A class of compounds and their use in the treatment of hDHODH-mediated diseases

Abstract

This invention pertains to the pharmaceutical field, specifically relating to a class of compounds, their preparation methods, and their use in treating hDHODH-mediated diseases. The invention relates to a class of novel small molecule compounds, as shown in Formula I, which exhibit prominent hDHODH enzyme inhibitory activity and can be used to treat various hDHODH-mediated diseases, including but not limited to tumors, autoimmune diseases, and viral infections.

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] Pyrimidine nucleotides are essential raw materials for the synthesis of DNA and RNA in organisms, and also participate in the biosynthesis of glycoproteins and phospholipids, playing a crucial role in cell proliferation and metabolism. Human dihydroorotated ehydrogenase (hDHODH) is the fourth-step catalytic enzyme in the de novo pyrimidine synthesis pathway and a key rate-limiting enzyme in this pathway. Tumor cells have a much higher demand for pyrimidine nucleotides than normal cells, and their synthesis mainly relies on the de novo pathway. Inhibiting hDHODH can block the synthesis of newly formed pyrimidine nucleotides, leading to impaired biosynthesis of DNA, RNA, glycoproteins, and phospholipids, thereby causing cell cycle arrest, inducing cell differentiation, and inhibiting abnormal cell proliferation, indicating that hDHODH is a potential target for anti-tumor drug development. Interfering with immune cell proliferation is an effective strategy for treating autoimmune diseases. Inhibiting hDHODH can effectively block the DNA synthesis of activated T and B lymphocytes, thereby inhibiting T and B lymphocyte proliferation and reducing inflammatory responses to self-antigens. In addition, the rapid replication of RNA and DNA viruses after infection depends on the synthesis of pyrimidines in the host cell. Therefore, compounds targeting the pyrimidine synthesis pathway can inhibit viral infection. Inhibiting hDHODH can effectively slow down viral replication and is a potential host-targeted antiviral target. Summary of the Invention

[0003] A class of small molecule compounds, characterized in that the compound is as shown in Formula I:

[0004]

[0005] Q is independently selected from the following structures:

[0006]

[0007] In each formula, R2~R 11 Independently selected from hydrogen, halogen, C1-C8 substituted alkyl, cycloalkyl, alkenyl, alkoxy, substituted alkyl, substituted alkoxy, trifluoromethyl, trifluoromethoxy.

[0008] X1, X2, Y1, Y2, and Y3 are independently selected from C and N.

[0009] R1 is independently selected from 0-5 R1s. 12 Substituted phenyl, pyrimidine, pyridine, wherein R 12The compounds are independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkenyl, C3-C9 cycloalkyl, C1-C6 haloalkyl, -CF3, -NH2, -NO2, -SH, -OH, -CH3COOH, -CH2OH, C1-C6 substituted alkoxy, (C3-C9)cycloalkyl, (C2-C6) alkynyl, aldehyde, and ester groups, as shown in I-1.

[0010]

[0011] Q is independently selected from the following structures:

[0012]

[0013] R2~R 11 Independently selected from hydrogen, halogen, C1-C8 substituted alkyl, cycloalkyl, alkenyl, alkoxy, substituted alkyl, substituted alkoxy, trifluoromethyl, trifluoromethoxy.

[0014] X1, X2, Y1, Y2, Z1, Z2, Z3, Z4, and Z5 are independently selected from C and N.

[0015] R 12 The compounds are independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkenyl, C3-C9 cycloalkyl, C1-C6 haloalkyl, -CF3, -NH2, -NO2, -SH, -OH, -CH3COOH, -CH2OH, C1-C6 substituted alkoxy, (C3-C9)cycloalkyl, (C2-C6) alkynyl, aldehyde, and ester groups, as shown in I-1.

[0016] Preferred compounds Z1 and Z5 are N, Z2 to Z4 are C, and compounds are shown in I-2;

[0017]

[0018] Q is independently selected from the following structures:

[0019]

[0020] R2~R 11 Independently selected from hydrogen, halogen, C1-C8 substituted alkyl, cycloalkyl, alkenyl, alkoxy, substituted alkyl, substituted alkoxy, trifluoromethyl, trifluoromethoxy.

[0021] X1, X2, Y1, and Y2 are independently selected from C and N.

[0022] R 12Independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkenyl, C3-C9 cycloalkyl, C1-C6 haloalkyl, -CF3, -NH2, -NO2, -SH, -OH, -CH3COOH, -CH2OH, C1-C6 substituted alkoxy, (C3-C9)cycloalkyl, (C2-C6) alkynyl, aldehyde, ester.

[0023] Further R 12 The following are selected independently: F, Cl, Br, methyl, ethyl, n-propyl, n-butyl, isopropyl, cyclopropyl, sec-butyl, cyclobutyl, cyclopentyl, isobutyl, 2-methylpentyl, allyl, 2-methylallyl, cyano, -NH2, -NO2, -SH, -OH, -CH3COOH, -CH2OH, -CH3COOCH3.

[0024] Further R 12 Selected from the following group:

[0025]

[0026] Further Q is selected from the following group:

[0027]

[0028] The further preferred compound structure is as follows:

[0029]

[0030]

[0031] This invention provides a method for synthesizing this type of molecule.

[0032] The preparation method and synthetic route 1 are as follows:

[0033]

[0034] (a) Starting material A reacts with halogen-substituted benzyl groups under alkaline conditions to generate intermediate B.

[0035] (b) Intermediate B is coupled with pinacol diboronic acid via Suzuki coupling to obtain intermediate C.

[0036] (c) Intermediate C is coupled with halogen-containing substituted phenyl, substituted pyridine or substituted pyrimidine via Suzuki coupling to obtain final product D.

[0037] The present invention describes a class of novel small molecule compounds that are pharmaceutically acceptable hydrates, solvates, crystal forms, or salts.

[0038] The use of a novel class of small molecule compounds described in this invention in the preparation of drugs for treating hDHODH-mediated diseases.

[0039] The hDHODH-mediated diseases described in this invention are selected from tumors, autoimmune diseases, and viral infections. Detailed Implementation

[0040] 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.

[0041] Example 1: Preparation of representative intermediate B1

[0042]

[0043] The starting material, 3-iodo-7-azaindole (1 equiv), was placed in a two-necked flask. DMF was added as a solvent, and the mixture was cooled and stirred at 0°C. Sodium hydride powder (1.1 equiv) was slowly added, and the reaction was continued at 0°C for 1 hour. Subsequently, 2-fluorobenzyl bromide (1.05 equiv) was added, and the mixture was stirred at room temperature for 4 hours after the addition was complete. After the reaction was monitored by TLC until complete, the mixture was extracted three times with ethyl acetate and water, and the organic phases were combined. The organic phase was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the mixture was concentrated under reduced pressure and purified by Biotage Isolera Prime with a 200-300 mesh silica gel column to give a pale yellow solid in 93% yield. 1H NMR(400MHz,DMSO)δ8.40–8.25(m,1H),7.82(s,1H),7.75–7.64(m,1H),7.45– 7.27(m,1H),7.27–7.15(m,2H),7.10(dd,J=11.8,6.4Hz,2H),5.56(s,2H).13C NMR(100MHz,DMSO)δ160.31(d,J=245.5Hz),147.31,144.42,133.54,130.24(d,J=8.1Hz),130.11 (d,J=4.0Hz),129.22,125.18,125.05(d,J=4.0Hz),122.92,117.37,115.88(d,J=20.9Hz),54.94.

