CN117126078A - Compounds and application thereof in treating hDHODH-mediated diseases - Google Patents

Compounds and application thereof in treating hDHODH-mediated diseases Download PDF

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CN117126078A
CN117126078A CN202210543547.0A CN202210543547A CN117126078A CN 117126078 A CN117126078 A CN 117126078A CN 202210543547 A CN202210543547 A CN 202210543547A CN 117126078 A CN117126078 A CN 117126078A
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compound
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赵瀛兰
罗有福
陈强
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Sichuan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/23—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same unsaturated acyclic carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms

Abstract

The invention belongs to the field of medicines, and particularly relates to a compound and application thereof in treating hDHODH-mediated diseases. The novel small molecule compounds are shown as formula I, have outstanding hDHODH enzyme inhibition activity, and can be used for treating various diseases mediated by hDHODH, including but not limited to tumors, autoimmune diseases, viral infections and the like.

Description

Compounds and application thereof in treating hDHODH-mediated diseases
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a compound, a preparation method and application thereof in treating hDHODH-mediated diseases.
Background
Pyrimidine is an important component essential for the synthesis of DNA and RNA in organisms. There are two pyrimidine synthesis pathways in human cells, the de novo synthesis pathway and the rescue pathway. Human dihydroorotate dehydrogenase (Human dihydroorotate dehydrogenase, hDHODH) is the fourth-step catalytic enzyme of the cellular pyrimidine de novo synthesis pathway and is also the key rate-limiting enzyme of this pathway. In rapidly proliferating cells, such as malignant cells, activated T lymphocytes, B lymphocytes, etc., the rescue pathway does not provide sufficient pyrimidine, and a high reliance on the hdhaodh mediated de novo synthesis pathway is required.
Inhibition of hDHODH can effectively block DNA synthesis of activated T, B lymphocytes, inhibit proliferation of the cells, and have potential in treating autoimmune diseases. In tumor cells, hDHODH also participates in iron death regulation and mitochondrial oxidative phosphorylation pathways, and inhibition of hDHODH can effectively inhibit pyrimidine synthesis of tumor cells, lead to tumor cell cycle retardation, induce cell differentiation and inhibit cell proliferation, thus indicating that hDHODH is a potential anti-tumor drug research and development target. In addition, the rapid replication after RNA and DNA virus infection is dependent on pyrimidine synthesis of host cells, and the inhibition of hDHODH can effectively slow down virus replication, so that the hDHODH is a potential target of host targeting antiviral.
Disclosure of Invention
A class of small molecule compounds is characterized in that the compounds are shown as a formula I:
q is independently selected from the following structures:
in the formulae, R 6 ～R 23 Independently selected from hydrogen, halogen, C1-C8 substitutionAlkyl, cycloalkyl, alkenyl, alkoxy, substituted alkyl, substituted alkoxy.
R 1 Independently selected from alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, arylalkyl, substituted alkyl, substituted cycloalkyl; r is R 2 、R 3 、R 4 Independently selected from hydrogen, halogen, methyl; r is R 5 Independently selected from alkyl, substituted alkyl.
Preferred compounds R 5 Is methyl.
Further R 2 Is fluorine, R 3 、R 4 Is hydrogen, and the compound is shown as a formula I-1;
q is independently selected from the following structures:
in the formulae, R 6 ～R 23 Independently selected from hydrogen, halogen, C1-C8 substituted alkyl, cycloalkyl, alkenyl, alkoxy, substituted alkyl, substituted alkoxy.
Wherein R is 1 Independently selected from alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, arylalkyl, substituted alkyl, substituted cycloalkyl.
Further R 1 Selected from the group consisting of: methyl, ethyl, n-propyl, n-butyl, isopropyl, cyclopropyl, sec-butyl, isobutyl, 2-methylpentyl, allyl, 2-methallyl, cyclopentylmethyl, cyclohexylmethyl, 2-fluorobenzyl, 2-chloro-6-fluorobenzyl, (S) -trifluoroisopropyl, (R) -trifluoroisopropyl, hexafluoro-2-propyl.
Further Q is selected from the group consisting of:
further preferred compounds are of the formula:
the invention provides a synthesis method of the molecules.
The preparation method, the synthetic route 1 is as follows:
(a) Synthesizing a raw material a1 in williamson ether to obtain an intermediate b1;
(b) Intermediate b1 intermediate c1 is obtained by nitro reduction;
(c) Intermediate c1 is subjected to one-step suzuki reaction to obtain intermediate d1;
(d) Intermediate d1 is condensed by amide to obtain intermediate e1;
(e) Intermediate e1 is ring opened by basic isoxazole to give the final product.
The preparation method, synthetic route 2 is as follows:
(f) Intermediate f1 synthesizes benzophenone intermediate g1 through palladium acetate catalysis and boric acid;
(g) Intermediate g1 is condensed by amide to obtain intermediate h1;
(h) Intermediate h1 is ring opened by basic isoxazole to obtain the final product.
The novel small molecule compounds of the invention contain isotopic substitution of any atom or atoms, preferably deuterium.
The novel small molecule compounds of the invention are pharmaceutically acceptable hydrates, solvates or crystal forms and salts.
The invention relates to application of a novel small molecule compound in preparing a medicament for treating hDHODH mediated diseases.
The hDHODH-mediated disease of the present invention is selected from the group consisting of tumors, autoimmune diseases, and viral infections.
Detailed Description
The invention is further illustrated below with reference to examples. The examples are intended to be illustrative of the invention only and are not intended to be limiting in any way.
