.6Hz,2H),4.28–4.14(m,1H),2.38(s,3H),1.60–1.51(m,2H),1.19(d,J=6.1Hz,3H),0.83(t,J=7.5Hz,3H). 13 13C NMR(100MHz,CDCl3)δ188.62,167.21,159.89(d,J=248.1Hz),151.67(d,J=2.0Hz),146.90(d,J=239.0Hz),131.89(d,J=3.4Hz),129.31(d,J=8.2Hz),124.90(dd,J=15.4,1.0Hz),124.20(d,J=11.5Hz),123.64,123.59(d,J=2.2Hz),117.59(dd,J=20.8,1.5Hz),115.91,115.46(d,J=22.5Hz),108.42,80.94,76.56,28.95,22.01,18.67,9.37.HRMS m / z(ESI)calculated for C 21 H 20F₂N₂O₃ 386.1442[M+H] + ,found:386.1428.

[0113] Compound A19

[0114]

[0115] 1 H NMR (400MHz, DMSO-d6) δ13.11(brs,1H),10.61(s,1H),7.80(d,J=6.8Hz,1H),7.48–7.41(m,1H),7.41–7.35(m,2H),7.29(d,J=1 1.4Hz,1H),7.17–7.12(m,1H),4.31–4.27(m,1H),2.30(s,3H),1.68–1.50(m,2H),1.19(d,J=6.1Hz,3H),0.86(t,J=7.4Hz,3H). 13 C NMR (100MHz, DMSO-d6) δ185.96, 165.92, 162.26 (d, J = 242.4Hz), 150.83, 148.39 (d, J=238.2Hz),139.67(d,J=8.1Hz),130.22(d,J=8.5Hz),126.27(d,J=12.6Hz),125.8 3(d,J=1.1Hz),125.73(d,J=2.5Hz),119.10,116.95(d,J=21.5Hz),116.39(d,J=22 .2Hz),114.17(d,J=20.9Hz),110.48,82.24,76.19,28.86,23.56,19.01,9.73.HRMS m / z(ESI)calculated for C 21 H 20 F₂N₂O₃ 386.1442[M+H] + ,found:386.1430.

[0116] Compound A20

[0117]

[0118] 11H NMR (400 MHz, DMSO-d6) δ 12.21 (s, 1H), 8.34 (d, J = 7.0 Hz, 1H), 7.62–7.48 (m, 2H), 7.20 (t, J = 8.6Hz, 2H), 7.13 (d, J = 11.9Hz, 1H), 4.22–4.18 (m, 1H), 2.06 (s, 3H), 1.63–1.49 (m, 2H), 1.16 (d, J = 5.8Hz, 3H), 0.85 (t, J = 7.3Hz, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ 188.68, 167.10, 161.47 (d, J = 243.4Hz), 150.71, 146.38 (d, J = 234.5Hz), 134.26 (d, J = 4.0Hz), 131.52, 131.44, 129.07 (d, J = 11.6Hz), 124.80, 122.22 (d, J = 6.8Hz), 116.01 (d, J = 22.0Hz), 115.21, 115.00, 107.54, 77.98, 76.06, 28.97, 27.27, 19.19, 9.86. HRMS m / z (ESI) calculated for C 21 H 20 F2N2O3 386.1442 [M+H] + , found: 386.1429。

[0119] Compound A21

[0120]

[0121] 1 1H NMR (400 MHz, CDCl3) δ 15.33 (s, 1H), 7.85 (s, 1H), 7.81 (d, J = 6.8Hz, 1H), 7.59 (dd, J = 7.1, 2.1Hz, 1H), 7.42–7.34 (m, 1H), 7.15 (t, J = 8.7Hz, 1H), 7.08 (d, J = 11.1Hz, 1H), 4.33–4.20 (m, 1H),​13C NMR(100MHz,CDCl3)δ188.69,167.20,157.34(d,J=249.4Hz),151.00(d,J=1.8Hz),147.24(d,J=239.5Hz),134.13(d,J=2.8Hz),131.61,129.16(d,J=7.1Hz),126.70(d,J=6.6Hz),124.10(d,J=11.6Hz),120.41(d,J=17.7Hz),116.54(d,J=20.9Hz),116.17,115.91(d,J=10.5Hz),108.82,80.93,76.80,28.95,22.00,18.81,9.51.HRMS m / z(ESI)calculated for C 21 H 19 F3N2O3 404.1348[M+H] + ,found:404.1073。

[0122] Compound A22

[0123]