[0044] Example 2: Preparation of representative intermediate C1

[0045]

[0046] Compound B1 (1 equiv) and pinacol diborate (1.1 equiv) were added to a two-necked flask, followed by dioxane and water (3:1) as solvents. The reaction system was purged twice with N2. Pd(dppf)Cl2·CH2Cl2 (0.1 equiv) and cesium carbonate (3 equiv) were then added under N2 conditions. After the addition was complete, the system was purged three more times with N2. Finally, the reaction was heated to 90°C for 8 hours under N2 protection. After the reaction was complete as monitored by TLC, the reaction solution was cooled to room temperature and extracted three times with dichloromethane and water. The organic phases were combined. The organic phase was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solution was concentrated under reduced pressure and purified using a Biotage Isolera Prime column equipped with a 200-300 mesh silica gel column to obtain a white solid in 76% yield. 1H NMR (400MHz, DMSO) δ8.30(d,J=4.2Hz,1H),8.14(d,J=7.6Hz,1H),7.91(s,1H),7.41–7.03(m,5H),5.58(s,2H),1.30(s,12H).13C NMR (100MHz, DMSO) δ160.40(d,J=245.4Hz),148.77,143.47,138.84,130.32,130.29,130.21,125.13(d,J= 5.8Hz), 125.04 (d, J = 5.6Hz), 124.17, 117.24, 115.98, 115.77, 83.27 (2C), 41.91 (d, J = 4.2Hz), 25.18 (4C).

[0047] Example 3: Preparation of representative end product D1

[0048]

[0049] Compound C1 (1 equivalent) and 5-cyclopropyl-2-chloropyrimidine (1.1 equivalent) were added to a two-necked flask, followed by dioxane and water (3:1) as solvent. The reaction system was purged twice with N2. Pd(dppf)Cl2·CH2Cl2 (0.1 equivalent) and cesium carbonate (3 equivalent) were then added under N2 conditions. After the addition was complete, the system was purged three more times with N2. Finally, the reaction was heated to 90°C for 8 hours under N2 protection. After the reaction was complete as monitored by TLC, the reaction solution was cooled to room temperature and extracted three times with dichloromethane and water. The organic phases were combined. The organic phase was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solution was concentrated under reduced pressure and purified using a Biotage Isolera Prime column equipped with a 200-300 mesh silica gel column to obtain a white solid in 82% yield. 1H NMR (400MHz, DMSO) δ8.79(d,J=7.9Hz,1H),8.56(d,J=6.2Hz,2H),8.44–8.27(m,2H),7.34(s,1H),7.31–7. 21(m,2H),7.21–7.09(m,2H),5.65(s,2H),1.94(s,1H),1.03(dd,J=5.4,2.9Hz,2H),0.94–0.69(m,2H).13C NMR (100MHz, DMSO) δ160.46 (d, J = 245.2Hz), 159.29 (d, J = 244.0Hz), 155.04 (2C), 148.25, 143.95, 143.95, 133.12, 131.61, 130.37 (d,J=3.3Hz),130.31,125.14(d,J=3.5Hz),124.92,118.74,117.80,115.94(d,J=20.9Hz),113.60,42.07,11.02,9.24(2C).HRMS m / z(ESI)calculated for C 21 H 17 FN4,345.1515,[M+H] + ,found:345.1505.

[0050] All final products were prepared according to the methods described above.

[0051] Compound D2

[0052]

[0053] 11H NMR (400 MHz, DMSO) δ 8.85 (dd, J = 8.1, 1.6 Hz, 1H), 8.71 (s, 2H), 8.67 (dd, J = 4.5, 1.6 Hz, 1H), 7.41 (dd, J = 8.1, 4.5 Hz, 1H), 7.39–7.30 (m, 1H), 7.29–7.19 (m, 2H), 7.15 (td, J = 7.6, 1.0 Hz, 1H), 5.86 (s, 2H), 2.09–1.94 (m, 1H), 1.09 (qd, J = 6.6, 3.4 Hz, 2H), 0.99–0.82 (m, 2H). 13 13C NMR (100 MHz, DMSO) δ 160.44 (d, J =

[0054] 246.1 Hz), 158.02, 155.28 (2C), 151.38, 149.87, 141.28, 136.05, 133.02, 130.74 (d, J = 3.8 Hz), 130.46 (d, J = 8.2 Hz), 125.10 (d, J = 3.1 Hz), 124.30 (d, J = 14.7 Hz), 119.06, 115.97 (d, J = 21.3 Hz), 114.77, 44.55, 11.17, 9.84 (2C). HRMS m / z (ESI) calculated for 346.1468, [M+H] + , found: 346.1462.

[0055] Compound D3

[0056]

[0057] 1 1H NMR (400 MHz, DMSO) δ 8.87 (dd, J = 8.1, 1.6 Hz, 1H), 8.81 (d, J = 0.4 Hz, 2H), 8.68 (dd, J = 4.5, 1.6 Hz, 1H), 7.42 (dd, J = 8.1, 4.5 Hz, 1H), 7.36 (s, 1H), 7.24 (t, J = 6.7 Hz, 2H), 7.19–7.12 (m, 1H), 5.86 (s, 2H), 2.35 (s, 3H). 1313C NMR (100 MHz, DMSO) δ 159.98 (d, J = 341.6 Hz), 158.07 (2C), 151.38, 149.92, 141.28, 133.09, 130.77 (d, J = 3.7 Hz), 130.50 (d, J = 8.1 Hz), 130.03, 125.14 (d, J = 3.3 Hz), 124.30 (d, J = 14.7 Hz), 119.12, 116.10, 115.89, 114.78. HRMS m / z (ESI) calculated for C 18 H 14 FN 5, 320.1311, [M+H] + , found: 320.1300.

[0058] Compound D4

[0059]

[0060] 1 1H NMR (400 MHz, DMSO) δ 8.99–8.77 (m, 3H), 8.72–8.64 (m, 1H), 7.49–7.33 (m, 2H), 7.24 (t, J = 8.5 Hz, 2H), 7.16 (t, J = 7.4 Hz, 1H), 5.87 (s, 2H), 2.70 (q, J = 7.3 Hz, 2H), 1.26 (t, J = 7.5 Hz, 3H). 13 13C NMR (100 MHz, DMSO) δ 160.43 (d, J = 245.6 Hz), 158.54 (2C), 157.39, 151.37, 149.90, 135.64, 133.06, 130.72 (d, J = 3.7 Hz), 130.47 (d, J = 8.1 Hz), 125.11 (d, J = 3.5 Hz), 124.30 (d, J = 14.8 Hz), 119.12, 116.08, 115.87, 114.80, 44.58 (d, J = 4.4 Hz), 23.20, 15.30. HRMS m / z (ESI)

[0061] calculated for C 19 H 16 FN 5, 334.1468, [M+H] + , found: 334.1465.