Table 1. Novel small molecule compound structures:
embodiment one: preparation of representative intermediate b1
The starting compound 2-bromo-4-fluoro-5-nitrophenol (2.0 g,8.5mmol,1 equiv) was added to a 150mL eggplant-shaped bottle, 40mL analytically pure acetonitrile was added, followed by potassium carbonate (3.5 g,25.3mmol,3 equiv) and methyl iodide (3.6 g,25.3mmol,3 equiv), and after completion of the addition the oil bath was heated to 80℃for reaction. After TLC monitoring reaction is completed, the reaction liquid is cooled to room temperature, filtered by suction, concentrated under reduced pressure, and then separated and purified by a silica gel column, and the mobile phase is separated and purifiedPetroleum ether is used, and the mixture is concentrated to obtain 1.9g of yellow solid with the yield of 90 percent. 1 H NMR(400MHz,DMSO-d 6 )δ8.06(d,J＝10.5Hz,1H),7.77(d,J＝6.6Hz,1H),3.95(s,3H)。
Embodiment two: preparation of representative intermediate c1
Intermediate b1 (1.9 g,7.6mmol,1 equiv) was added to a 150mL eggplant-shaped bottle, 20mL ethanol and 20mL water were added, followed by reduced iron powder (1.3 g,22.8mmol,3 equiv) and NH 4 Cl (2.1 g,38.0mmol,5 equiv) was heated to 85℃in an oil bath after the addition was complete and reacted for 5h, the reaction turned black. After completion of the TLC monitoring, the reaction mixture was cooled to room temperature, filtered through celite, washed with water, extracted with EA, dried over anhydrous sodium sulfate and concentrated under reduced pressure to a brown oil, 1.4g, which was not further purified, yield 85%. 1 H NMR(400MHz,DMSO-d 6 )δ7.16(d,J＝10.5Hz,1H),6.73(d,J＝6.6Hz,1H),5.28(s,2H),3.95(s,3H)。
Embodiment III: preparation of representative intermediate d1
Intermediate c1 (150 mg,0.7mmol,1 equiv) was added to a25 mL two-necked flask, and 15mL dioxane/H was added 2 O (v/v, 3/1) followed by addition of 3-methoxyphenylboronic acid (154 mg,1.0mmol,1.5 equiv) and Cs 2 CO 3 (660 mg,2.1mmol,3 equiv) after addition was complete at N 2 Under conditions, 2 times, followed by addition of PdCl 2 (dppf) 2 (75 mg,0.09mmol,0.15 equiv), again N 2 3 times and under N 2 The reaction is carried out for 5h by heating in an oil bath under the protection condition at 80 ℃, TLC monitoring reaction is complete, the reaction liquid is cooled to room temperature, EA extraction is carried out, anhydrous sodium sulfate is dried, then decompression concentration is carried out, silica gel column separation and purification are carried out, the mobile phase system is PE/EA=80:20, and thus, 140mg of tan solid is obtained, and the yield is 81%. 1 H NMR(400MHz,DMSO-d 6 )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)。
Embodiment four: preparation of representative end product A1
Biphenyl intermediate d1 (90 mg,0.4mmol,1 equiv) was added to a25 mL eggplant-shaped bottle, 15mL of analytically pure THF was added, followed by stirring at-10 ℃ in a cold trap for 10min, followed by slowly dropping 5-methyl-4-isoxazolecarbonyl chloride (66 mg,0.5mmol,1.25 equiv), finally triethylamine (55 mg,0.6mmol,1.5 equiv) was dropped, stirring for 30min, and then room temperature reaction was changed to 2h, tlc monitoring reaction was complete, and crude intermediate e1 was obtained after concentrating under reduced pressure; direct solution in 10mL of isopropanol/H without purification 2 And (3) dropwise adding A1M NaOH solution into a mixed solvent of O (v/v, 2/1) until the pH value of a reaction system is 12, then reacting for 2 hours at room temperature, monitoring the reaction completely by TLC, regulating the pH value to 4 by dilute hydrochloric acid, precipitating white solid from the solution, and obtaining a final product A1 by suction filtration and drying, wherein the yield is 65%. 1 H NMR(400MHz,CDCl 3 )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,CDCl 3 )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)calculated for C 19 H 17 FN 2 O 4 357.1272[M+H] + ,found:357.1239。
Fifth embodiment: preparation of representative intermediate g1
In a50 mL two-port flask, intermediate f1 (260 mg,1.9mmol,1 equiv) was added, 20mL TFA/H 2 O (v/v, 1/3) mixed solvent, followed by phenylboronic acid (280 mg,2.4mmol,1.2 equiv.) CsF (887 mg,5.9mmol,3 equiv.) in N 2 The displacement is carried out 2 times under conditions, and Pd (OAc) is added subsequently 2 (44 mg,0.2mmol,0.1 equiv) and ligand 2- (3, 5-dimethyl-1H-pyrazol-1-yl) pyridine (L) 1 34mg,0.2mmol,0.1 equiv) and N again after the addition was complete 2 3 times and under N 2 The reaction is carried out for 10 hours by heating to 95 ℃ in an oil bath under the protection. TLC monitoring reaction is complete, the reaction liquid is cooled to room temperature, pH is regulated to be alkaline by NaOH aqueous solution, EA extraction, anhydrous sodium sulfate drying, decompression concentration and silica gel column separation and purification are carried out, the mobile phase system is PE/EA=50:50, and light yellow solid 260mg is obtained, and the yield is 70%. 1 H NMR(400MHz,CDCl 3 )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)。
The preparation of the compound A2-A51 was carried out according to the preparation method described above.
