The application is a divisional application, and the Chinese application number of the parent case is as follows: 201980004340.2, International application number PCT/CN2019/071704, International application date 2019, month 01 and 15.
The present invention claims priority from chinese patent application CN201810044798.8, and the contents of the specification, drawings and claims of this priority document are incorporated in their entirety into the present specification and are included as part of the original description of the present specification. Applicants further claim that applicants have the right to amend the description and claims of this invention based on this priority document.
Disclosure of Invention
In one aspect, the present invention provides a compound represented by formula (I), a salt, a solvate, a prodrug, a metabolite, a nitrogen oxide, a stereoisomer, or an isotopic derivative thereof:
wherein
Represents: - (O) b,
Or
Cy
1Selected from 5-15 membered rings optionally substituted with a substituent selected from: halogen, hydroxy, C
1-6Alkyl, amino, halo C
1-6Alkyl, mercapto, C
1-6Alkyl mercapto group, C
1-6Alkylamino radical, di (C)
1-6Alkyl) amino and cyano;
Cy2selected from optionally substituted by one, two or more R2Substituted C6-10Cycloalkyl having a ring system of6-10A heterocyclic radical, C6-10Aryl radicals or C6-10A membered heteroaryl group; preferably by one, two or more R2Substituted phenyl, pyridyl, cyclohexyl, piperidinyl, piperazinyl, pyrazinyl, pyrimidinyl, morpholinyl; a pyridazinyl group;
R1and R2Independently selected from hydrogen atom, halogen, hydroxyl, nitro, cyano, sulfonic acid group, C1-6Alkyl radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy, halo C1-C6Alkyl, halo C1-C6Alkoxy, halo C3-C6Cycloalkyl radical, C1-6Alkylthio radical, C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl, di (C)1-6Alkyl) amino C2-6Alkoxycarbonyl, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, carbamoyl, C1-6Alkylcarbamoyl, di (C)1-6Alkyl) carbamoyl, di (C)1-6Alkyl) amino C2-6Alkylcarbamoyl, sulfamoyl, C1-6Alkylsulfamoyl, di (C)1-6Alkyl) sulfamoyl, di (C)1-6Alkyl) amino C2-6Alkylsulfamoyl, C1-6Alkylsulfonyl radical, C1-6Alkylsulfinyl, di (C)1-6Alkyl) phosphono, hydroxy C1-6Alkyl, hydroxy carbonyl C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylsulfonyl radical C1-6Alkyl radical, C1-6Alkylsulfinyl C1-6Alkyl, di (C)1-6Alkyl) phosphono C1-6Alkyl, hydroxy C2-6Alkoxy radical, C1-6Alkoxy radical C2-6Alkoxy, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, di (C)1-6Alkyl) amino C1-6Alkyl, di (C)1-6Alkyl) aminoacetyl, amino C2-6Alkoxy radical, C1-6Alkylamino radical C2-6Alkoxy, di (C)1-6Alkyl) amino C2-6Alkoxy, hydroxy C2-6Alkylamino radical, C1-6Alkoxy radical C2-6Alkylamino radical, amino radical C2-6Alkylamino radical, C1-6Alkylamino radical C2-6Alkylamino radical, di (C)1-6Alkyl) amino C2-6An alkylamino group; or two adjacent R1Or R2Are mutually surroundedAnd are combined to form a 3-8 membered ring containing 0-3 heteroatoms in the ring;
m, n are integers selected from 0, 1,2, 3 and 4;
Ra、Rbeach independently selected from hydrogen and C1-C6Alkyl or C3-6A cycloalkyl group;
x is selected from CRaRb、NReOr O;
y is selected from CReOr N; wherein R iseRepresents hydrogen, C1-6Alkyl or C3-6Cycloalkyl radical, C1-6A haloalkyl group.
In another aspect, the present invention provides a compound represented by formula (II), a salt, a solvate, a prodrug, a metabolite, a nitrogen oxide, a stereoisomer, or an isotopic derivative thereof:
wherein, W1、W2、W3、W4Are each independently selected from CReC ═ O or N; p is an integer selected from 0, 1,2, 3 and 4; r1、R2、Cy1、Ra、Rb、ReX, Y, m, n are as defined for formula I; the dotted line represents a single bond or a double bond.