[0062] Compound D5

[0063] [[ID=

[0064] 1 1H NMR (400 MHz, DMSO) δ 9.08 (s, 2H), 8.94–8.84 (m, 1H), 8.69 (dd, J = 4.5, 1.6 Hz, 1H), 7.44 (dd, J = 8.1, 4.5 Hz, 1H), 7.37 (ddd, J = 15.4, 5.5, 1.8 Hz, 1H), 7.30–7.21 (m, 2H), 7.16 (td, J = 7.6, 1.0 Hz, 1H), 6.83 (dd, J = 17.8, 11.2 Hz, 1H), 6.20 (d, J = 17.8 Hz, 1H), 5.88 (s, 2H), 5.56 (d, J = 11.3 Hz, 1H). 13 13C NMR (100 MHz, DMSO) δ 160.46 (d, J = 246.0 Hz), 159.39 (2C), 155.43, 151.40, 149.99, 141.02, 133.06, 130.79 (d, J = 3.4 Hz), 130.52 (d, J = 8.2 Hz), 129.31, 125.13 (d, J = 3.5 Hz), 124.23 (d, J = 14.7 Hz), 119.20 (d, J = 18.4 Hz), 116.00 (d, J = 21.0 Hz), 114.94, 73.98, 44.68 (d, J = 4.2 Hz), 25.43. HRMS m / z (ESI) calculated for C 19 H 14 FN5, 332.1311, [M+H] + , found: 332.1303.

[0065] Compound D6 '

[0066]

[0067] 1 1H NMR (400 MHz, DMSO) δ 9.08 (d, J = 13.4 Hz, 2H), 8.93–8.83 (m, 1H), 8.69 (dd, J = 4.5, 1.6 Hz, 1H), 7.44 (dd, J = 8.1, 4.5 Hz, 1H), 7.37 (ddd, J = 15.4, 5.5, 1.8 Hz, 1H), 7.30–7.21 (m, 2H), 7.16 (td, J = 7.5, 1.1 Hz, 1H), 5.88 (s, 2H), 5.76 (d, J = 4.6 Hz, 1H), 5.33 (s, 1H), 2.19 (d, J = 8.8 Hz, 3H). 1313C NMR (100 MHz, DMSO) δ 160.50 (d, J = 237.6 Hz), 154.67 (2C), 151.39, 149.98, 141.00, 137.77, 137.77, 133.00, 131.86, 130.79 (d, J = 3.9 Hz), 130.52 (d, J = 8.2 Hz), 125.12 (d, J = 3.5 Hz), 124.23 (d, J = 14.7 Hz), 119.27, 116.19 (d, J = 19.0 Hz), 115.89, 114.94, 44.67 (d, J = 3.8 Hz), 21.02. HRMS m / z (ESI) calculated for C 20 H 16 FN5, 346.1468, [M+H] + , found: 346.1457.

[0068] Compound D7

[0069]

[0070] 1 1H NMR (400 MHz, DMSO) δ 8.91–8.86 (m, 1H), 8.82 (s, 2H), 8.68 (dd, J = 4.5, 1.5 Hz, 1H), 7.42 (dd, J = 8.1, 4.5 Hz, 1H), 7.37 (d, J = 7.0 Hz, 1H), 7.28–7.21 (m, 2H), 7.16 (d, J = 7.5 Hz, 1H), 5.87 (s, 2H), 2.63 (t, J = 7.6 Hz, 2H), 1.66 (dd, J = 15.0, 7.4 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H). 13 13C NMR (10 MHz, DMSO) δ 160.44 (d, J = 246.1 Hz), 158.59 (2C), 157.74, 151.37, 149.87, 141.27, 134.06, 133.05, 130.73 (d, J = 3.8 Hz), 130.46 (d, J = 8.1 Hz), 125.09 (d, J = 3.5 Hz), 124.30 (d, J = 14.7 Hz), 119.08, 115.96 (d, J = 21.0 Hz), 114.80, 44.57 (d, J = 4.1 Hz), 31.80, 23.86, 13.85. HRMS m / z (ESI) calculated for C 20 H 18 FN5, 348.1624, [M+H] +,found:348.1612.

[0071] Compound D8

[0072]

[0073] 1 H NMR(400MHz,DMSO)δ8.89(dd,J=8.1,1.6Hz,1H),8.79(s,2H),8.68(dd,J=4.5,1.6Hz,1H),7.43(dd,J=8.1,4.5Hz,1H),7.39–7.33(m,1H),7.29–7.20(m,2H),7.19–7.10(m,1H),5.87(s,2H),2.54(d,J=7.1Hz,2H),1.97–1.87(m,1H),0.91(d,J=6.6Hz,6H). 13 C NMR(100MHz,DMSO)δ160.46(d,J=246.2Hz),158.64,158.18(2C),151.40,149.91,141.28,133. = 08,133.05,130.78,130.48(d,J=8.0Hz),125.13,124.29(d,J=14. = 7Hz),119.12,115.98(d,J=20.2Hz),114.82,44.60(d,J=4. = 0Hz),38.82,29.58,22.30(2C).HRMS m / z(ESI)calculated for C 21 H 20 FN5,362.1781,[M+H] + ,found:362.1768.

[0074] Compound D9

[0075]

[0076] 1 H NMR(400MHz,DMSO)δ8.89(d,J=8.1Hz,1H),8.83(s,2H),8.68(d,J= = 4.3Hz,1H),7.49–7.32(m,2H),7.32–7.21(m,2H),7.16(t,J=7. = 4Hz,1H),6.28(s,1H),5.87(s,2H),1.95(d,J=12.9Hz,6H). 1313C NMR (100 MHz, DMSO) δ 160.46 (d, J = 246.1 Hz), 157.66, 156.93 (2C), 151.38, 149.93, 141.08 (d, J = 9.8 Hz), 133.07, 130.81 (d, J = 3.9 Hz), 130.51 (d, J = 8.0 Hz), 130.40, 125.12 (d, J = 3.5 Hz), 124.26 (d, J = 14.6 Hz), 119.17, 118.64, 115.98 (d, J = 21.0 Hz), 114.86, 100.00, 44.60, 27.36, 20.00 (2C). HRMS m / z (ESI) calculated for C 21 H 18 FN5, 360.1624, [M+H] + , found: 360.1618.

[0077] Compound D10

[0078]

[0079] 1 1H NMR (400 MHz, CDCl3) δ 8.96 (dd, J = 8.1, 1.3 Hz, 1H), 8.84 (s, 1H), 8.75 (s, 1H), 8.61 (dd, J = 4.5, 1.4 Hz, 1H), 7.32–7.27 (m, 1H), 7.26–7.17 (m, 1H), 7.14–6.86 (m, 3H), 5.97 (s, 2H), 3.61 (s, 1H), 2.55–1.85 (m, 5H). HRMS m / z (ESI)

[0080] calculated for C 21 H 18 FN5, 382.1444, [M+Na] + , found: 382.1438.

[0081] Compound D11

[0082] [[ID=3-1]]

[0083] 11H NMR (400 MHz, DMSO) δ 8.76 (d, J = 7.9 Hz, 1H), 8.44 (s, 1H), 8.33 (d, J = 4.5 Hz, 1H), 8.28 (s, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.38–7.29 (m, 1H), 7.24 (dd, J = 10.9, 7.2 Hz, 2H), 7.16–7.06 (m, 2H), 5.61 (s, 2H), 1.96 (s, 1H), 1.08–0.93 (m, 2H), 0.75 (d, J = 5.0 Hz, 2H). 13 13C NMR (100 MHz, DMSO) δ 160.35 (d, J = 245.2 Hz), 151.73, 148.20, 147.74, 143.74, 136.23, 133.25, 130.73, 130.20 (d, J = 8.0 Hz), 130.08 (d, J = 4.0 Hz), 128.61, 125.23 (d, J = 14.9 Hz), 125.11 (d, J = 3.4 Hz), 119.54, 118.42, 117.32, 115.89 (d, J = 20.9 Hz), 114.37, 41.80, 13.01, 9.51 (2C). HRMS m / z (ESI) calculated for C 22 18 18 18FN3, 344.1563, [M+H] + , found: 344.1555.