Compound A2
1 H NMR(400MHz,CDCl 3 )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,CDCl 3 )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 FN 2 O 4 371.1329[M+H] + ,found:371.1396。
Compound A3
1 H NMR(400MHz,CDCl 3 )δ15.36(s,1H),7.83(s,1H),7.77(d,J＝6.7Hz,1H),7.30(t,J＝8.1Hz,1H),7.14(d,J＝11.3Hz,1H),7.10–7.08(m,2H),6.91–6.84(m,1H),3.91(t,J＝6.4Hz,2H),3.83(s,3H),2.37(s,3H),1.86–1.66(m,2H),0.97(t,J＝7.4Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ188.60,167.16,159.26,152.18(d,J＝1.9Hz),147.36(d,J＝238.8Hz),138.21,129.01,128.13(d,J＝6.6Hz),123.52(d,J＝11.6Hz),121.84,116.81(d,J＝20.8Hz),115.93,114.95,113.19,106.93,80.92,70.86,55.26,22.54,22.01,10.70.HRMS m/z(ESI)calculated for C 21 H 21 FN 2 O 4 385.1485[M+H] + ,found:385.1552。
Compound A4
1 H NMR(400MHz,DMSO-d 6 )δ10.63(s,1H),7.79(d,J＝6.7Hz,1H),7.32(t,J＝8.2Hz,1H),7.27(d,J＝11.4Hz,1H),7.12–7.11(m,2H),6.90(dd,J＝8.2,1.6Hz,1H),6.04–5.97(m,1H),5.34(dd,J＝17.3,1.7Hz,1H),5.22(dd,J＝10.6,1.7Hz,1H),4.53(d,J＝4.9Hz,2H),3.78(s,3H),2.29(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ186.07,165.96,159.38,151.40,148.60(d,J＝238.1Hz),138.47,133.82,129.48,126.49(d,J＝6.8Hz),125.81(d,J＝12.6Hz),121.99,119.17,117.57,116.91(d,J＝21.4Hz),115.17,113.35,109.25,82.10,69.68,55.46,23.63.HRMS m/z(ESI)calculated for C 21 H 19 FN 2 O 4 383.1329[M+H] + ,found:383.1396。
Compound A5
1 H NMR(400MHz,DMSO-d 6 )δ10.62(s,1H),7.74(d,J＝6.8Hz,1H),7.31(t,J＝7.9Hz,1H),7.25(d,J＝11.5Hz,1H),7.13–7.10(m,2H),6.89(dd,J＝8.2,2.1Hz,1H),4.46–4.40(m,1H),3.79(s,3H),2.28(s,3H),1.22(d,J＝6.0Hz,6H). 13 C NMR(100MHz,DMSO-d 6 )δ186.25,166.10,159.31,150.61,148.61(d,J＝238.6Hz),138.74,129.44,127.37,125.70(d,J＝12.6Hz),121.89,119.20,116.96(d,J＝21.2Hz),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 FN 2 O 4 407.1385[M+Na] + ,found:407.1374。
Compound A6
1 H NMR(400MHz,CDCl 3 )δ15.39(s,1H),7.82(s,1H),7.79(d,J＝6.8Hz,1H),7.30(t,J＝7.9Hz,1H),7.14(d,J＝11.3Hz,1H),7.13–7.10(m,2H),6.87(dd,J＝8.2,1.7Hz,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＝6.1Hz,3H),0.90(t,J＝7.5Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ188.59,167.16,159.17,151.10(d,J＝2.0Hz),147.39(d,J＝239.1Hz),138.51,129.33(d,J＝6.6Hz),128.94,123.46(d,J＝11.7Hz),121.86,116.89(d,J＝20.6Hz),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 FN 2 O 4 421.1542[M+Na] + ,found:421.1528。
Compound A7
1 H NMR(400MHz,DMSO-d 6 )δ10.58(s,1H),7.74(d,J＝6.8Hz,1H),7.31(t,J＝7.8Hz,1H),7.24(d,J＝11.4Hz,1H),7.11(d,J＝2.2Hz,1H),7.09(d,J＝7.8Hz,1H),6.89(dd,J＝8.2,2.1Hz,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＝6.0Hz,3H),0.85(t,J＝7.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ186.14,166.07,159.28,150.80(d,J＝1.6Hz),148.53(d,J＝238.2Hz),138.76,129.39,127.41(d,J＝6.6Hz),125.63(d,J＝12.5Hz),121.93,119.05,116.98(d,J＝21.4Hz),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 FN 2 O 4 435.1698[M+Na] + ,found:435.1687。
Compound A8
1 H NMR(400MHz,DMSO-d 6 )δ10.55(s,1H),7.74(d,J＝6.8Hz,1H),7.31(t,J＝7.8Hz,1H),7.24(d,J＝11.4Hz,1H),7.12(d,J＝2.2Hz,1H),7.10(d,J＝7.8Hz,1H),6.89(dd,J＝8.2,2.0Hz,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＝7.4Hz,6H). 13 C NMR(100MHz,DMSO-d 6 )δ186.05,166.03,159.25,151.13,148.41(d,J＝238.2Hz),138.78,129.36,127.31(d,J＝6.6Hz),125.61(d,J＝12.6Hz),121.94,118.98,116.96(d,J＝21.2Hz),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 FN 2 O 4 435.1698[M+Na] + ,found:435.1686。
Compound A9
1 H NMR(400MHz,DMSO-d 6 )δ10.61(s,1H),7.77(d,J＝6.7Hz,1H),7.31(t,J＝7.9Hz,1H),7.25(d,J＝11.4Hz,1H),7.13–7.10(m,2H),6.95–6.85(m,1H),3.79(s,3H),3.71(d,J＝6.4Hz,2H),2.29(s,3H),2.00–1.91(m,1H),0.92(d,J＝6.7Hz,6H). 13 C NMR(100MHz,DMSO-d 6 )δ185.98,165.94,159.33,151.99(d,J＝1.4Hz),148.35(d,J＝237.6Hz),138.53,129.36,126.21(d,J＝6.5Hz),125.82(d,J＝12.8Hz),122.02,119.19,116.82(d,J＝21.2Hz),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 FN 2 O 4 399.1642[M+H] + ,found:399.1702。
Compound A10
1 H NMR(400MHz,DMSO-d 6 )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-d 6 )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 FN 2 O 4 397.1485[M+H] + ,found:397.1554。
Compound A11
1 H NMR(400MHz,DMSO-d 6 )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 H 27 FN 2 O 4 461.1855[M+Na] + ,found:461.1842。
Compound A12