[0124] 1 1H NMR(400MHz,CDCl3)δ15.30(s,1H),7.86(s,1H),7.84(d,J=6.8Hz,1H),7.11(d,J=11.1Hz,1H),7.07(dd,J=8.5,2.0Hz,2H),6.76(tt,J=8.9,2.3Hz,1H),4.35–4.16(m,1H),2.39(s,3H),1.78–1.51(m,2H),1.25(d,J=6.1Hz,3H),0.91(t,J=7.5Hz,3H). 13CNMR(100MHz,CDCl3)δ188.73,167.22,162.59(dd,J=247.0,13.1Hz,2C),151.12(d,J=2.0Hz),147.13(d,J=239.4Hz),140.16(t,J=10.8Hz),126.47(d,J=6.6Hz),124.56(d,J=11.5Hz),116.55(d,J=21.1Hz),115.82,112.42(d,J=6.9Hz),112.24(d,J=6.9Hz),108.73,102.57(t,J=25.4Hz),80.96,76.91,28.94,22.00,18.82,9.52.HRMS m / z(ESI)calculated for C 21 H 19 F3N2O3 404.1348[M+H] + ,found:404.1076。

[0125] Compound A23

[0126]

[0127] 1 H NMR(400MHz,DMSO-d6)δ11.80(s,1H),8.25(d,J=6.9Hz,1H),8.22(d,J=5.3Hz,1H),7.57(d,J=5.2Hz,1H),7.43(d,J=11.9Hz,1H),7.35(s,1H),4.54–4.10(m,1H),2.13(s,3H),1.80–1.50(m,2H),1.22(d,J=6.1Hz,3H),0.88(t,J=7.4Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ18​H 19 F2N3O3 388.1394 [M+H] + , found: 388.1462

[0128] Compound A24

[0129]

[0130] 1 H NMR(400 MHz, DMSO-d6) δ 10.66(s, 1H), 8.38(s, 1H), 8.14(td, J = 8.2, 2.2 Hz, 1H), 7.85(d, J = 5.0 Hz, 1H), 7.36(d, J = 11.3 Hz, 1H), 7.23(dd, J = 8.5, 2.6 Hz, 1H), 4.36–4.26(m, 1H), 2.30(s, 3H), 1.69–1.52(m, 2H), 1.19(d, J = 6.0 Hz, 3H), 0.85(t, J = 7.4 Hz, 3H). 13 C NMR(100 MHz, DMSO-d6) δ 185.93, 165.89, 162.36(d, J = 235.9 Hz), 150.90, 148.32(d, J = 237.8 Hz), 147.80(d, J = 15.1 Hz), 143.08(d, J = 8.0 Hz), 131.42(d, J = 4.3 Hz), 126.72(dd, J = 12.7, 3.5 Hz), 122.34, 119.22(d, J = 4.7 Hz), 116.90(d, J = 21.7 Hz), 110.04, 109.15(d, J = 37.7 Hz), 82.23, 76.26, 28.81, 23.59, 19.01, 9.74. HRMS m / z(ESI) calculated for C 20 H 19 F2N3O3 388.1394 [M+H] + , found: 388.1460

[0131] Compound A25

[0132]

[0133] 11H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 8.12 (d, J = 6.9 Hz, 1H), 7.22 (dd, J = 14.1, 7.5 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 6.99 (s, 1H), 6.96 (d, J = 2.9 Hz, 1H), 4.18–4.05 (m, 1H), 2.13 (s, 3H), 2.01 (s, 3H), 1.52–1.36 (m, 2H), 1.08 (brs, 3H), 0.72 (brs, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ 187.84, 166.77, 160.96 (d, J = 241.2 Hz), 150.92, 146.65 (d, J = 236.3 Hz), 140.57, 128.28 (d, J = 11.9 Hz), 126.99, 126.90, 126.52 (d, J = 2.3 Hz), 126.51, 123.97, 123.81, 116.79 (d, J = 20.6 Hz), 114.04 (d, J = 23.0 Hz), 108.47 (d, J = 1.5 Hz), 79.26, 76.00, 28.95, 26.11, 19.11, 12.36 (d, J = 4.6 Hz), 9.60. HRMS m / z (ESI) calculated for C 22 H 22 F2N2O3 401.1598 [M+H] + , found: 401.1663。

[0134] Compound A26

[0135]

[0136] 1 1H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 8.33 (d, J = 7.1 Hz, 1H), 7.62–7.44 (m, 1H), 7.40–7.27 (m, 3H), 6.96 (d, J = 11.4 Hz, 1H), 4.16–4.06 (m, 1H), 2.05 (s, 3H), 1.56–1.37 (m, 2H), 1.10 (d, J = 6.0 Hz, 3H), 0.75 (t, J = 7.4 Hz, 3H). 1313C NMR (100 MHz, DMSO-d6) δ 188.84, 167.19, 151.19, 145.65 (d, J = 235.0 Hz), 137.10, 133.49, 132.71, 129.68 (d, J = 11.6 Hz), 129.47, 129.25, 127.08, 121.32 (d, J = 6.9 Hz), 116.67 (d, J = 2.3 Hz), 116.46 (d, J = 2.4 Hz), 107.19, 77.78, 75.96, 29.03, 27.44, 19.16, 9.65. HRMS m / z (ESI) calculated for C 21 H 20 ClFN2O3 425. .1046 [M+H] + , found: 425.1035。