[0084] Compound D12

[0085]

[0086] 1 1H NMR (400 MHz, DMSO) δ 8.30 (ddd, J = 9.5, 6.3, 1.5 Hz, 2H), 7.92 (s, 1H), 7.66–7.51 (m, 2H), 7.39–7.29 (m, 1H), 7.27–7.04 (m, 6H), 5.59 (s, 2H), 1.99–1.90 (m, 1H), 1.04–0.91 (m, 2H), 0.79–0.64 (m, 2H). 1313C NMR (100 MHz, DMSO) δ 160.33 (d, J = 245.2 Hz), 148.03, 143.53, 141.90, 131.89, 130.13 (d, J = 8.1 Hz), 130.05 (d, J = 4.0 Hz), 128.55, 126.68, 126.56, 126.42, 125.38 (d, J = 14.8 Hz), 125.11, 118.14, 116.94, 115.87 (d, J = 21.0 Hz), 114.60, 41.66, 15.31, 9.76 (2C). HRMS m / z (ESI) calculated for C 23 H 19 FN2, 343.161, [M+H] + , found:

[0087] Compound D13

[0088]

[0089] 1 1H NMR (400 MHz, DMSO) δ 9.00 (s, 2H), 8.48–8.30 (m, 2H), 8.18 (s, 1H), 7.40–7.29 (m, 1H), 7.23 (dd, J = 9.7, 4.7 Hz, 2H), 7.13 (d, J = 4.2 Hz, 2H), 5.61 (s, 2H), 2.24 (dd, J = 7.4, 4.9 Hz, 1H), 1.16–0.92 (m, 4H). 13 13C NMR (100 MHz, DMSO) δ

[0090] 168.68, 160.34 (d, J = 245.4 Hz), 154.29 (2C), 147.99, 144.01, 130.22 (d, J = 8.0 Hz), 130.10 (d, J = 4.0 Hz), 128.77, 127.75, 125.73, 125.14 (d, J = 3.5 Hz), 125.05 (d, J = 7.8 Hz), 117.78, 117.37, 115.89 (d, J = 20.9 Hz), 108.18, 41.86 (d, J =4.5 Hz), 18.15, 10.65 (2C). HRMS m / z (ESI) calculated for C 21 H 17 FN4, 345.1515, [M+H] + , found: 345.1504.

[0091] Compound D14

[0092]

[0093] 1 H NMR (400 MHz, DMSO) δ 8.97 (d, J = 1.3 Hz, 1H), 8.71 (dd, J = 7.9, 1.5 Hz, 1H), 8.60 (d, J = 1.3 Hz, 1H), 8.43 (s, 1H), 8.36 (dd, J = 4.6, 1.4 Hz, 1H), 7.34 (dd, J = 5.7, 2.9 Hz, 1H), 7.29–7.20 (m, 2H), 7.13 (dd, J = 5.1, 3.0 Hz, 2H), 5.63 (s, 2H), 2.24–2.15 (m, 1H), 1.11–1.01 (m, 2H), 1.00–0.88 (m, 2H). 13 C NMR (100 MHz, DMSO) δ 160.35 (d, J = 245.3 Hz), 154.13, 148.17, 147.24, 144.12, 142.46, 140.81, 130.56, 130.26 (d, J = 8.2 Hz), 130.07 (d, J = 3.9 Hz), 129.19, 125.14 (d, J = 3.4 Hz), 124.98, 118.24, 117.65, 115.92 (d, J = 20.9 Hz), 111.49, 41.97 (d, J = 3.9 Hz), 14.50, 10.13 (2C). HRMS m / z (ESI) calculated for C 21 H 17 FN4, 345.1515, [M + H] + , found: 345.1504.

[0094] Compound D15

[0095]

[0096] 1 H NMR (400 MHz, DMSO) δ 8.30 (t, J = 7.3 Hz, 2H), 7.82 (s, 1H), 7.33 (s, 1H), 7.28–7.17 (m, 2H), 7.16–7.03 (m, 3H), 6.95 (s, 1H), 6.83 (d, J = 7.5 Hz, 1H), 6.49 (d, J = 7.9 Hz, 1H), 5.59 (s, 2H), 5.13 (s, 2H).<00000¹³C NMR (100 MHz, DMSO) δ 160.36 (d, J = 245.3 Hz), 149.62, 148.03, 143.45, 135.26, 130.13 (d, J = 10.9 Hz), 130.113, 129.88, 128.66, 126.39, 125.42 (d, J = 15.0 Hz), 125.11, 118.26, 116.80, 115.87 (d, J = 21.0 Hz), 115.41, 114.58, 112.43, 112.33, 41.64. HRMS m / z (ESI) calculated for C 20 H 16 FN₃, 318.1406, [M+H] + , found: 318.1398.

[0097] Compound D16

[0098]

[0099] 1 ¹H NMR (400 MHz, DMSO) δ 8.57–8.31 (m, 2H), 8.30–8.12 (m, 2H), 8.12–7.94 (m, 1H), 7.83–7.52 (m, 2H), 7.46–6.99 (m, 5H), 5.61 (s, 2H). 13 ¹³C NMR (100 MHz, DMSO) δ 160.37 (d, J = 245.4 Hz), 148.05, 143.91, 136.23, 131.10 (d, J = 3.5 Hz), 130.58 (d, J = 4.6 Hz), 130.26 (d, J = 3.3 Hz), 130.20, 129.75, 128.67 (d, J = 4.3 Hz), 128.37 (d, J = 4.2 Hz), 125.15, 125.08 (d, J = 2.5 Hz), 125.00, 119.39, 117.73, 117.39, 115.89 (d, J = 20.9 Hz), 112.61, 112.57, 41.81 (d, J = 4.1 Hz). HRMS m / z (ESI) calculated for C 21 H 14 FN₃, 328.125, [M+H] + , found: 328.1239.

[0100] Compound D17

[0101]

[0102] 1 1H NMR (400 MHz, DMSO) δ 8.35 (dd, J = 11.9, 6.2 Hz, 2H), 8.25 (s, 1H), 8.15 (s, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.34 (d, J = 5.1 Hz, 1H), 7.28–7.20 (m, 2H), 7.13 (d, J = 4.7 Hz, 2H), 5.66 (d, J = 29.4 Hz, 2H), 3.90 (s, 3H). 13 13C NMR (100 MHz, DMSO) δ 162.94 (d, J = 769.3 Hz), 148.08, 143.84, 135.45, 131.39, 130.85, 130.21, 130.10 (d, J = 5.7 Hz), 130.01, 128.34, 127.86, 127.03, 126.98, 125.26 (d, J = 14.9 Hz), 125.13, 117.95, 117.32, 115.98, 115.77, 113.46, 52.7(2), 41.81 (d, J = 4.1 Hz). HRMS m / z (ESI) calculated for C 22 1 17 19FN2O2, 361.1352, [M + H] + , found: 361.1218.

[0103] Compound D18

[0104]

[0105] 1 1H NMR (400 MHz, DMSO) δ 13.07 (s, 1H), 8.34 (dd, J = 14.3, 6.2 Hz, 2H), 8.27 (s, 1H), 8.13 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.33 (dd, J = 7.6, 3.4 Hz, 1H), 7.29–7.17 (m, 2H), 7.13 (d, J = 4.8 Hz, 2H), 5.63 (s, 2H). 1313C NMR (100 MHz, DMSO) δ 167.85, 160.34 (d, J = 245.3 Hz), 148.08, 143.80, 135.25, 131.97, 130.96, 130.15 (d, J = 9.4 Hz), 130.06, 129.80, 128.33, 127.70, 127.22, 125.27 (d, J = 14.8 Hz), 125.10 (d, J = 3.3 Hz), 117.98, 117.27, 115.97, 115.76, 113.65, 41.81 (d, J = 4.2 Hz). HRMS m / z (ESI) calculated for C 21 H 15 FN2O2, 347.1196, [M+H] + , found: 347.1183.