1 H NMR(400MHz,DMSO-d 6 )δ10.67(s,1H),7.94(d,J＝6.7Hz,1H),7.48(t,J＝7.3Hz,1H),7.40(dd,J＝13.6,6.3Hz,1H),7.32–7.25(m,2H),7.23–7.19(m,2H),7.12(d,J＝1.4Hz,1H),7.10(d,J＝7.8Hz,1H),6.87(dd,J＝8.2,2.1Hz,1H),5.11(s,2H),3.70(s,3H),2.30(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ186.19,166.05,160.71(d,J＝246.1Hz),159.33,151.36(d,J＝1.4Hz),148.86(d,J＝238.5Hz),138.36,130.85(d,J＝4.1Hz),130.74,129.48,126.73(d,J＝7.0Hz),125.87(d,J＝12.7Hz),124.88(d,J＝3.4Hz),124.05(d,J＝14.5Hz),121.91,119.17,117.06(d,J＝21.3Hz),115.77(d,J＝20.9Hz),114.83,113.79,109.43,82.07,65.15(d,J＝3.7Hz),55.32,23.63.HRMS m/z(ESI)calculated for C 25 H 20 F 2 N 2 O 4 451.1391[M+H] + ,found:451.1458。
Compound A13
1 H NMR(400MHz,DMSO-d 6 )δ10.68(s,1H),7.98(d,J＝6.6Hz,1H),7.47(dd,J＝14.4,8.2Hz,1H),7.38(d,J＝8.0Hz,1H),7.32–7.20(m,3H),7.06–7.03(m,2H),6.82(dd,J＝8.2,1.7Hz,1H),5.11(s,2H),3.65(s,3H),2.31(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ186.26,166.11,161.85(d,J＝250.1Hz),159.26,151.45,149.20(d,J＝239.1Hz),138.20,135.86(d,J＝5.1Hz),132.24(d,J＝9.8Hz),129.47,127.06(d,J＝6.7Hz),126.09(d,J＝3.1Hz),125.87(d,J＝13.0Hz),122.20(d,J＝17.9Hz),121.74,119.09,117.13(d,J＝21.8Hz),115.17(d,J＝22.4Hz),114.46,113.96,110.17,82.03,62.68,55.20,23.60.HRMS m/z(ESI)calculated for C 25 H 19 ClF 2 N 2 O 4 485.1001[M+H] + ,found:485.1071。
Compound A14
1 H NMR(400MHz,CDCl 3 )δ15.32(s,1H),7.74(s,1H),7.71(d,J＝6.8Hz,1H),7.48–7.40(m,2H),7.31(t,J＝7.4Hz,2H),7.23(t,J＝7.3Hz,1H),7.05(d,J＝11.3Hz,1H),4.15–4.10(m,1H),2.30(s,3H),1.63–1.43(m,2H),1.12(d,J＝6.1Hz,3H),0.80(t,J＝7.5Hz,3H). 13 C NMR(100MHz,CDCl 3 )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 FN 2 O 3 368.1536[M+H] + ,found:368.1523。
Compound A15
1 H NMR(400MHz,CDCl 3 )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 C NMR(100MHz,CDCl 3 )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),116.57(d,J＝20.4Hz),115.99,113.41(2C),109.37,80.87,76.78,55.27,28.97,22.01,18.88,9.61.HRMS m/z(ESI)calculated for C 22 H 23 FN 2 O 4 421.1542[M+Na] + ,found:421.1529。
Compound A16
1 H NMR(400MHz,DMSO-d 6 )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-d 6 )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 FN 2 O 5 412.1434[M+H] + ,found:412.1409。
Compound A17
1 H NMR(400MHz,DMSO-d 6 )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＝11.4Hz,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). 13 C NMR(100MHz,DMSO-d 6 )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 FN 2 O 3 383.1693[M+H] + ,found:383.1754。
Compound A18
1 H NMR(400MHz,CDCl 3 )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 C NMR(100MHz,CDCl 3 )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 20 F 2 N 2 O 3 386.1442[M+H] + ,found:386.1428。
Compound A19
1 H NMR(400MHz,DMSO-d 6 )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＝11.4Hz,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-d 6 )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),125.83(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 F 2 N 2 O 3 386.1442[M+H] + ,found:386.1430。
Compound A20
1 H NMR(400MHz,DMSO-d 6 )δ12.21(s,1H),8.34(d,J＝7.0Hz,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 C NMR(100MHz,DMSO-d 6 )δ188.68,167.10,161.47(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 F 2 N 2 O 3 386.1442[M+H] + ,found:386.1429。
Compound A21
1 H NMR(400MHz,CDCl 3 )δ15.33(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),2.38(s,3H),1.67–1.58(m,2H),1.23(d,J＝6.1Hz,3H),0.91(t,J＝7.5Hz,3H). 13 C NMR(100MHz,CDCl 3 )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 F 3 N 2 O 3 404.1348[M+H] + ,found:404.1073。
Compound A22
1 H NMR(400MHz,CDCl 3 )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). 13 C NMR(100MHz,CDCl 3 )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 F 3 N 2 O 3 404.1348[M+H] + ,found:404.1076。
Compound A23
1 H NMR(400MHz,DMSO-d 6 )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-d 6 )δ186.58,166.06,163.84(d,J＝233.7Hz),151.47(d,J＝1.5Hz),150.85(d,J＝7.9Hz),147.51,147.49(d,J＝235.3Hz)147.36,129.05(d,J＝12.0Hz),122.58(d,J＝3.7Hz),120.79,116.69(d,J＝21.9Hz),109.41(d,J＝38.5Hz),108.73,81.29,76.36,28.83,24.71,19.03,9.79.HRMS m/z(ESI)calculated for C 20 H 19 F 2 N 3 O 3 388.1394[M+H] + ,found:388.1462。