[0137] Compound A27

[0138]

[0139] 1 1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 7.80 (d, J = 6.8 Hz, 1H), 7.61 (s, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 11.4 Hz, 1H), 4.31–4.27 (m, 1H), 2.31 (s, 3H), 1.60–1.54 (m, 2H), 1.18 (d, J = 6.0 Hz, 3H), 0.87 (t, J = 7.4 Hz, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ 185.85, 165. . .86, 150.80, 148.42 (d, J = 238.4 Hz), 139.37, 133.07, 130.21, 129.45, 128.25, 127.28, 12 . . .31 (d, J = 12.5 Hz), 125.62 (d, J = 7.0 Hz), 119.01, 116.92 (d, J = 21.5 Hz), 110.47, 82.37, 76.15, 28.86, 23.50, 18.97, 9.68. HRMS m / z (ESI) calculated for C 21 H 20 ClFN2O3 402.1146 [M+H] + , found: 402.1137。

[0140] Compound A28

[0141]

[0142] 1 H NMR(400MHz,CDCl3)δ15.27(s,1H),7.74(s,1H),7.72(d,J=6.8Hz,1H),7.37(d,J=8.2Hz,2H),7.27(d,J=8.2Hz,2H),7.01(d,J=11.2Hz,1H),4.17–4.13(m,1H),2.30(s,3H),1.58–1.47(m,2H),1.13(d,J=5.9Hz,3H),0.81(t,J=7.4Hz,3H). 13 C NMR(100MHz,CDCl3)δ187.58,166.13,150.01,​​​​​​​​​​​​​​​​​13C NMR (100 MHz, DMSO-d6) δ 188.84, 167.22, 150.81, 145.82 (d, J = 234.4 Hz), 140.46, 134.84, 133.90, 129.58, 129.47, 128.17, 127.03, 125.20, 122.82 (d, J = 1.9 Hz), 116.39 (d, J = 21.3 Hz), 107.28 (d, J = 38.1 Hz), 77.69, 75.72, 28.99, 27.52, 19.15, 18.06, 9.50. HRMS m / z (ESI) calculated for C 22 H 22 ClFN2O3 416.1303 [M+H] + , found: 416.1292。

[0146] Compound A30

[0147]

[0148] 1 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 7.75 (d, J = 6.3 Hz, 1H), 7.33–7.25 (m, 2H), 7.16 (s, 1H), 7.08 (d, J = 10.9 Hz, 1H), 4.21–4.12 (m, 1H), 2.29 (s, 3H), 2.09 (s, 3H), 1.51–1.39 (m, 2H), 1.10 (d, J = 5.9 Hz, 3H), 0.74 (t, J = 7.4 Hz, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ 186.06, 165.99, 150.88, 148.06 (d, J = 239.0 Hz), 139.58, 135.83, 131.67, 130.07, 129.89, 127.58, 126.55 (d, J = 5.3 Hz), 126.15 (d, J = 十二点八赫兹), 119.21, 117.27 (d, J = 21.1 Hz), 110.50, 82.06, 76.11, 28.91, 23.63, 19.60, 19.05, 9.54. HRMS m / z (ESI) calculated for C 22 H 22 ClFN2O3 416.1303 [M+H] + , found: 416.1293。

[0149] Compound A31

[0150]

[0151] 1 1H NMR (400 MHz, CDCl3) δ 15.33 (brs, 1H), 7.89–7.81 (m, 3H), 7.67 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.15 (d, J = 11.1 Hz, 1H), 4.37–4.21 (m, 1H), 2.38 (s, 3H), 1.73–1.49 (m, 2H), 1.23 (d, J = 6.1 Hz, 3H), 0.89 (t, J = 7.5 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 188.70, 167.22, 151.11 (d, J = 2.0 Hz), 147.28 (d, J = 239.3 Hz), 137.77 (d, J = 1.2 Hz), 132.51 (d, J = 0.9 Hz), 130.31 (q, J = 32.2 Hz), 128.49, 127.34 (d, J = 6.5 Hz), 126.50 (q, J = 3.9 Hz), 124.27 (d, J = 11.5 Hz), 124.23 (q, J = 272.2 Hz), 123.89 (q, J = 3.6 Hz), 116.68 (d, J = 20.9 Hz), 115.87, 108.65, 80.95, 28.91, 22.00, 18.75, 9.43. HRMS m / z (ESI) calculated for C 22 H 20 F4N2O3 436.1410 [M + H] + , found: 436.1398. HPLC purity = 98.09%.