In one embodiment of the invention, Cy1Selected from the following groups:
wherein R is3Selected from hydrogen, C1-C6Alkyl radical, C3-C6A cycloalkyl group;
the above groups may be substituted by one or more groups selected from halogen, hydroxy, C1-6Alkyl, amino, halo C1-6Alkyl, mercapto, C1-6Alkyl mercapto group, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, cyano, or substituted radicalsAnd (4) generation.
In one aspect, the present invention provides a compound represented by formula (III), a salt, a solvate, a prodrug, a metabolite, a nitrogen oxide, a stereoisomer, or an isotopic derivative thereof:
wherein R is1、R2、Ra、Rb、X、Y、W1、W2、W3、W4M, n, p are as defined for formula II.
In one aspect, the present invention provides a compound represented by formula (IV), a salt, a solvate, a prodrug, a metabolite, a nitrogen oxide, a stereoisomer, or an isotopic derivative thereof:
wherein Q1And Q2Are each independently selected from CRaRb、NReOr O; q3Selected from the group consisting of CRaOr N; wherein R is1、R2、Ra、Rb、Re、X、Y、W1、W2、W3、W4M, p are as defined for formula II;
in another embodiment of the present invention, the compound of formula II has the structure of formula (V):
wherein R is1、R2、Ra、Rb、X、Y、W1、W2、W3、W4M, p are as defined above for formula II.
In the context of the present disclosure, it is,
is shown to,
Or
In the context of the present disclosure, it is,
preferably, it is
Unless otherwise indicated, all compound structures of the present invention also include stereoisomers (including enantiomers, diastereomers, stereoisomers, conformations, and enantiomers) that may exist. For example, the R and S configurations of each chiral center, and the E and Z isomers of each olefinic double bond are included in the invention. For some freely rotatable bonds, the position of the substituent may also follow the free rotation, for example:
structural formula (I)
The method also represents the following steps:
also representative of tautomers thereof:
thus, a single stereochemical isomer, as well as enantiomeric mixtures, geometric isomer mixtures, conformational isomer mixtures, tautomers thereof, are all within the scope of the present application.
The compounds of the present invention may also be prepared in the form of pharmaceutically acceptable salts formed using, for example, inorganic or organic acids such as: hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, mandelic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, methanesulfonic, benzenesulfonic and toluenesulfonic acids. When referring to the compounds of the present invention, these pharmaceutically acceptable salts of the compounds of the present invention are also encompassed.
The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in a water-miscible organic solvent (e.g., acetone, methanol, ethanol and acetonitrile), adding thereto an excess of an organic acid or an aqueous solution of an inorganic acid to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid therefrom, and then separating the precipitated salt.
Design and reaction examples
The compound of the present invention can be synthesized by known procedures with reference to the following descriptions. All solvents and reagents purchased were used directly without treatment. All synthesized compounds can be analytically validated by, but not limited to, the following methods: LCMS (liquid chromatography mass spectrometry) and NMR (nuclear magnetic resonance). Nuclear Magnetic Resonance (NMR) was measured by Bruker AVANCE-500 NMR spectrometer using deuterated solvents such as deuterated dimethyl sulfoxide (d6-DMSO), deuterated chloroform (CDCl3) and Tetramethylsilane (TMS) as internal standard. The following abbreviations represent various types of split peaks: singlet(s), doublet (d), triplet (t), multiplet (m), broad (br). Mass Spectrometry (MS) determination Using Thermo Fisher-MSQ Plus LC Mass spectrometer, of xylonite for resolution of chiral Compounds
AD-H chiral column (0.46cm i.d. × 15cm L, HEP: ETOH (0.1% DEA) ═ 60:40 (V/V)).
The compounds of the invention can be prepared as follows.
General route one:
synthesis of intermediate F (mixture of cis and trans, racemic Compound)
The first step is as follows: ethyl 4-oxocyclohexaneacetate (2.0g,10.86mmol) was dissolved in 60mL of ultra-dry tetrahydrofuran, and to this solution was added dropwise sodium bis (trimethylsilyl) amide (2mol/L tetrahydrofuran solution) (6.5mL,13.03mmol) under a nitrogen atmosphere at-78 ℃. The reaction solution was stirred at this temperature for 1 hour. A solution of N-phenylbis (trifluoromethanesulfonyl) imide (4.65g,13.03mmol) in tetrahydrofuran (20mL) was then added. After the addition was complete, the reaction mixture was stirred at room temperature overnight until complete consumption of the starting material by TLC. The reaction solution was quenched with 5mL of an aqueous potassium hydrogen sulfate solution, filtered to remove solids, and the filtrate was concentrated. To the residue was added 50mL of methyl t-butyl ether, and the organic layer was washed with 1.0mol/L sodium hydroxide solution (3X20 mL) and with 20mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate a (3.12g) as an orange oily liquid in 91% yield.1H NMR(500MHz,CDCl3)δ5.74–5.70(m,1H),4.15(q,J=7.0Hz,2H),2.48–2.40(m,1H),2.38–2.32(m,2H),2.30(d,J=7.0Hz,2H),2.18–2.10(m,1H),1.97–1.89(m,2H),1.57–1.48(m,1H),1.27(t,J=7.0Hz,3H).