Compound A24
1 H NMR(400MHz,DMSO-d 6 )δ10.66(s,1H),8.38(s,1H),8.14(td,J＝8.2,2.2Hz,1H),7.85(d,J＝5.0Hz,1H),7.36(d,J＝11.3Hz,1H),7.23(dd,J＝8.5,2.6Hz,1H),4.36–4.26(m,1H),2.30(s,3H),1.69–1.52(m,2H),1.19(d,J＝6.0Hz,3H),0.85(t,J＝7.4Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ185.93,165.89,162.36(d,J＝235.9Hz),150.90,148.32(d,J＝237.8Hz),147.80(d,J＝15.1Hz),143.08(d,J＝8.0Hz),131.42(d,J＝4.3Hz),126.72(dd,J＝12.7,3.5Hz),122.34,119.22(d,J＝4.7Hz),116.90(d,J＝21.7Hz),110.04,109.15(d,J＝37.7Hz),82.23,76.26,28.81,23.59,19.01,9.74.HRMS m/z(ESI)calculated for C 20 H 19 F 2 N 3 O 3 388.1394[M+H] + ,found:388.1460。
Compound A25
1 H NMR(400MHz,DMSO-d 6 )δ11.70(s,1H),8.12(d,J＝6.9Hz,1H),7.22(dd,J＝14.1,7.5Hz,1H),7.11(t,J＝9.0Hz,1H),6.99(s,1H),6.96(d,J＝2.9Hz,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 C NMR(100MHz,DMSO-d 6 )δ187.84,166.77,160.96(d,J＝241.2Hz),150.92,146.65(d,J＝236.3Hz),140.57,128.28(d,J＝11.9Hz),126.99,126.90,126.52(d,J＝2.3Hz),126.51,123.97,123.81,116.79(d,J＝20.6Hz),114.04(d,J＝23.0Hz),108.47(d,J＝1.5Hz),79.26,76.00,28.95,26.11,19.11,12.36(d,J＝4.6Hz),9.60.HRMS m/z(ESI)calculated for C 22 H 22 F 2 N 2 O 3 401.1598[M+H] + ,found:401.1663。
Compound A26
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1 H NMR(400MHz,DMSO-d 6 )δ12.30(s,1H),8.33(d,J＝7.1Hz,1H),7.62–7.44(m,1H),7.40–7.27(m,3H),6.96(d,J＝11.4Hz,1H),4.16–4.06(m,1H),2.05(s,3H),1.56–1.37(m,2H),1.10(d,J＝6.0Hz,3H),0.75(t,J＝7.4Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ188.84,167.19,151.19,145.65(d,J＝235.0Hz),137.10,133.49,132.71,129.68(d,J＝11.6Hz),129.47,129.25,127.08,121.32(d,J＝6.9Hz),116.67(d,J＝2.3Hz),116.46(d,J＝2.4Hz),107.19,77.78,75.96,29.03,27.44,19.16,9.65.HRMS m/z(ESI)calculated for C 21 H 20 ClFN 2 O 3 425.1046[M+H] + ,found:425.1035。
Compound A27
1 H NMR(400MHz,DMSO-d 6 )δ10.58(s,1H),7.80(d,J＝6.8Hz,1H),7.61(s,1H),7.49(d,J＝7.6Hz,1H),7.43(t,J＝7.8Hz,1H),7.37(d,J＝7.8Hz,1H),7.29(d,J＝11.4Hz,1H),4.31–4.27(m,1H),2.31(s,3H),1.60–1.54(m,2H),1.18(d,J＝6.0Hz,3H),0.87(t,J＝7.4Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ185.85,165.86,150.80,148.42(d,J＝238.4Hz),139.37,133.07,130.21,129.45,128.25,127.28,126.31(d,J＝12.5Hz),125.62(d,J＝7.0Hz),119.01,116.92(d,J＝21.5Hz),110.47,82.37,76.15,28.86,23.50,18.97,9.68.HRMS m/z(ESI)calculated for C 21 H 20 ClFN 2 O 3 402.1146[M+H] + ,found:402.1137。
Compound A28
1 H NMR(400MHz,CDCl 3 )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,CDCl 3 )δ187.58,166.13,150.01,146.28(d,J＝239.3Hz),134.52,132.17,129.69(2C),127.12(2C),126.97(d,J＝6.5Hz),122.74(d,J＝11.5Hz),115.57(d,J＝20.7Hz),114.85,107.91,79.89,75.79,27.91,20.97,17.82,8.53.HRMS m/z(ESI)calculated for C 21 H 20 ClFN 2 O 3 402.1146[M+H] + ,found:402.1135。
Compound A29
1 H NMR(400MHz,DMSO-d 6 )δ12.33(s,1H),8.35(d,J＝6.7Hz,1H),7.39(d,J＝7.9Hz,1H),7.21(t,J＝7.8Hz,1H),7.10(d,J＝7.4Hz,1H),6.94(d,J＝11.3Hz,1H),4.09(brs,1H),2.13(s,3H),2.05(s,3H),1.40(brs,2H),1.08(dd,J＝54.7,4.2Hz,3H),0.73(d,J＝43.5Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ188.84,167.22,150.81,145.82(d,J＝234.4Hz),140.46,134.84,133.90,129.58,129.47,128.17,127.03,125.20,122.82(d,J＝1.9Hz),116.39(d,J＝21.3Hz),107.28(d,J＝38.1Hz),77.69,75.72,28.99,27.52,19.15,18.06,9.50.HRMS m/z(ESI)calculated for C 22 H 22 ClFN 2 O 3 416.1303[M+H] + ,found:416.1292。
Compound A30
1 H NMR(400MHz,DMSO-d 6 )δ10.61(s,1H),7.75(d,J＝6.3Hz,1H),7.33–7.25(m,2H),7.16(s,1H),7.08(d,J＝10.9Hz,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＝5.9Hz,3H),0.74(t,J＝7.4Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ186.06,165.99,150.88,148.06(d,J＝239.0Hz),139.58,135.83,131.67,130.07,129.89,127.58,126.55(d,J＝5.3Hz),126.15(d,J＝12.8Hz),119.21,117.27(d,J＝21.1Hz),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 ClFN 2 O 3 416.1303[M+H] + ,found:416.1293。
Compound A31
1 H NMR(400MHz,CDCl 3 )δ15.33(brs,1H),7.89–7.81(m,3H),7.67(d,J＝7.6Hz,1H),7.57(d,J＝7.8Hz,1H),7.51(t,J＝7.7Hz,1H),7.15(d,J＝11.1Hz,1H),4.37–4.21(m,1H),2.38(s,3H),1.73–1.49(m,2H),1.23(d,J＝6.1Hz,3H),0.89(t,J＝7.5Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ188.70,167.22,151.11(d,J＝2.0Hz),147.28(d,J＝239.3Hz),137.77(d,J＝1.2Hz),132.51(d,J＝0.9Hz),130.31(q,J＝32.2Hz),128.49,127.34(d,J＝6.5Hz),126.50(q,J＝3.9Hz),124.27(d,J＝11.5Hz),124.23(q,J＝272.2Hz),123.89(q,J＝3.6Hz),116.68(d,J＝20.9Hz),115.87,108.65,80.95,28.91,22.00,18.75,9.43.HRMS m/z(ESI)calculated for C 22 H 20 F 4 N 2 O 3 436.1410[M+H] + ,found:436.1398.HPLC purity＝98.09％。