[0152] Compound A32

[0153]

[0154] 11H NMR (400 MHz, DMSO-d6) δ 12.07 (brs, 1H), 10.67 (s, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.81–7.64 (m, 4H), 7.31 (d, J = 11.4 Hz, 1H), 4.38–4.22 (m, 1H), 2.30 (s, 3H), 1.75–1.41 (m, 2H), 1.19 (d, J = 6.0 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ 185.88, 165.86, 150.94 (d, J = 1.3 Hz), 148.31 (d, J = 238.0 Hz), 141.57, 130.40, 127.81 (q, J = 31.8 Hz), 126.77 (d, J = 12.5 Hz), 125.37 (d, J = 6.8 Hz), 125.19, 125.16, 125.12, 124.81 (q, J = 271.7 Hz), 119.20, 117.00 (d, J = 21.5 Hz), 110.18, 82.30, 76.26, 28.83, 23.60, 19.00, 9.76. HRMS m / z (ESI) calculated for C 22 H 20 F4N2O3 436.1410 [M+H] + , found: 436.1397。

[0155] Compound A33

[0156]

[0157] 1 1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 8.11 (d, J = 6.7 Hz, 1H), 7.65–7.43 (m, 3H), 7.33–7.20 (m, 2H), 4.46–4.12 (m, 1H), 2.15 (s, 3H), 1.69–1.47 (m, 2H), 1.17 (d, J = 6.0 Hz, 3H), 0.84 (t, J = 7.4 Hz, 3H). 1313C NMR (100 MHz, DMSO-d6) δ 186.35, 166.08, 150.80 (d, J = 1.6 Hz), 148.40 (d, J = 1.6 Hz), 148.10 (d, J = 236.5 Hz), 139.54, 130.42, 128.52, 126.98 (d, J = 12.3 Hz), 124.60 (d, J = 7.0 Hz), 122.24, 120.64 (q, J = 254.5 Hz), 119.91 (d, J = 4.2 Hz), 116.94, 116.74, 109.82, 81.66, 76.18, 28.79, 24.11, 19.04, 9.72. HRMS m / z (ESI) calculated for C 22 H 20 F4N2O4 452.1359 [M+H] + , found: 452.1347。

[0158] Compound A34

[0159]

[0160] 1 1H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.39 (s, 1H), 7.91 (dd, J = 16.5, 7.9 Hz, 2H), 7.58–7.33 (m, 5H), 7.02 (dd, J = 11.4, 2.6 Hz, 1H), 4.13–3.93 (m, 1H), 2.05 (s, 3H), 1.38–1.15 (m, 2H), 0.97 (dd, J = 17.5, 5.8 Hz, 3H), 0.63–0.41 (m, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ 188.68, 185.90, 167.17, 151.54, 136.48, 133.47, 132.14, 132.07, 129.3, 129.24, 128.41, 127.96, 127.89, 127.80, 126.78, 126.72, 126.08, 125.80, 117.44, 1, 107.66, 77.98, 75.98, 28.91, 27.31, 19.03, 9.56. HRMS m / z (ESI) calculated for C 25 H 23 FN2O3 419.1693 [M+H][[ID=​​

[0161] Compound A35

[0162]

[0163] 1 H NMR (400MHz, DMSO-d6) δ12.15(s,1H),8.35(d,J=7.0Hz,1H),8.04(s,1H),7.92–7.89(m,3H),7.73(d,J=8.4Hz,1H),7.56–7.46( m,2H),7.29(d,J=11.9Hz,1H),4.33–4.17(m,1H),2.09(s,3H),1.61–1.54(m,2H),1.18(d,J=6.0Hz,3H),0.86(t,J=7.4Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ188.52,167.05,151.03,146.67(d,J=235.3Hz),1 35.64,133.45,132.19,128.97(d,J=12.4Hz),128.41,128.31,127.97,127 .82,127.32,126.49,126.27,124.42(d,J=2.5Hz),123.40(d,J=6.0Hz),11 6.39(d,J=19.6Hz),107.83,78.31,75.98,28.99,27.06,19.17,9.85.HRMS m / z(ESI)calculated forC 25 H 23 FN₂O₃ 419.1693[M+H] + ,found:419.1748.HPLC purity=98.18%.