The second step is that: intermediate A (3.12g,9.86mmol) was dissolved in 15mL dioxane, and pinacol diboron (3.26g,12.82mmol), potassium acetate (2.90g,29.59mmol), sodium bromide (406mg,3.95mmol) and Pd (dppf) Cl were added sequentially2(722mg,0.98 mmol). The reaction mixture was refluxed overnight under nitrogen atmosphere. The reaction solvent dioxane was then evaporated to dryness, ethyl acetate was added, filtration was carried out over celite, the filtrate was concentrated and then separated by flash column chromatography to give intermediate B (1.66g) as a colourless liquid in 57% yield.1H NMR(500MHz,CDCl3)δ6.54–6.48(m,1H),4.12(q,J=6.5Hz,2H),2.30–2.02(m,7H),1.84–1.72(m,2H),1.27–1.23(m,15H).
The third step: intermediate B (1.66g,5.64mmol) was dissolved in 12mL/3mL dioxane/water and 4-chloro-6-fluoroquinoline (860mg,4.74mmol), potassium carbonate (1.96g,14.21mmol) and Pd (PPh) were added sequentially3)4(274mg,0.24 mmol). The reaction mixture was refluxed overnight under nitrogen atmosphere. The reaction was then concentrated, diluted with 50mL of water, extracted with ethyl acetate (3X50mL), and the organic layer was washed with waterAfter phase concentration, intermediate C (1.48g) was isolated by flash column chromatography as a pale yellow liquid in 100% yield. MS (ESI) M/z313.9(M + H)+.1H NMR(500MHz,CDCl3)δ8.81(d,J=4.5Hz,1H),8.16(dd,J=8.5,5.5Hz,1H),7.62(dd,J=10.0,2.5Hz,1H),7.52–7.46(m,1H),7.22(d,J=4.5Hz,1H),5.86–5.81(m,1H),4.19(q,J=7.0Hz,2H),2.56–2.26(m,6H),2.08–1.98(m,2H),1.64–1.55(m,1H),1.30(t,J=7.0Hz,3H).
The fourth step: intermediate C (1.48g,4.72mmol) was dissolved in 30mL ethanol and 10% palladium on carbon (300mg) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere overnight. The palladium on carbon was then filtered off with celite and the filtrate was concentrated. The residue was isolated by flash column chromatography to give intermediate D (1.31g) as a pale yellow liquid in 88% yield. MS (ESI) M/z316.0(M + H)+.1H NMR(500MHz,CDCl3)δ8.84–8.79(m,1H),8.13(dd,J=9.0,5.5Hz,1H),7.66(dd,J=10.5,2.5Hz,1H),7.51–7.44(m,1H),7.34(d,J=4.5Hz,1H),4.20–4.14(m,2H),3.26–3.18(m,1H),2.53–2.43(m,2H),2.31(d,J=7.0Hz,1H),2.07–1.97(m,2H),1.90–1.70(m,5H),1.68–1.58(m,1H),1.31–1.25(m,3H).
The fifth step: diisopropylamine (1.54g,15.22mmol) was dissolved in 18mL tetrahydrofuran. To the solution was added dropwise a 2.5M solution of n-butyllithium (6.1mL,15.22mmol) in n-hexane under a nitrogen atmosphere at-78 ℃. A solution of intermediate D (2.4g,7.61mmol) in tetrahydrofuran (6mL) was then added dropwise. The reaction mixture was stirred at-78 ℃ for 1.5 hours. Methyl iodide (2.16g,15.22mmol) was then added dropwise and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate (3 × 50mL), the organic phases combined, washed with 50mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was isolated by flash column chromatography to give intermediate E (1.96g) as a pale yellow liquid in 78% yield. MS (ESI) M/z330.5(M + H)+.1H NMR(500MHz,CDCl3)δ8.84–8.79(m,1H),8.16–8.10(dd,1H),7.66(d,J=10.5Hz,1H),7.51–7.44(m,1H),7.35(d,J=4.5Hz,1H),4.22–4.14(m,2H),3.32–3.23(m,1H),2.82–2.72(m,1H),2.12–1.98(m,2H),1.96–1.55(m,7H),1.32–1.24(m,3H),1.20(d,J=6.5Hz,3H).