Compound A32
1 H NMR(400MHz,DMSO-d 6 )δ12.07(brs,1H),10.67(s,1H),7.86(d,J＝6.8Hz,1H),7.81–7.64(m,4H),7.31(d,J＝11.4Hz,1H),4.38–4.22(m,1H),2.30(s,3H),1.75–1.41(m,2H),1.19(d,J＝6.0Hz,3H),0.85(t,J＝7.4Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ185.88,165.86,150.94(d,J＝1.3Hz),148.31(d,J＝238.0Hz),141.57,130.40,127.81(q,J＝31.8Hz),126.77(d,J＝12.5Hz),125.37(d,J＝6.8Hz),125.19,125.16,125.12,124.81(q,J＝271.7Hz),119.20,117.00(d,J＝21.5Hz),110.18,82.30,76.26,28.83,23.60,19.00,9.76.HRMS m/z(ESI)calculated for C 22 H 20 F 4 N 2 O 3 436.1410[M+H] + ,found:436.1397。
Compound A33
1 H NMR(400MHz,DMSO-d 6 )δ11.50(s,1H),8.11(d,J＝6.7Hz,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＝6.0Hz,3H),0.84(t,J＝7.4Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ186.35,166.08,150.80(d,J＝1.6Hz),148.40(d,J＝1.6Hz),148.10(d,J＝236.5Hz),139.54,130.42,128.52,126.98(d,J＝12.3Hz),124.60(d,J＝7.0Hz),122.24,120.64(q,J＝254.5Hz),119.91(d,J＝4.2Hz),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 F 4 N 2 O 4 452.1359[M+H] + ,found:452.1347。
Compound A34
1 H NMR(400MHz,DMSO-d 6 )δ12.29(s,1H),8.39(s,1H),7.91(dd,J＝16.5,7.9Hz,2H),7.58–7.33(m,5H),7.02(dd,J＝11.4,2.6Hz,1H),4.13–3.93(m,1H),2.05(s,3H),1.38–1.15(m,2H),0.97(dd,J＝17.5,5.8Hz,3H),0.63–0.41(m,3H). 13 C NMR(100MHz,DMSO-d 6 )δ188.68,185.90,167.17,151.54,136.48,133.47,132.14,132.07,129.36,129.24,128.41,127.96,127.89,127.80,126.78,126.72,126.08,125.80,117.44,117.41,107.66,77.98,75.98,28.91,27.31,19.03,9.56.HRMS m/z(ESI)calculated for C 25 H 23 FN 2 O 3 419.1693[M+H] + ,found:419.1757。
Compound A35
1 H NMR(400MHz,DMSO-d 6 )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-d 6 )δ188.52,167.05,151.03,146.67(d,J＝235.3Hz),135.64,133.45,132.19,128.97(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),116.39(d,J＝19.6Hz),107.83,78.31,75.98,28.99,27.06,19.17,9.85.HRMS m/z(ESI)calculated for C 25 H 23 FN 2 O 3 419.1693[M+H] + ,found:419.1748.HPLC purity＝98.18％。
Compound A36
1 H NMR(400MHz,CDCl 3 )δ7.92(d,J＝6.6Hz,1H),7.85(d,J＝12.0Hz,2H),7.60(d,J＝7.6Hz,1H),7.49(d,J＝8.2Hz,1H),7.39(s,1H),7.30(d,J＝7.2Hz,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＝6.1Hz,3H),1.06(t,J＝7.5Hz,3H).HRMS m/z(ESI)calculated for C 23 H 21 FN 2 O 4 409.1385[M+H] + ,found:409.1322。
Compound A37
1 H NMR(400MHz,CDCl 3 )δ15.32(s,1H),7.91–7.80(m,3H),7.68(d,J＝7.6Hz,1H),7.58(d,J＝7.6Hz,1H),7.51(t,J＝7.6Hz,1H),7.15(d,J＝11.1Hz,1H),4.45(m,1H),2.39(s,3H),1.27(d,J＝6.1Hz,6H). 13 C NMR(100MHz,CDCl 3 )δ188.70,167.21,150.92(d,J＝2.0Hz),147.41(d,J＝239.6Hz),137.73(d,J＝1.1Hz),132.47,130.37(q,J＝32.1Hz),128.53(2C),127.42(d,J＝6.6Hz),126.45(q,J＝3.9Hz),124.28(d,J＝11.6Hz),124.22(q,J＝272.3Hz),116.67(d,J＝20.9Hz),115.85,109.08,80.96,72.05,22.00,21.82(2C).HRMS m/z(ESI)calculated for C 21 H 18 F 4 N 2 O 3 423.1254[M+H] + ,found:423.1202。
Compound A38
1 H NMR(400MHz,DMSO-d 6 )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-d 6 )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 FN 2 O 4 355.1016[M+H] + ,found:355.1082。
Compound A39
1 H NMR(400MHz,DMSO-d 6 )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). 13 C NMR(100MHz,DMSO-d 6 )δ194.43,185.84,165.53,153.53,147.14(d,J＝238.1Hz),138.44,133.24,130.71(d,J＝12.4Hz),129.41(2C),128.78(2C),122.81(d,J＝5.5Hz),120.34,115.98(d,J＝21.8Hz),107.05,82.19,64.71,24.41,14.42.HRMS m/z(ESI)calculated for C 20 H 17 FN 2 O 4 369.1172[M+H] + ,found:369.1237。
Compound A40
1 H NMR(400MHz,DMSO-d 6 )δ11.02(s,1H),8.01(d,J＝6.3Hz,1H),7.72–7.65(m,2H),7.63(t,J＝7.4Hz,1H),7.50(t,J＝7.4Hz,2H),7.33(d,J＝10.6Hz,1H),4.43–4.37(m,1H),2.27(s,3H),0.98(d,J＝6.0Hz,6H). 13 C NMR(100MHz,DMSO-d 6 )δ194.75,185.80,165.58,152.31,147.21(d,J＝238.4Hz),138.48,133.21,130.36(d,J＝12.3Hz),129.44(2C),128.72(2C),123.92(d,J＝5.2Hz),120.08,116.06(d,J＝21.8Hz),108.39,82.29,71.44,24.24,21.71(2C).HRMS m/z(ESI)calculated for C 21 H 19 FN 2 O 4 383.1329[M+H] + ,found:383.1395。
Compound A41