[0164] Compound A36

[0165]

[0166] 11H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 6.6 Hz, 1H), 7.85 (d, J = 12.0 Hz, 2H), 7.60 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.39 (s, 1H), 7.30 (d, J = 7.2 Hz, 1H), 7.25–7.18 (m, 2H), 4.55–4.47 (m, 1H), 2.39 (s, 3H), 1.97–1.77 (m, 2H), 1.44 (d, J = 6.1 Hz, 3H), 1.06 (t, J = 7.5 Hz, 3H). HRMS m / z (ESI) calculated for C 23 H 21 FN2O4 409.1385 [M+H] + , found: 409.1322。

[0167] Compound A37

[0168]

[0169] 1 1H NMR (400 MHz, CDCl3) δ 15.32 (s, 1H), 7.91–7.80 (m, 3H), 7.68 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 11.1 Hz, 1H), 4.45 (m, 1H), 2.39 (s, 3H), 1.27 (d, J = 6.1 Hz, 6H). 13 13C NMR (100 MHz, CDCl3) δ 188.70, 167.21, 150.92 (d, J = 2.0 Hz), 147.41 (d, J = 239.6 Hz), 137.73 (d, J = 1.1 Hz), 132.47, 130.37 (q, J = 32.1 Hz), 128.53 (2C), 127.42 (d, J = 6.6 Hz), 126.45 (q, J = 3.9 Hz), 124.28 (d, J = 11.6 Hz), 124.22 (q, J = 272.3 Hz), 116.67 (d, J = 20.9 Hz), 115.85, 109.08, 80.96, 72.05, 22.00, 21.82 (2C). HRMS m / z (ESI) calculated for C 21 H 18 F4N2O3 423.1254 [M+H] + , found: 423.1202。

[0170] Compound A38

[0171]

[0172] 1 H NMR(400MHz,DMSO-d6)δ11.24(s,1H),8.11(d,J=6.2Hz,1H),7.71(d,J=7.8Hz,2H),7.64(t,J=7.1Hz,1H),7.51(t,J=7.8Hz,2H),7.30(d,J=10.6Hz,1H),7.01(brs,2H),3.62(s,3H),2.25(s,3H). 13 C NMR(100MHz,DMSO-d6)δ194.15,186.22,165.74,154.00,146.99(d,J=237.7Hz),137.87,133.58,130.67(d,J=12.2Hz),129.65(2C),128.96(2C),122.45(d,J=5.3Hz),120.70,115.95(d,J=22.1Hz),106.07,81.77,56.42,24.67.HRMS m / z(ESI)calculated for C 19 H 15 FN2O4 355.1016[M+H] + ,found:355.1082。

[0173] Compound A39

[0174]

[0175] 1 H NMR(400MHz,DMSO-d6)δ11.11(s,1H),10.97(brs,1H),8.06(d,J=6.3Hz,1H),7.68(d,J=7.3Hz,2H),7.63(t,J=7.3Hz,1H),7.50(t,J=7.6Hz,2H),7.33(d,J=10.7Hz,1H),3.90(q,J=6.9Hz,2H),2.26(s,3H),0.91(t,J=6.9Hz,3H). 1313C NMR (100 MHz, DMSO-d6) δ 194.43, 185.84, 165.53, 153.53, 147.14 (d, J = 238.1 Hz), 138.44, 133.24, 130.71 (d, J = 12.4 Hz), 129.41 (2C), 128.78 (2C), 122.81 (d, J = 5.5 Hz), 120.34, 115.98 (d, J = 21.8 Hz), 107.05, 82.19, 64.71, 24.41, 14.42. HRMS m / z (ESI) calculated for C 20 H 17 FN2O4 369.1172 [M+H] + , found: 369.1237。

[0176] Compound A40

[0177]

[0178] 1 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.01 (d, J = 6.3 Hz, 1H), 7.72–7.65 (m, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.4 Hz, 2H), 7.33 (d, J = 10.6 Hz, 1H), 4.43–4.37 (m, 1H), 2.27 (s, 3H), 0.98 (d, J = 6.0 Hz, 6H). 13 13C NMR (100 MHz, DMSO-d6) δ 194.75, 185.80, 165.58, 152.31, 147.21 (d, J = 238.4 Hz), 138.48, 133.21, 130.36 (d, J = 12.3 Hz), 129.44 (2C), 128.72 (2C), 123.92 (d, J = 5.2 Hz), 120.08, 116.06 (d, J = 21.8 Hz), 108.39, 82.29, 71.44, 24.24, 21.71 (2C). HRMS m / z (ESI) calculated for C 21 H 19 FN2O4 383.1329 [M+H] + , found: 383.1395。

[0179] Compound A41

[0180]