And a sixth step: intermediate E (400mg,1.21mmol) was dissolved in 4mL/4mL tetrahydrofuran/ethanol and 2mL water was added. Sodium hydroxide (243mg,6.07mmol) was then added to the solution. The reaction mixture was stirred at 50 ℃ overnight and concentrated. After dilution with 3mL of water, pH was adjusted to 3 with 4mol/L hydrochloric acid solution, and the mixture was filtered to obtain intermediate F (330mg) as a white solid with a yield of 90%. MS (ESI) M/z302.6(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.22(s,1H),8.81(d,J=4.5Hz,1H),8.14–8.06(m,1H),8.01–7.94(m,1H),7.66(t,J=8.5Hz,1H),7.52(s,1H),3.32–3.23(m,1H),2.76–2.66(m,1H),1.97–1.62(m,7H),1.61–1.51(m,1H),1.49–1.31(m,1H),1.09(d,J=6.5Hz,3H).
General route two: asymmetric synthetic route
The asymmetric synthesis method of the intermediate K' adopts a synthesis method reported in the literature (WO2016073774A2)
A general route III:
the first step is as follows: intermediate F (or K', 1.0eq) was dissolved in N, N-dimethylformamide and HATU (1.1eq) and diisopropylethylamine (3.0eq) were added. Further, a substituted 1, 2-diamine or a substituted o-aminoaniline (1.5eq) was added to the reaction solution. The reaction mixture was stirred at 30 ℃ overnight. Then, water and ethyl acetate were added to the reaction solution, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude intermediate which was used in the next step without purification.
The second step is that: the crude intermediate (1.0eq) obtained in the previous step was dissolved in acetic acid, and the mixture was reacted with stirring at 100 ℃ for 19 hours, followed by concentrating the reaction solution. The residue was purified by reverse phase high performance liquid preparative chromatography to give the final compound.
The general route is four:
the first step is as follows: triethyl phosphonoacetate (968mg,4.32mmol) was dissolved in 16mL of ultra dry tetrahydrofuran and sodium tert-butoxide (415mg,4.32mmol) was added at 0 ℃ in an ice bath. After 10 min, a solution of intermediate E' (1g,4.12mmol) in tetrahydrofuran (4mL) was added to the reaction. After 2 hours of reaction, quench with water. The aqueous solution was extracted three times with 20mL of ethyl acetate, the organic phases were combined, washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was isolated by flash column chromatography to give intermediate F "(1.18 g) as a white solid in 92% yield. MS (ESI) M/z314.0(M + H)+.1H NMR(500MHz,CDCl3)δ8.81(d,J=4.5Hz,1H),8.17(dd,J=9.0,5.5Hz,1H),7.72(dd,J=10.0,2.5Hz,1H),7.53–7.47(m,1H),7.28(d,J=4.5Hz,1H),5.75(s,1H),4.19(q,J=7.0Hz,2H),3.52–3.42(m,1H),2.54–2.48(m,2H),2.26–2.11(m,4H),1.80–1.68(m,2H),1.30(t,J=7.0Hz,3H).
The second step is that: NaH (383mg,9.57mmol) was added to 15mL of dimethyl sulfoxide, and trimethyl sulfoxide iodide (2.11g,9.57mmol) was added to the suspension. The mixture was stirred at room temperature for 1.5 hours. A solution of intermediate F "(1.0 g,3.19mmol) in dimethyl sulfoxide (5mL) was then added to the reaction. The reaction was stirred at room temperature overnight. It was then quenched with water, extracted with ethyl acetate and isolated by flash column chromatography to give intermediate G "(820 mg) as a colorless oily liquid in 78% yield. MS (ESI) M/z328.1(M + H)+.1H NMR(500MHz,CDCl3)δ8.83(d,J=4.5Hz,1H),8.24(dd,J=9.0,5.5Hz,1H),7.71(dd,J=10.0,2.5Hz,1H),7.55–7.49(m,1H),7.35(d,J=4.5Hz,1H),4.19(q,J=7.0Hz,2H),3.32–3.24(m,1H),2.17(td,J=13.0,3.5Hz,1H),2.07–1.90(m,4H),1.87–1.78(m,1H),1.58(dd,J=8.0,5.5Hz,1H),1.46–1.37(m,1H),1.30(t,J=7.0Hz,3H),1.28–1.24(m,2H),1.16–1.11(m,1H),1.00(dd,J=8.0,4.5Hz,1H).