1 H NMR(400MHz,DMSO-d 6 )δ11.12(s,1H),8.03(d,J＝6.3Hz,1H),7.69–7.65(m,2H),7.62(t,J＝7.4Hz,1H),7.49(t,J＝7.4Hz,2H),7.31(d,J＝10.7Hz,1H),4.24–4.20(m,1H),2.25(s,3H),1.34–1.25(m,2H),1.01(d,J＝6.0Hz,3H),0.59(t,J＝7.4Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ194.79,186.07,165.73,152.40,147.03(d,J＝238.1Hz),138.54,133.24,129.44(2C),128.76(2C),123.70(d,J＝5.3Hz),120.42,116.02(d,J＝21.9Hz),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 FN 2 O 4 397.1485[M+H] + ,found:397.1551。
Compound A42
1 H NMR(400MHz,DMSO-d 6 )δ12.64(d,J＝1.9Hz,1H),8.52(d,J＝6.4Hz,1H),7.68(d,J＝7.2Hz,2H),7.62(t,J＝7.4Hz,1H),7.50(t,J＝7.6Hz,2H),7.30(d,J＝10.9Hz,1H),4.92–4.86(m,1H),2.07(s,3H),1.18(d,J＝6.4Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ194.13,189.42,167.28,151.06,146.60(d,J＝238.3Hz),138.52,133.27,133.16,129.50(2C),128.77(2C),124.74(q,J＝281.4Hz),124.69,121.28(d,J＝5.5Hz),115.92(d,J＝21.7Hz),106.71,77.76,72.89(q,J＝31.1Hz),27.51,13.50.HRMS m/z(ESI)calculated for C 21 H 16 F 4 N 2 O 4 437.1046[M+H] + ,found:437.1114。
Compound A43
1 H NMR(400MHz,CDCl 3 )δ15.00(s,1H),7.99–7.97(m,2H),7.65(td,J＝7.5,1.4Hz,1H),7.54–7.43(m,2H),7.23(t,J＝7.5Hz,1H),7.09–7.02(m,1H),4.63–4.50(m,1H),2.40(s,3H),1.25(d,J＝6.5Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ189.93(d,J＝1.0Hz),189.21,167.33,160.96(d,J＝253.9Hz),151.60,147.31(d,J＝242.0Hz),133.94(d,J＝8.8Hz),130.38(d,J＝2.0Hz),128.77(d,J＝11.6Hz),128.08(d,J＝12.4Hz),126.90(d,J＝5.4Hz),124.24(d,J＝3.5Hz),123.69(q,J＝281.6Hz),116.87(d,J＝21.8Hz),115.89(d,J＝22.0Hz),115.45,106.72,81.19,73.09(q,J＝32.7Hz),22.08,13.04(d,J＝1.6Hz).HRMS m/z(ESI)calculated for C 21 H 15 F 5 N 2 O 4 455.1052[M+H] + ,found:455.1008.HPLC purity＝99.01％。
Compound A44
1 H NMR(400MHz,DMSO-d 6 )δ12.68(s,1H),8.53(d,J＝6.2Hz,1H),7.59–7.38(m,4H),7.35(d,J＝10.9Hz,1H),4.97–4.91(m,1H),2.08(s,3H),1.20(d,J＝6.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ192.89,189.52,167.30,162.37(d,J＝244.9Hz),151.29,146.60(d,J＝238.2Hz),141.09(d,J＝6.4Hz),133.82(d,J＝12.2Hz),130.95(d,J＝7.9Hz),125.64,124.67(q,J＝281.7Hz),124.62,120.33(d,J＝5.7Hz),119.90(d,J＝21.3Hz),116.18(d,J＝21.8Hz),115.54(d,J＝22.4Hz),106.21,77.78,72.60(q,J＝31.8Hz),27.50,13.40.HRMS m/z(ESI)calculated for C 21 H 15 F 5 N 2 O 4 455.1052[M+H] + ,found:455.1022。
Compound A45
1 H NMR(400MHz,DMSO-d 6 )δ11.62(s,1H),8.28(d,J＝6.2Hz,1H),7.77(dd,J＝8.6,5.6Hz,2H),7.39–7.31(m,3H),5.04–4.95(m,1H),2.21(s,3H),1.22(d,J＝6.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )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 F 5 N 2 O 4 455.1052[M+H] + ,found:455.1021。
Compound A46
1 H NMR(400MHz,CDCl 3 )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,CDCl 3 )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 15 ClF 4 N 2 O 4 471.0656[M+H] + ,found:471.0725.HPLC purity＝99.61％。
Compound A47
1 H NMR(400MHz,DMSO-d 6 )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-d 6 )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),130.89,128.85,127.97,124.63(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 ClF 4 N 2 O 4 471.0656[M+H] + ,found:471.0726。
Compound A48
1 H NMR(400MHz,DMSO-d 6 )δ11.33(s,1H),9.97(brs,1H),8.21(d,J＝6.1Hz,1H),7.70(d,J＝8.4Hz,2H),7.58(d,J＝8.4Hz,2H),7.41(d,J＝10.5Hz,1H),5.05–4.99(m,1H),2.25(s,3H),1.22(d,J＝6.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ192.84,186.53,165.84,150.65,148.02(d,J＝240.3Hz),138.42,136.82,131.34(2C),131.05(d,J＝12.6Hz),129.02(2C),124.66(d,J＝281.5Hz),123.54(d,J＝5.9Hz),120.69,116.34(d,J＝22.4Hz),108.84,81.51,72.79(q,J＝31.7Hz),24.72,13.42.HRMS m/z(ESI)calculated for C 21 H 15 ClF 4 N 2 O 4 471.0656[M+H] + ,found:471.0726。
Compound A49
1 H NMR(400MHz,DMSO-d 6 )δ12.64(d,J＝1.5Hz,1H),8.52(d,J＝6.3Hz,1H),7.41(t,J＝8.2Hz,1H),7.28(d,J＝10.9Hz,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＝6.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ193.80,189.43,167.29,159.59,151.12,146.51(d,J＝238.1Hz),139.91,133.22(d,J＝12.1Hz),129.96,124.77(q,J＝281.6Hz),124.68,122.31,121.24(d,J＝5.5Hz),119.27,115.90(d,J＝21.8Hz),113.78,106.71,77.76,72.88(q,J＝31.5Hz),55.73,27.50,13.52.HRMS m/z(ESI)calculated for C 22 H 18 F 4 N 2 O 5 467.1152[M+H] + ,found:467.1222。
Compound A50