[0181] 1 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.03 (d, J = 6.3 Hz, 1H), 7.69–7.65 (m, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.4 Hz, 2H), 7.31 (d, J = 10.7 Hz, 1H), 4.24–4.20 (m, 1H), 2.25 (s, 3H), 1.34–1.25 (m, 2H), 1.01 (d, J = 6.0 Hz, 3H), 0.59 (t, J = 7.4 Hz, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ 194.79, 186.07, 165.73, 152.40, 147.03 (d, J = 238.1 Hz), 138.54, 133.24, 129.44 (2C), 128.76 (2C), 123.70 (d, J = 5.3 Hz), 120.42, 116.02 (d, J = 21.9 Hz), 115.91, 107.93, 81.94, 75.77, 28.63, 24.47, 18.54, 9.26. HRMS m / z (ESI) calculated for C 22 H 21 FN2O4 397.1485 [M + H] + , found: 397.1551。

[0182] Compound A42​​​​​​​​13C NMR (100 MHz, DMSO-d6) δ 194.13, 189.42, 167.28, 151.06, 146.60 (d, J = 238.3 Hz), 138.52, 133.27, 133.16, 129.50 (2C), 128.77 (2C), 124.74 (q, J = 281.4 Hz), 124.69, 121.28 (d, J = 5.5 Hz), 115.92 (d, J = 21.7 Hz), 106.71, 77.76, 72.89 (q, J = 31.1 Hz), 27.51, 13.50. HRMS m / z (ESI) calculated for C 21 H 16 F4N2O4 437.1046 [M+H] + , found: 437.1114。

[0185] Compound A43

[0186]

[0187] 1 1H NMR (400 MHz, CDCl3) δ 15.00 (s, 1H), 7.99–7.97 (m, 2H), 7.65 (td, J = 7.5, 1.4 Hz, 1H), 7.54–7.43 (m, 2H), 7.23 (t, J = 7.5 Hz, 1H), 7.09–7.02 (m, 1H), 4.63–4.50 (m, 1H), 2.40 (s, 3H), 1.25 (d, J = 6.5 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 189.93 (d, J = 1.0 Hz), 189.21, 167.33, 160.96 (d, J = 253.9 Hz), 151.60, 147.31 (d, J = 242.0 Hz), 133.94 (d, J = 8.8 Hz), 130.38 (d, J = 2.0 Hz), 128.77 (d, J = 11.6 Hz), 128.08 (d, J = 12.4 Hz), 126.90 (d, J = 5.4 Hz), 124.24 (d, J = 3.5 Hz), 123.69 (q, J = 281.6 Hz), 116.87 (d, J = 21.8 Hz), 115.89 (d, J = 22.0 Hz), 115.45, 106.72, 81.19, 73.09 (q, J = 32.7 Hz), 22.08, 13.04 (d, J = 1.6 Hz). HRMS m / z (ESI) calculated for C 21 H 15F5N2O4 455.1052 [M+H] + , found: 455.1008. HPLC purity = 99.01%.

[0188] Compound A44

[0189]

[0190] 1 H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.53 (d, J = 6.2 Hz, 1H), 7.59–7.38 (m, 4H), 7.35 (d, J = 10.9 Hz, 1H), 4.97–4.91 (m, 1H), 2.08 (s, 3H), 1.20 (d, J = 6.3 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 192.89, 189.52, 167.30, 162.37 (d, J = 244.9 Hz), 151.29, 146.60 (d, J = 238.2 Hz), 141.09 (d, J = 6.4 Hz), 133.82 (d, J = 12.2 Hz), 130.95 (d, J = 7.9 Hz), 125.64, 124.67 (q, J = 281.7 Hz), 124.62, 120.33 (d, J = 5.7 Hz), 119.90 (d, J = 21.3 Hz), 116.18 (d, J = 21.8 Hz), 115.54 (d, J = 22.4 Hz), 106.21, 77.78, 72.60 (q, J = 31.8 Hz), 27.50, 13.40. HRMS m / z (ESI) calculated for C 21 H 15 F5N2O4 455.1052 [M+H] + , found: 455.1022.

[0191] Compound A45

[0192]

[0193] 1 H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.28 (d, J = 6.2 Hz, 1H), 7.77 (dd, J = 8.6, 5.6 Hz, 2H), 7.39–7.31 (m, 3H), 5.04–4.95 (m, 1H), 2.21 (s, 3H), 1.22 (d, J = 6.3 Hz, 3H). 13CNMR(100MHz,DMSO-d6)δ192.54,187.19,166.17,165.40(d,J=251.5Hz),150.61(d,J=1.6Hz),147.72(d,J=239.6Hz),134.84(d,J=2.6Hz),132.50(d,J=9.5Hz,2C),131.41(d,J=12.5Hz),124.69(q,J=281.4Hz).123.20(d,J=5.7Hz),121.59,116.18(d,J=22.3Hz),115.91(d,J=22.1Hz,2C),108.38,80.65,72.80(q,J=31.7Hz),25.33,13.44.HRMS m / z(ESI)calculated for C 21 H 15 F5N2O4 455.1052[M+H] + ,found:455.1021。