The third step: intermediate G "(200 mg,0.61mmol) was dissolved in 10mL ethanol and 4mL of 2mol/L sodium hydroxide solution was added. The reaction solution is heated to 50 ℃, and the reaction 2And (4) hours. After the reaction solution was cooled to room temperature, it was neutralized with a 4mol/L hydrochloric acid solution to pH 1. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was isolated by preparative thin layer chromatography to give intermediate H "(150 mg) as a white solid in 83% yield. MS (ESI) M/z300.0(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.02(br,1H),8.83(d,J=4.5Hz,1H),8.10(dd,J=9.0,5.5Hz,1H),8.03(dd,J=10.0,2.5Hz,1H),7.71–7.64(m,1H),7.38(d,J=4.5Hz,1H),3.48–3.41(m,1H),2.21–2.13(m,1H),2.01–1.80(m,4H),1.75–1.65(m,1H),1.51(dd,J=8.0,5.5Hz,1H),1.38–1.32(m,1H),1.11–1.05(m,1H),1.04–0.99(m,1H),0.95(dd,J=7.5,4.0Hz,1H).
The fourth step: intermediate H "(1.0 eq) was dissolved in N, N-dimethylformamide and HATU (1.1eq) and diisopropylethylamine (3.0eq) were added. Further, a substituted 1, 2-diamine or a substituted o-aminoaniline (1.5eq) was added to the reaction solution. The reaction mixture was stirred at 30 ℃ overnight. Then, water and ethyl acetate were added to the reaction solution, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude intermediate obtained was dissolved in acetic acid, and the mixture was stirred at 100 ℃ for reaction for 19 hours, followed by concentrating the reaction solution. The residue was purified by reverse phase high performance liquid preparative chromatography to give the final compound.
General route five:
the first step is as follows: n-butyllithium (0.49mL,1.22mmol) was added dropwise to a solution of diisopropylamine (123mg,1.22mmol) in tetrahydrofuran (15mL) at-78 ℃. A solution of intermediate G "(200 mg,0.61mmol) in tetrahydrofuran (5mL) was added dropwise. The reaction was stirred at-78 ℃ for 1 hour. Then, a solution of iodomethane (173mg,1.22mmol) in tetrahydrofuran (2mL) was added dropwise to the reaction mixture, and the reaction was maintained at-78 ℃ for half an hour, then warmed to room temperature, and stirred overnight. Quench with saturated ammonium chloride solution and extract the aqueous phase with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue is prepared withLayer chromatography gave compound intermediate H "' (121mg) as a colourless oily liquid in 58% yield. MS (ESI) M/z342.4(M + H)+.
The second step is that: intermediate H' (100mg,0.29mmol) was dissolved in 10mL ethanol and 2mL of 2mol/L sodium hydroxide solution was added. The reaction solution was heated to 50 ℃ and reacted for 2 hours. After the reaction solution was cooled to room temperature, it was neutralized with a 4mol/L hydrochloric acid solution to pH 1. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was isolated by preparative thin layer chromatography to give intermediate I "' (76mg) as a white solid in 83% yield. MS (ESI) M/z314.3(M + H)+.
The third step: intermediate I "' (1.0eq) was dissolved in N, N-dimethylformamide and HATU (1.1eq) and diisopropylethylamine (3.0eq) were added. Further, a substituted 1, 2-diamine or a substituted o-aminoaniline (1.5eq) was added to the reaction solution. The reaction mixture was stirred at 30 ℃ overnight. Then, water and ethyl acetate were added to the reaction solution, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude intermediate obtained was dissolved in acetic acid, and the mixture was stirred at 100 ℃ for reaction for 19 hours, followed by concentrating the reaction solution. The residue was purified by reverse phase high performance liquid preparative chromatography to give the final compound.