1 H NMR(400MHz,DMSO-d 6 )δ11.15(s,1H),8.15(d,J＝6.0Hz,1H),7.69(d,J＝8.7Hz,2H),7.32(d,J＝10.4Hz,1H),7.04(d,J＝8.7Hz,2H),5.03–4.97(m,1H),3.85(s,3H),2.26(s,3H),1.23(d,J＝6.3Hz,3H). 13 C NMR(100MHz,DMSO-d 6 )δ192.21,186.41,165.88,163.85,150.15,148.32(d,J＝240.6Hz),132.22(2C),130.39,129.71(d,J＝12.8Hz),125.37,124.79(q,J＝281.4Hz),120.30,115.88(d,J＝22.1Hz),114.24(2C),109.87,81.64,73.10(q,J＝31.4Hz),56.01,24.43,13.59.HRMS m/z(ESI)calculated for C 22 H 18 F 4 N 2 O 5 467.1152[M+H] + ,found:467.1221。
Compound A51
1 H NMR(400MHz,DMSO-d 6 )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-d 6 )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),130.05,129.12,128.64,128.13,127.34,124.72,124.67(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 F 4 N 2 O 4 487.1203[M+H] + ,found:487.1271。
Example eight: determination of hDHODH enzyme inhibitory Activity of Compounds
The experimental method comprises the following steps:
2nM purified full-length hDHODH eggs were added to 96-well platesWhite, 60. Mu.M sodium 2, 6-Dichloroindophenol (DCIP), 0.1mM coenzyme Q (CoQ), followed by addition of test compound to a final concentration gradient of 1000nM,100nM,50nM,25nM,12.5nM,6.25nM,3.125nM, incubation of the above system at 37℃for 30min, 1mM dihydroorotic acid (DHO) was added, followed by detection of absorbance of the reaction system at 600nm by an enzyme-labeled instrument, determination of the dynamic reduction rate of sodium 2, 6-dichloroindophenol (30 s/time, 12 repetitions), inhibition rate = (1-V by the formula = i /V 0 ) "calculate, wherein V 0 And V i The initial and final reaction rates of the system, respectively.
TABLE 2 results of hDHODH enzyme inhibitory Activity of the Compounds of the present invention
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Note that: ND represents not measured.

Claims (10)

1. A class of small molecule compounds is characterized in that the compounds are shown as a formula I:
q is independently selected from the following structures:
in the formulae, R 6 ～R 23 Independently selected from hydrogen, halogen, C1-C8 substituted alkyl, cycloalkyl, alkenyl, alkoxy, substituted alkyl, substituted alkoxy;
R 1 independently selected from alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, arylalkyl, substituted alkyl, substitutedCycloalkyl; r is R 2 、R 3 、R 4 Independently selected from hydrogen, halogen, methyl; r is R 5 Independently selected from alkyl, substituted alkyl.
2. The compound according to claim 1, wherein R 5 Selected from methyl groups.
3. The compound according to claim 2, wherein the compound is of formula i-1;
q is independently selected from the following structures:
in the formulae, R 6 ～R 23 Independently selected from hydrogen, halogen, C1-C8 substituted alkyl, cycloalkyl, alkenyl, alkoxy, substituted alkyl, substituted alkoxy;
R 1 independently selected from alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, arylalkyl, substituted alkyl, substituted cycloalkyl.
4. A compound according to claim 3, wherein R 1 Selected from the group consisting of: methyl, ethyl, n-propyl, n-butyl, isopropyl, cyclopropyl, sec-butyl, isobutyl, 2-methylpentyl, allyl, 2-methallyl, cyclopentylmethyl, cyclohexylmethyl, 2-fluorobenzyl, 2-chloro-6-fluorobenzyl, (S) -trifluoroisopropyl, (R) -trifluoroisopropyl, hexafluoro-2-propyl.
5. A compound according to claim 3, wherein Q is selected from the group consisting of:
6. the compound of claim 1, characterized by the structural formula:
7. a compound as claimed in claim 1 wherein the isotope of any atom or atoms of the compound is substituted, preferably the isotope is deuterium.
8. A novel class of small molecule compounds as claimed in claim 1, characterized in that the pharmaceutically acceptable hydrates, solvates or crystal forms, salts.
9. The novel class of small molecule compounds as claimed in claim 1, characterized by their use in the manufacture of a medicament for the treatment of hdhaodh mediated diseases.
10. The hdhaodh mediated disease of claim 9, characterized by being selected from the group consisting of tumors, autoimmune diseases and viral infections.
CN202210543547.0A 2022-05-19 2022-05-19 Compounds and application thereof in treating hDHODH-mediated diseases Pending CN117126078A (en)

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