[0106] Compound D19

[0107]

[0108] 1 1H NMR (400 MHz, DMSO) δ 8.29 (t, J = 6.5 Hz, 2H), 7.77 (s, 1H), 7.33 (s, 1H), 7.28–7.16 (m, 2H), 7.11 (d, J = 5.7 Hz, 2H), 7.01 (s, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.79 (d, J = 7.1 Hz, 1H), 5.58 (s, 2H), 5.03 (s, 2H), 1.69 (s, 1H), 0.86 (d, J = 7.6 Hz, 2H), 0.50 (d, J = 4.4 Hz, 2H). 13 13C NMR (100 MHz, DMSO) δ 160.36 (d, J = 245.5 Hz), 148.52, 148.01, 143.41, 132.91, 130.18, 130.10, 128.67, 127.48, 126.08, 125.10 (d, J = 2.9 Hz), 124.30, 118.28, 116.73, 115.98, 115.77, 115.34, 114.68, 112.12, 41.64 (d, J = 4.5 Hz), 11.27, 6.18 (2C). HRMS m / z (ESI) calculated for C 23 H 20 FN3, 358.1719, [M+H] + , found: 358.1711.

[0109] Compound D20

[0110]

[0111] 1 H NMR (400MHz, DMSO) δ12.96(s,1H),8.38–8.31(m,1H),8.28(d,J=7.9Hz,1H),8.03(d,J=12.2Hz,2H),7.76(d,J=8.1Hz,1H),7.34(d,J=6.0Hz ,1H),7.23(t,J=7.3Hz,2H),7.09(dd,J=18.7,6.3Hz,3H),5.61(s,2H),2.69(d,J=3.5Hz,1H),0.99(d,J=8.1Hz,2H),0.72(d,J=4.8Hz,2H). 13 C NMR(100MHz,DMSO)δ169.79,160.32(d,J=245.0Hz),148.03,143.69,141.71, 133.11,131.79,130.13(d,J=8.2Hz),130.04(d,J=4.0Hz),129.64,128.32,12 7.40,127.22,125.87,125.31(d,J=14.9Hz),125.09(d,J=3.2Hz),118.01,117 .14,115.86(d,J=21.0Hz),113.57,41.75(d,J=4.4Hz),12.98,9.68(2C).HRMS m / z(ESI) calculated for C 24 H 19 FN₂O₂, 387.1509, [M+H] + ,found:387.1498.

[0112] Compound D21

[0113]

[0114] 11H NMR (400 MHz, DMSO) δ 8.32 (s, 2H), 7.91 (s, 1H), 7.73 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 4.9 Hz, 1H), 7.23 (t, J = 8.8 Hz, 2H), 7.11 (s, 2H), 7.02 (d, J = 7.7 Hz, 1H), 5.60 (s, 2H), 5.17 (d, J = 5.2 Hz, 1H), 4.75 (d, J = 5.2 Hz, 2H), 1.97 (s, 1H), 0.91 (d, J = 7.1 Hz, 2H), 0.63 (d, J = 3.5 Hz, 2H). 13 13C NMR (100 MHz, DMSO) δ 160.35 (d, J = 245.2 Hz), 148.06, 143.54, 142.28, 138.03, 131.95, 130.13 (d, J = 8.2 Hz), 130.05 (d, J = 4.2 Hz), 128.56, 126.49, 125.68, 125.42 (d, J = 14.6 Hz), 125.09 (d, J = 3.5 Hz), 124.94, 124.69, 118.22, 116.92, 115.87 (d, J = 21.0 Hz), 114.87, 61.15, 41.70 (d, J = 4.3 Hz), 19.03, 12.03, 7.50 (2C). HRMS m / z (ESI) calculated for C 24 H 21 FN2O, 373.1716, [M + H] + , found: 373.1707.

[0115] Compound D22

[0116]

[0117] 1 1H NMR (400 MHz, DMSO) δ 8.43–8.30 (m, 2H), 8.13 (s, 1H), 8.06 (s, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.34 (d, J = 6.7 Hz, 1H), 7.24 (dd, J = 11.2,​13C NMR (100 MHz, DMSO) δ 160.36 (d, J = 245.4 Hz), 148.00, 144.86, 143.81, 133.08, 131.36, 130.23 (d, J = 4.3 Hz), 130.17, 129.98, 128.58, 127.88, 125.59, 125.15 (d, J = 10.3 Hz), 125.06, 118.67, 117.75, 117.27, 115.88 (d, J = 21.0 Hz), 112.92, 112.49, 41.76 (d, J = 4.3 Hz), 14.09, 9.89 (2C). HRMS m / z (ESI) calculated for C 24 H 18 FN3, 368.1563, [M+H] + , found: 368.1554.

[0118] Compound D23

[0119]

[0120] 1 1H NMR (400 MHz, DMSO) δ 8.56 (d, J = 8.0 Hz, 1H), 8.37 (d, J = 4.5 Hz, 1H), 8.22 (s, 1H), 7.83 (s, 1H), 7.43–7.05 (m, 6H), 6.75 (s, 2H), 5.62 (s, 2H), 1.65 (s, 1H), 0.92 (d, J = 8.1 Hz, 2H), 0.59 (d, J = 5.1 Hz, 2H). 13 13C NMR (100 MHz, DMSO) δ 160.44 (d, J = 245.2 Hz), 154.47, 151.92, 148.08, 147.75, 143.43, 130.30, 130.23 (d, J = 5.9 Hz), 127.72, 125.38, 125.23, 125.11 (d, J = 3.5 Hz), 119.14, 118.46, 116.99, 116.01, 115.80, 115.19, 103.82, 8.99, 5.53 (2C). HRMS m / z (ESI) calculated for C 22 H 19 FN4, 359.1672, [M+H] + , found: 359.1659.

[0121] Compound D24

[0122]

[0123] 1 H NMR(400MHz,DMSO)δ8.90(dd,J=7.9,1.3Hz,1H),8.32(dd,J=4.5,1.2Hz,1H),8.10(s,1H),7.38–7.27(m,1H),7.28–7.16(m,2H),7.18–7.04(m,3H),6.97(d,J=7.6Hz,1H),5.87(s,2H),5.61(s,2H),1.80–1.55(m,1H),0.99–0.65(m,2H),0.61–0.39(m,2H). 13 C NMR(101MHz,DMSO)δ160.38(d,J=245.3Hz),159.01,150.05,148.16,143.48,134.69,131.22,130.18,130.07(d,J=4.2Hz),127.88,125.35(d,J=14.9Hz),125.06(d,J=3.4Hz),118.65,118.05,117.01,115.86(d,J=21.0Hz),114.97,108.36,41.74(d,J=3.9Hz),11.09,6.24(2C).HRMS m / z(ESI)calculated for C 22 H 19 FN4,358.1594,[M+H] + ,found:359.1662.