Example 1: compound 1
Compound 1 was prepared from intermediate F (20mg) and 4-chloro-1, 2-phenylenediamine via general scheme one and general scheme three. Compound 1(10.05mg) was obtained as a white solid in 37% yield. MS (ESI) M/z408.3(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.40(s,1H),8.79(d,J=4.5Hz,1H),8.11–8.04(m,1H),7.97(d,J=10.5Hz,1H),7.65(t,J=8.5Hz,1H),7.60–7.45(m,2H),7.42(d,J=4.0Hz,1H),7.15(d,J=8.5Hz,1H),3.30–3.24(m,1H),2.95–2.88(m,1H),1.95(t,J=10.5Hz,2H),1.90–1.79(m,2H),1.61–1.47(m,3H),1.45–1.32(m,5H).
Example 2: compound 17 and compound 18
Compound 17 (trans, racemic) and compound 18 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (40mg) and 4-fluoro-1, 2-phenylenediamine.
Compound 17(8.49mg) was obtained as the first eluting isomer in 16% yield as a white solid. MS (ESI) M/z392.5(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.28(s,1H),8.79(s,1H),8.11–8.04(m,1H),7.97(d,J=10.5Hz,1H),7.65(t,J=8.5Hz,1H),7.45–7.39(m,2H),7.34(d,J=10.0Hz,1H),7.02–6.92(m,1H),3.29–3.23(m,1H),2.93–2.87(m,1H),2.00–1.91(m,2H),1.89–1.79(m,2H),1.61–1.46(m,3H),1.45–1.33(m,5H).
Compound 18(9.24mg), the second eluting isomer, was obtained as a white solid in 18% yield. MS (ESI) M/z392.5(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.31(s,1H),8.86(s,1H),8.13–8.06(m,1H),7.97(d,J=11.0Hz,1H),7.66(t,J=8.5Hz,1H),7.58(s,1H),7.44–7.39(m,1H),7.23(d,J=9.0Hz,1H),7.01–6.92(m,1H),3.45–3.35(m,2H),2.15–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.53(m,1H),1.34(d,J=6.5Hz,3H),1.21–1.14(m,1H).
Example 3: compound 21 and compound 22
Compound 21 (trans, racemic) and compound 22 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (40mg) and 4-methyl-1, 2-phenylenediamine.
Compound 21(11.40mg) was obtained as the first eluting isomer in 22% yield as a white solid. MS (ESI) M/z388.5(M + H)+.1H NMR(500MHz,d6-DMSO)δ11.98(s,1H),8.79(s,1H),8.11–8.04(m,1H),7.97(d,J=10.5Hz,1H),7.65(t,J=8.5Hz,1H),7.44–7.38(m,2H),7.20(s,1H),6.93(t,J=9.5Hz,1H),3.30–3.23(m,1H),2.91–2.83(m,1H),2.39(s,3H),2.00–1.91(m,2H),1.89–1.78(m,2H),1.61–1.46(m,3H),1.44–1.33(m,5H).
Compound 22(13.51mg), the second eluting isomer, was obtained as a white solid in 26% yield. MS (ESI) M/z388.5(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.02(s,1H),8.86(s,1H),8.13–8.06(m,1H),7.97(d,J=11.0Hz,1H),7.66(t,J=9.0Hz,1H),7.58(s,1H),7.39(d,J=8.5Hz,1H),7.20(s,1H),6.93(t,J=10.0Hz,1H),3.46–3.34(m,2H),2.38(s,3H),2.16–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.70(m,2H),1.67–1.51(m,2H),1.33(d,J=6.5Hz,3H),1.21–1.14(m,1H).
Example 4: compound 13 and compound 14
Compound 13 (trans, racemic) and compound 14 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (50mg) and 4-chloro-1, 2-phenylenediamine.
Compound 13(7.93mg) was obtained as the first eluting isomer in 12% yield as a white solid. MS (ESI) M/z408.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.36(s,1H),8.80(s,1H),8.11–8.04(m,1H),7.97(d,J=11.0Hz,1H),7.65(t,J=8.5Hz,1H),7.60(s,1H),7.46–7.40(m,2H),7.15(t,J=10.5Hz,1H),3.30–3.23(m,1H),2.95–2.88(m,1H),2.00–1.91(m,2H),1.89–1.79(m,2H),1.61–1.46(m,3H),1.45–1.32(m,5H).