[0194] Compound A46

[0195]

[0196] 1 H NMR(400MHz,CDCl3)δ14.96(s,1H),8.02(d,J=2.1Hz,1H),7.98(d,J=6.0Hz,1H),7.61(d,J=10.7Hz,1H),7.43–7.30(m,4H),4.84–4.38(m,1H),2.40(s,3H),1.19(d,J=6.4Hz,3H). 13 C NMR(100MHz,CDCl3)δ192.18(d,J=1.1Hz),189.28,167.35,152.17(d,J=1.9Hz),147.27(d,J=242.0Hz),140.12,131.51,131.15,129.83,129.57(d,J=11.7Hz),129.27,126.82,125.15(d,J=5.3Hz),123.63(q,J=281.7Hz),117.35(d,J=21.6Hz),115.40,81.23,72.61(q,J=32.9Hz),22.10,12.98(d,J=1.7Hz).HRMS m / z(ESI)calculated for C 21 H 15ClF4N2O4 471.0656 [M+H] + ,found:471.0725.HPLC purity=99.61%.

[0197] Compound A47

[0198]

[0199] 1 H NMR (400MHz, DMSO-d6) δ11.40(s,1H),11.13(brs,1H),8.24(d,J=6.1Hz,1H),7.71(dd,J=8.0,0.8Hz,1H),7.63(dd,J= 4.8,1.5Hz,2H),7.54(t,J=8.0Hz,1H),7.43(d,J=10.6Hz,1H),5.08–5.02(m,1H),2.24(s,3H),1.21(d,J=6.3Hz,3H). 13 C NMR (100MHz, DMSO-d6) δ192.70,186.61,165.85,150.80,147.90(d,J=240.0Hz),140.20,133.71,133.03,131.52(d,J=12.4Hz),130.89,128.8 5,127.97,124.63(q,J=281.3Hz),122.84(d,J=5.7Hz),120.86,116.55(d,J=22.4Hz),108.31,81.42,72.49(q,J=31.3Hz),24.86,13.33.HRMS m / z(ESI)calculated for C 21 H 15 ClF4N2O4 471.0656 [M+H] + ,found:471.0726.

[0200] Compound A48

[0201]

[0202] 11H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 9.97 (brs, 1H), 8.21 (d, J = 6.1 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 10.5 Hz, 1H), 5.05–4.99 (m, 1H), 2.25 (s, 3H), 1.22 (d, J = 6.3 Hz, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ 192.84, 186.53, 165.84, 150.65, 148.02 (d, J = 240.3 Hz), 138.42, 136.82, 131.34 (2C), 131.05 (d, J = 12.6 Hz), 129.02 (2C), 124.66 (d, J = 281.5 Hz), 123.54 (d, J = 5.9 Hz), 120.69, 116.34 (d, J = 22.4 Hz), 108.84, 81.51, 72.79 (q, J = 31.7 Hz), 24.72, 13.42. HRMS m / z (ESI) calculated for C 21 H 15 ClF4N2O4 471.0656 [M+H] + , found: 471.0726。

[0203] Compound A49

[0204]

[0205] 1 1H NMR (400 MHz, DMSO-d6) δ 12.64 (d, J = 1.5 Hz, 1H), 8.52 (d, J = 6.3 Hz, 1H), 7.41 (t, J = 8.2 Hz, 1H), 7.28 (d, J = 10.9 Hz, 1H), 7.25–7.18 (m, 3H), 4.94–4.88 (m, 1H), 3.79 (s, 3H), 2.07 (s, 3H), 1.20 (d, J = 6.3 Hz, 3H). 1313C NMR(100MHz, DMSO-d6) δ 193.80, 189.43, 167.29, 159.59, 151.12, 146.51 (d, J = 238.1 Hz), 139.91, 133.22 (d, J = 12.1 Hz), 129.96, 124.77 (q, J = 281.6 Hz), 124.68, 122.31, 121.24 (d, J = 5.5 Hz), 119.27, 115.90 (d, J = 21.8 Hz), 113.78, 106.71, 77.76, 72.88 (q, J = 31.5 Hz), 55.73, 27.50, 13.52. HRMS m / z (ESI) calculated for C 22 H 18 F4N2O5 467.1152 [M+H] + , found: 467.1222。

[0206] Compound A50

[0207]