[0124] Compound D25

[0125]

[0126] 1 H NMR(400MHz,DMSO)δ8.88(d,J=7.9Hz,1H),8.38(dd,J=8.4,2.9Hz,2H),8.19(s,1H),7.48–7.30(m,2H),7.29–7.21(m,2H),7.16–7.08(m,2H),5.67(s,2H),2.03(s,1H),1.08–0.99(m,2H),0.90–0.71(m,2H). 1313C NMR(100MHz,DMSO)δ160.40(d,J=245.1Hz),156.50(d,J=257.3Hz),147.61,144.14,143.73(d,J=3.6Hz),139.98(d,J=12.0Hz),138.91(d,J=2.7Hz),131.42,130.45(d,J=17.5Hz),130.19(d,J=8.2Hz),130.03(d,J=4.0Hz),125.17(d,J=18.0Hz),119.71(d,J=19.9Hz),118.88,117.51,115.99,115.78,109.03(d,J=6.5Hz),41.98,12.72,10.11(2C).HRMS m / z(ESI)calculated for C 22 H 17 F2N3,362.1469,[M+H] + ,found:362.1460.

[0127] Compound D26

[0128]

[0129] 1 1H NMR(400MHz,DMSO)δ8.68(s,1H),8.37(dd,J=14.8,6.0Hz,2H),8.17(s,1H),7.93(d,J=11.5Hz,1H),7.40–7.30(m,1H),7.28–7.17(m,2H),7.13(d,J=4.7Hz,2H),5.60(s,2H),2.38–2.23(m,1H),1.03(d,J=6.1Hz,4H). 1313C NMR (100 MHz, DMSO) δ 160.34 (d, J = 245.4 Hz), 158.03 (d, J = 253.2 Hz), 147.98, 147.17 (d, J = 14.6 Hz), 143.94, 142.74 (d, J = 4.4 Hz), 130.23 (d, J = 8.3 Hz), 130.13 (d, J = 3.8 Hz), 129.45 (d, J = 4.0 Hz), 128.80, 128.20, 125.14 (d, J = 2.8 Hz), 125.05 (d, J = 8.2 Hz), 119.66 (d, J = 19.7 Hz), 117.81, 117.38, 116.00, 115.90 (d, J = 21.0 Hz), 41.85, 10.32, 9.38 (2C). HRMS m / z (ESI) calculated for C 22 H 17 F2N3, 362.1469, [M + H] + , found: 362.1459.

[0130] Compound D27

[0131]

[0132] 1 1H NMR (400 MHz, DMSO) δ 8.81 (d, J = 7.9 Hz, 1H), 8.55 (d, J = 0.8 Hz, 2H), 8.35 (d, J = 4.6 Hz, 1H), 8.23 (s, 1H), 7.28 (dd, J = 4.9, 3.0 Hz, 1H), 7.21 (d, J = 7.3 Hz, 2H), 7.13 (d, J = 7.1 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 5.57 (s, 2H), 2.33 (s, 3H), 2.08–1.76 (m, 1H), 1.02 (dd, J = 5.4, 2.9 Hz, 2H), 0.84 (d, J = 4.9 Hz, 2H). 13 13C NMR (100 MHz, DMSO) δ 160.56, 155.02 (2C), 148.42, 143.86, 136.20, 136.14, 133.03, 131.41, 130.89, 130.75, 128.05, 126.59, 118.66, 117.73, 113.50, 45.88, 19.22, 11.01, 9.22 (2C). HRMS m / z (ESI) calculated for C 22 H 20 N4, 341.1766, [M + H]+ , found: 341.1757.

[0133] Compound D28

[0134]

[0135] 1 H NMR (400 MHz, DMSO) δ 8.82 (d, J = 7.8 Hz, 1H), 8.57 (s, 2H), 8.47–8.21 (m, 2H), 7.53 (d, J = 7.8 Hz, 1H), 7.29 (ddd, J = 21.5, 17.0, 7.1 Hz, 3H), 6.92 (d, J = 7.5 Hz, 1H), 5.68 (s, 2H), 1.93 (d, J = 4.9 Hz, 1H), 1.11–0.92 (m, 2H), 0.92–0.76 (m, 2H). 13 C NMR (100 MHz, DMSO) δ 160.51, 155.02 (2C), 148.33, 143.99, 135.49, 133.13, 132.40, 131.67, 130.97, 129.95, 129.85, 129.38, 128.​​​​​​​​​​​​​​​​​C NMR(100MHz,DMSO)δ160.50,155.05(2C),148.32,144.02,137.05,133.22,131.65,130.99,13 0.10,129.28,128.61,128.05,122.57,118.78,117.91,113.72,48.28,11.03,9.27(2C).HRMS m / z(ESI)calculated forC 21 H 17 BrN4, 405.0715, [M+H] + ,found:405.0706.

[0139] Compound D30

[0140]

[0141] 1 H NMR(400MHz, DMSO)δ8.80(dd,J=7.9,1.2Hz,1H),8.57(s,2H),8.39–8.27(m,2H),7.44(d,J=7.0Hz,2H),7.3 7–7.24(m,2H),7.12(d,J=7.5Hz,1H),5.67(s,2H),2.02–1.86(m,1H),1.10–0.95(m,2H),0.92–0.78(m,2H). 13 C NMR(101MHz,DMSO)δ160.49,155.06(2C),,148.30,146.63,144.01,133.18,131.65,130.91,130.57,130 .12(2C),128.19,121.06,120.68(q,J=257.3Hz),118.70,117.85,113.72,42.82,11.02,9.25(2C).HRMS m / z(ESI)calculated for C 22 H 17 F3N4O, 411.1432, [M+H] + ,found:411.1424.

[0142] Compound D31

[0143]

[0144] 11H NMR (400 MHz, DMSO) δ 8.79 (d, J = 7.9 Hz, 1H), 8.56 (d, J = 0.9 Hz, 2H), 8.46 (s, 1H), 8.40–8.28 (m, 1H), 7.40–7.22 (m, 6H), 5.58 (s, 2H), 1.93 (dd, J = 8.2, 3.3 Hz, 1H), 1.02 (d, J = 8.1 Hz, 2H), 0.93–0.71 (m, 2H). 13 13C NMR (100 MHz, DMSO) δ 160.61, 155.03 (2C), 148.28, 143.87, 138.38, 133.02, 131.73, 130.83, 129.08 (2C), 128.08 (2C), 128.00, 118.81, 117.68, 113.41, 47.92, 11.02, 9.22 (2C). HRMS m / z (ESI) calculated for C 21 H 18 N4, 327.1609, [M+H] + , found: 327.1598.

[0145] Compound D32

[0146] <00005​​​​​​​​​​​H NMR (400MHz, DMSO) δ8.80(dd,J=7.9,1.6Hz,1H),8.57(s,2H),8.53(s,1H),8.37(dd,J=4.7,1.6Hz,1H),7.59(d,J=1.6Hz,1H),7.49–7.43( m,1H),7.30(ddd,J=12.1,7.8,6.3Hz,3H),5.58(s,2H),1.95(tt,J=8.5,5.1Hz,1H),1.03(ddd,J=8.4,6.5,4.3Hz,2H),0.91–0.78(m,2H).

[0151] Compound D34

[0152]

[0153] 1 H NMR (400MHz, DMSO) δ8.83–8.76(m,1H),8.57(s,2H),8.52(s,1H),8.40–8.32(m,1H),7.44(s,1H),7.35(d,J=6. 3Hz, 2H), 7.28 (dd, J=7.8, 4.7Hz, 2H), 5.59 (s, 2H), 1.94 (d, J=4.9Hz, 1H), 1.11–0.97 (m, 2H), 0.92–0.76 (m, 2H). 13 C NMR (100MHz, DMSO) δ160.54,155.04(2C),148.18,143.98,140.88,133.61,133.12,131.76,130.98(d,J=10 .8Hz),128.00,127.89,126.75,118.83,117.81,113.60,47.36,11.02,9.24(2C).HRMSm / z(ESI)calculated for C 21 H 17 ClN4, 361.1220, [M+H] + ,found:361.1210.