[0208] 1 1H NMR(400MHz, DMSO-d6) δ 11.15 (s, 1H), 8.15 (d, J = 6.0 Hz, 1H), 7.69 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 10.4 Hz, 1H), 7.04 (d, J = 8.7 Hz, 2H), 5.03–4.97 (m, 1H), 3.85 (s, 3H), 2.26 (s, 3H), 1.23 (d, J = 6.3 Hz, 3H). 13 13C NMR(100MHz, DMSO-d6) δ 192.21, 186.41, 165.88, 163.85, 150.15, 148.32 (d, J = 240.6 Hz), 132.22 (2C), 130.39, 129.71 (d, J = 12.8 Hz), 125.37, 124.79 (q, J = 281.4 Hz), 120.30, 115.88 (d, J = 22.1 Hz), 114.24 (2C), 109.87, 81.64, 73.10 (q, J = 31.4 Hz), 56.01, 24.43, 13.59. HRMS m / z (ESI) calculated for C 22 H 18 F4N​​​Compound A51

[0210]

[0211] 1 H NMR (400MHz, DMSO-d6) δ11.32(s,1H),8.26(d,J=6.2Hz,2H),8.09(d,J=8.1Hz,1H),8.03(t,J=8.9Hz,2H),7.87(dd,J=8.6,1.4Hz ,1H),7.68(t,J=7.4Hz,1H),7.60(t,J=7.4Hz,1H),7.47(d,J=10.5Hz,1H),5.07–5.01(m,1H),2.27(s,3H),1.17(d,J=6.3Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ193.88,186.44,165.85,150.63,148.11(d,J=240.0Hz) ,135.54,135.24,132.46,132.07,130.60(d,J=12.6Hz),130.05,129.12,128.6 4,128.13,127.34,124.72,124.67(q,J=281.3Hz),124.45(d,J=5.3Hz),120.60 ,116.38(d,J=22.1Hz),109.09,81.64,72.75(q,J=31.5Hz),24.65,13.44.HRMS m / z(ESI)calculated for C 25 H 18 F4N2O4487.12O3[M+H] + ,found:487.1271.

[0212] Example 8: Determination of the hDHODH enzyme inhibitory activity of the compound

[0213] Experimental methods:

[0214] 2 nM of purified full-length hDHODH protein, 60 μM of sodium 2,6-dichlorophenolindophenol (DCIP), and 0.1 mM of coenzyme Q (CoQ) were added to 96-well plates, followed by the analyte compound to create a final concentration gradient of 1000 nM, 100 nM, 50 nM, 25 nM, 12.5 nM, 6.25 nM, and 3.125 nM. The mixture was incubated at 37°C for 30 min, and then 1 mM of dihydroorotic acid (DHO) was added. The absorbance of the reaction mixture at 600 nm was then measured using a microplate reader to determine the dynamic reduction rate of sodium 2,6-dichlorophenolindophenol (30 s / time, repeated 12 times). The inhibition rate was calculated using the formula: "Inhibition rate = (1 - V...". i The calculation is performed using " / V0)," where V0 and V i These represent the initial and final reaction rates of the system, respectively.

[0215] Table 2. Results of the hDHODH enzyme inhibitory activity of the compounds of the present invention.

[0216]

[0217]

[0218] Note: ND indicates not measured.

Claims

1. A class of small molecule compounds or their pharmaceutically acceptable salts, characterized in that, The compound is shown in Formula I: The Q is selected from the following group: R 1 Independently selected from the group consisting of: methyl, ethyl, n-propyl, n-butyl, isopropyl, cyclopropyl, sec-butyl, isobutyl, 2-methylpentyl, allyl, 2-methylallyl, cyclopentylmethyl, cyclohexylmethyl, 2-fluorobenzyl, 2-chloro-6-fluorobenzyl, (S)-trifluoroisopropyl, (R)-trifluoroisopropyl; R 2 R 3 and R 4 Independently selected from the group consisting of: hydrogen, halogen, methyl; and R 5 Independently selected from methyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound shown is that of formula I-1; The Q is selected from the following group: R 1 It is independently selected from methyl, ethyl, n-propyl, n-butyl, isopropyl, cyclopropyl, sec-butyl, isobutyl, 2-methylpentyl, allyl, 2-methylallyl, cyclopentylmethyl, cyclohexylmethyl, 2-fluorobenzyl, 2-chloro-6-fluorobenzyl, (S)-trifluoroisopropyl, (R)-trifluoroisopropyl.

3. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The compounds are selected from the following group:

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Any one or more atoms of the compound are replaced by isotopes.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, characterized in that, The isotope is deuterium.

6. The use of a small molecule compound according to claim 1 in the preparation of a pharmaceutical product, characterized in that, The drug is used to treat hDHODH-mediated diseases.

7. The use according to claim 6, characterized in that, The diseases mediated by hDHODH are selected from tumors, autoimmune diseases, and viral infections.

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