[0154] Compound D35

[0155]

[0156] 1H NMR (400MHz, DMSO) δ8.79(dd,J=7.9,1.3Hz,1H),8.56(s,2H),8.46(s,1H),8.37(dd,J=4.5,1.2Hz,1H),7.39–7.12(m,2H),6. 96(s,1H),6.93–6.74(m,2H),5.55(s,2H),3.71(s,3H),2.07–1.81(m,1H),1.03(qd,J=6.2,2.8Hz,2H),0.85(q,J=4.8Hz,2H).

[0157] Compound D36

[0158]

[0159] H NMR (400MHz, DMSO) δ8.80(t,J=8.2Hz,1H),8.59(d,J=10.3Hz,2H),8.55(s,1H),8.35(t,J=8.5Hz,1H),7.86(s,1H),7.76(d,J=7.6Hz,1H), 7.65(d,J=7.8Hz,1H),7.54(t,J=7.7Hz,1H),7.33–7.23(m,1H),1.97(tdd,J=13.4,8.5,5.1Hz,1H),1.13–0.98(m,2H),0.91–0.79(m,2H).

[0160] Compound D37

[0161]

[0162] 1 H NMR (400MHz, DMSO) δ8.80(d,J=7.9Hz,1H),8.57(d,J=2.2Hz,2H),8.50(d,J=1.6Hz,1H),8.41–8.31(m,1H) ,7.38(s,4H),7.33–7.23(m,1H),5.59(s,2H),1.94(d,J=3.2Hz,1H),1.11–0.98(m,2H),0.91–0.79(m,2H).

[0163] Compound D38

[0164]

[0165] 11H NMR (400 MHz, DMSO) δ 8.76 (d, J = 7.9 Hz, 1H), 8.56 (s, 2H), 8.36 (d, J = 4.6 Hz, 1H), 8.23 (s, 1H), 7.55–7.40 (m, 1H), 7.34–7.23 (m, 1H), 7.16 (t, J = 7.9 Hz, 2H), 5.66 (s, 2H), 2.03–1.85 (m, 1H), 1.08–0.94 (m, 2H), 0.85 (t, J = 4.7 Hz, 2H). 13 13C NMR (100 MHz, DMSO) δ 162.70 (d, J = 7.8 Hz), 160.38, 160.23 (d, J = 7.8 Hz), 155.04 (2C), 148.15, 143.97, 133.16, 131.47 (t, J = 10.3 Hz), 131.00, 130.79, 118.55, 117.80, 113.68, 113.13 (t, J = 19.1 Hz), 112.49 (d, J = 6.1 Hz), 112.30 (d, J = 6.0 Hz), 36.22, 11.01, 9.24 (2C). HRMS m / z (ESI) calculated for C 21 H 16 F2N4, 363.1421, [M+H] + , found: 393.1409.

[0166] Compound D39

[0167]

[0168] 1 1H NMR (400 MHz, DMSO) δ 8.90–8.67 (m, 1H), 8.54 (d, J = 1.9 Hz, 2H), 8.45–8.27 (m, 1H), 8.05 (s, 1H), 7.55–7.39 (m, 2H), 7.39–7.21 (m, 2H), 5.70 (s, 2H), 2.00–1.78 (m, 1H), 1.09–0.91 (m, 2H), 0.91–0.69 (m, 2H).

[0169] Compound D40

[0170]

[0171] 1H NMR (400MHz, DMSO) δ8.76(d,J=7.9Hz,1H),8.55(d,J=9.4Hz,2H),8.41–8.30(m,1H),8.26(s,1H ),7.37–7.15(m,3H),5.61(s,2H),2.00–1.83(m,1H),1.03(d,J=8.1Hz,2H),0.92–0.68(m,2H).

[0172] Compound D41

[0173]

[0174] 1 H NMR (400MHz, DMSO) δ8.77(d,J=7.9Hz,1H),8.56(d,J=5.2Hz,2H),8.39–8.34(m,1H),8.32(s,1H),7.59–7.43(m,1H), 7.27(dd,J=7.9,4.7Hz,1H),7.23–7.12(m,1H),5.70(s,2H),1.99–1.89(m,1H),1.10–0.99(m,2H),0.90–0.79(m,2H).

[0175] Compound D42

[0176]

[0177] 1 H NMR (400MHz, DMSO) δ8.82(d,J=7.9Hz,1H),8.53(s,2H),8.42(d,J=2.6Hz,1H),8.31–8.21(m,2H),8.02–7.94(m,1H),7.91(d,J=8.2Hz,1H ),7.62–7.51(m,2H),7.46(t,J=7.7Hz,1H),7.34–7.23(m,2H),6.06(s,2H),1.90(d,J=5.0Hz,1H),1.04–0.96(m,2H),0.85–0.79(m,2H).

[0178] Compound D43

[0179]

[0180] 11H NMR (400 MHz, DMSO) δ 8.81 (d, J = 7.9 Hz, 1H), 8.56 (d, J = 0.8 Hz, 2H), 8.51 (s, 1H), 8.38 (d, J = 4.6 Hz, 1H), 8.00–7.79 (m, 4H), 7.50 (dd, J = 11.0, 6.5 Hz, 3H), 7.29 (ddd, J = 7.8, 4.7, 1.0 Hz, 1H), 5.75 (s, 2H), 1.93 (s, 1H), 1.02 (d, J = 8.1 Hz, 2H), 0.84 (d, J = 4.9 Hz, 2H).

[0181] Compound D44

[0182]

[0183] 1 1H NMR (400 MHz, DMSO) δ 8.77 (d, J = 7.6 Hz, 1H), 8.57 (s, 2H), 8.33 (s, 2H), 7.24 (dd, J = 6.9, 4.8 Hz, 1H), 4.20 (d, J = 6.9 Hz, 2H), 1.95 (s, 2H), 1.56 (dd, J = 39.2, 17.9 Hz, 5H), 1.20–0.95 (m, 7H), 0.85 (d, J = 4.3 Hz, 2H).

[0184] Compound D45

[0185]

[0186] 1 1H NMR (400 MHz, DMSO) δ 8.82 (d, J = 7.9 Hz, 1H), 8.59 (s, 2H), 8.54 (s, 1H), 8.51 (d, J = 4.7 Hz, 2H), 8.34 (d, J = 4.5 Hz, 1H), 7.29 (dd, J = 7.8, 4.7 Hz, 1H), 7.21 (d, J = 4.9 Hz, 2H), 5.65 (s, 2H), 1.95 (dd, J = 8.6, 3.8 Hz, 1H), 1.14–0.95 (m, 2H), 0.86 (q, J = 5.0 Hz, 2H).

[0187] Compound D46

[0188]

[0189] 1H NMR (400MHz, DMSO) δ8.86–8.71(m,1H),8.55(s,2H),8.43–8.25(m,2H),7.41–7.05(m,6H),4.60(t,J =7.2Hz,2H),3.20(t,J=7.2Hz,2H),2.05–1.74(m,1H),1.02(d,J=8.2Hz,2H),0.85(d,J=5.0Hz,2H).

[0190] Compound D47

[0191]

[0192] 1 H NMR (400MHz, DMSO) δ8.78(d,J=7.8Hz,1H),8.57(s,2H),8.42(s,1H),8.34(d,J=4.3Hz,1H),7.32–7.23(m,3H),7.22–7.14(m,4H ),4.39(t,J=7.0Hz,2H),2.65–2.57(m,2H),2.29–2.12(m,2H),2.05–1.89(m,1H),1.03(d,J=6.6Hz,2H),0.86(d,J=5.2Hz,2H).

[0193] Compound D48

[0194]

[0195] 1 H NMR (400MHz, DMSO) δ8.76(dd,J=7.9,1.5Hz,1H),8.56(s,2H),8.38(s,1H),8.33(dd,J=4.6,1.5Hz,1H),7.24(dd,J=7.9,4.7Hz,1H),4.37(t,J=7.3Hz, 2H),1.94(s,1H),1.75(dd,J=14.3,6.5Hz,4H),1.70–1.48(m,3H),1.11(d, J=7.6Hz,4H),1.07–0.98(m,2H),0.95(s,2H),0.85(dd,J=5.0,1.8Hz,2H).

[0196] Compound D49

[0197]

[0198] 11H NMR (400 MHz, DMSO) δ 8.75 (dd, J = 7.9, 1.4 Hz, 1H), 8.55 (s, 2H), 8.33 (dd, J = 4.6, 1.3 Hz, 1H), 8.28 (s, 1H), 7.28–7.18 (m, 3H), 7.13 (d, J = 9.9 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 4.61 (t, J = 7.2 Hz, 2H), 3.24 (t, J = 7.1 Hz, 2H), 2.05–1.84 (m, 1H), 1.15–0.97 (m, 2H), 0.93–0.75 (m, 2H).

[0199] Compound D50

[0200] 1-(2-chlorophenethyl)-3-(5-cyclopropylpyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine (s32)

[0201]

[0202] 1 1H NMR (400 MHz, DMSO) δ 8.75 (dd, J = 7.9, 1.6 Hz, 1H), 8.55 (s, 2H), 8.33 (dd, J = 4.6, 1.5 Hz, 1H), 8.26 (s, 1H), July 4, 2023 7.44–7.38 (m, 1H), 7.23 (ddd, J = 6.5, 3.7, 1.8 Hz, 4H), 4.62 (t, J = 7.2 Hz, 2H), 3.31 (d, J = 7.1 Hz, 2H), 1.99–1.87 (m, 1H), 1.11–

[0203] 0.98 (m, 2H), 0.90–0.76 (m, 2H).

[0204] Compound D51

[0205]

[0206] 11H NMR (400 MHz, DMSO) δ 8.76 (d, J = 7.9 Hz, 1H), 8.55 (s, 2H), 8.35 (d, J = 5.6 Hz, 2H), 7.36–7.19 (m, 2H), 7.09 (d, J = 10.1 Hz, 1H), 7.06–6.94 (m, 2H), 4.62 (t, J = 7.2 Hz, 2H), 3.23 (t, J = 7.2 Hz, 2H), 2.00–1.83 (m, 1H), 1.11–0.96 (m, 2H), 0.85 (q, J = 4.9 Hz, 2H).

[0207] Compound D52

[0208]

[0209] 1 1H NMR (400 MHz, DMSO) δ 9.04–8.80 (m, 1H), 8.35 (dd, J = 3.1, 1.5 Hz, 1H), 8.05 (s, 1H), 7.90 (s, 1H), 7.54–7.39 (m, 1H), �.29–7.07 (m, 3H), 6.78 (s, 2H), 5.63 (s, 2H), 1.63 (dd, J = 8.5, 3.6 Hz, 1H), 0.94–0.73 (m, 2H), 0.57 (d, J = 5.1 Hz, 2H).

[0210] Compound D53

[0211]

[0212] 1 1H NMR (400 MHz, DMSO) δ 8.91 (d, J = 7.9 Hz, 1H), 8.45–8.28 (m, 1H), 7.87 (d, J = 11.4 Hz, 2H), 7.58–7.39 (m, 2H), 7.35 (t, J = 8.9 Hz, 1H), 7.29–7.17 (m, 1H), 6.75 (s, 2H), 5.68 (s, 2H), 1.69–1.51 (m, 1H), 0.86 (d, J = 8.0 Hz, 2H), 0.55 (d, J = 5.0 Hz, 2H). 13C NMR (100MHz, DMSO) δ 163.47, 162.00 (d, J = 249.8Hz), 160.12, 152.31, 148.21, 143.63, 135.46 (d, J = 5.1Hz), 131.83 (d, J = 9.9Hz), 131. 41,129.11,126.45(d,J=3.2Hz),122.71(d,J=17.6Hz),118.86,117.43,115.48(d,J=22.2Hz),115.00,114.70,8.76,5.62(2C).HRMS m / z(ESI)calculated for C 21 H 17 ClFN5,394.1235,[M+H] + ,found:394.1225.

[0213] Assay of the inhibitory activity of the compound against hDHODH enzyme

[0214] The Assay Buffer was prepared as follows: 100 mM HEPES buffer, 150 mM NaCl, 10% glycerol, 0.1% Triton X-100, pH adjusted to 8.0, and MILIQ water added to bring the volume to a final volume. The total volume of the enzyme activity assay was 60 μL. The specific steps were as follows: 1 μL of the small molecule (final concentration 1 μM) was added to a 96-well microplate, followed by 39 μL of a mixed solution containing hDHODH purified protein solution (final concentration 40 nM), sodium 2,6-dichlorophenolindophenol (final concentration 100 μM), and CoQ (final concentration 20 μM). After addition, the plate was incubated at 37°C in the dark with shaking for 30 min. After incubation, 20 μL of DHO (final concentration 200 μM) was added to each well, and the plate was immediately analyzed using a microplate reader. The assay program was: kinetic assay; wavelength 600 nm, total duration 10 min, assay every 20 s. The group without inhibitor served as a negative control, with an equal volume of DMSO added; the group without substrate DHO served as a blank control, with an equal volume of ultrapure water added. Each group had three replicates. Data processing: Inhibition rate = 1 - (Vcompound - Vblank) / (Vcontrol - Vblank) * 100% [V is the average rate determined by kinetics]. The IC50 value of the analyte was calculated using a nonlinear fitting plot in GraphPad Prism 8.0, with the logarithm of the compound concentration on the x-axis and the inhibition rate on the y-axis. This experiment was repeated three times, with three replicates per group.

[0215] Table 1. Results of the hDHODH enzyme inhibitory activity of the compounds of the present invention

[0216]

[0217] Note: ND indicates not measured.

Claims

1. A class of small molecule compounds, characterized in that... The compound is shown in Formula I: Q is independently selected from the following structures: In each formula, R1 is independently selected from 0-5 R... 12 Substituted pyrimidines, R 12 The radicals are independently selected from cyano, C1-C6 alkyl, C1-C6 alkenyl, C3-C9 cycloalkyl, -NH2, -CH2OH, and ester; X1 is independently selected from N, and X2 is independently selected from C.

2. The compound according to claim 1, characterized in that... Further R 12 The individual is selected independently from the group consisting of methyl, ethyl, n-propyl, n-butyl, isopropyl, sec-butyl, isobutyl, and 2-methylpentyl.

3. The compound according to claim 1, characterized in that... Further R1 values ​​are selected independently from the following groups: 。 4. A small molecule compound, characterized in that... The structural formula is: 。

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