Compound 14(10.25mg), the second eluting isomer, was obtained as a white solid in 15% yield. MS (ESI) M/z408.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.42(s,1H),8.86(d,J=4.0Hz,1H),8.13–8.07(m,1H),7.98(d,J=11.0Hz,1H),7.67(t,J=8.5Hz,1H),7.61–7.56(m,2H),7.45(d,J=8.5Hz,1H),7.17–7.11(m,1H),3.45–3.37(m,2H),2.16–2.09(m,1H),2.07–2.00(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J=6.5Hz,3H),1.19–1.12(m,1H).
Example 5: compound 33 and compound 34
Compound 33 (trans, racemic) and compound 34 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (40mg) and 4-trifluoromethyl-1, 2-phenylenediamine.
Compound 33(5.95mg) was obtained as the first eluting isomer in 10% yield as a white solid. MS (ESI) M/z442.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.63(s,1H),8.79(s,1H),8.10–8.04(m,1H),7.97(d,J=11.0Hz,1H),7.91(s,1H),7.67–7.61(m,2H),7.49–7.40(m,2H),3.30–3.23(m,1H),3.02–2.94(m,1H),2.00–1.91(m,2H),1.91–1.82(m,2H),1.61–1.47(m,3H),1.46–1.35(m,5H).
Compound 34(4.55mg), the second eluting isomer, was obtained as a white solid in 8% yield. MS (ESI) M/z442.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.66(s,1H),8.87(s,1H),8.12–8.06(m,1H),7.98(d,J=10.5Hz,1H),7.90(s,1H),7.69–7.62(m,2H),7.59(s,1H),7.48–7.41(m,1H),3.52–3.38(m,2H),2.21–2.11(m,1H),2.09–2.01(m,1H),1.94–1.73(m,4H),1.69–1.61(m,1H),1.60–1.54(m,1H),1.37(d,J=6.0Hz,3H),1.19–1.13(m,1H).
Example 6: compound 27 and compound 28
Compound 27 (trans, racemic) and compound 28 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (50mg) and 4-methoxy-1, 2-phenylenediamine.
To obtain a chemical combinationMaterial 27(3.67mg), first eluting isomer, white solid, yield 5%. (ESI): M/z404.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ11.99(s,1H),8.80(s,1H),8.10–8.07(m,1H),7.98(d,J=10.0Hz,1H),7.69–7.62(m,1H),7.46–7.39(m,2H),6.92(s,1H),6.78–6.70(m,1H),3.77(s,3H),3.30–3.22(m,1H),2.89–2.82(m,1H),2.00–1.91(m,2H),1.90–1.76(m,2H),1.60–1.46(m,3H),1.44–1.31(m,5H).
Compound 28(6.69mg) was obtained as a second eluting isomer in 9% yield as a white solid. (ESI): M/z404.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.02(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J=11.0Hz,1H),7.67(t,J=8.5Hz,1H),7.58(s,1H),7.39(d,J=8.5Hz,1H),7.08(s,1H),6.74(t,J=10.0Hz,1H),3.76(s,3H),3.46–3.36(m,2H),2.15–2.07(m,1H),2.06–1.98(m,1H),1.92–1.83(m,2H),1.82–1.69(m,2H),1.67–1.59(m,1H),1.58–1.51(m,1H),1.33(d,J=6.5Hz,3H),1.22–1.14(m,1H).
Example 7: compound 35 and compound 36
Compound 35 (trans, racemic) and compound 36 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (50mg) and 4-bromo-1, 2-phenylenediamine.
Compound 35(12.85mg) was obtained as the first eluting isomer in 17% yield as a white solid. (ESI): M/z452.3(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.39(d,J=22.9Hz,1H),8.80(s,1H),8.10–8.04(m,1H),7.98(d,J=11.0Hz,1H),7.74(s,1H),7.65(t,J=8.5Hz,1H),7.46–7.38(m,2H),7.26(t,J=9.0Hz,1H),3.31–3.24(m,1H),2.95–2.87(m,1H),1.99–1.90(m,2H),1.89–1.79(m,2H),1.61–1.46(m,3H),1.46–1.30(m,5H).
Compound 36(15.29mg) was obtained as a second eluting isomer in 20% yield as a white solid. (ESI): M/z452.3(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.42(s,1H),8.86(s,1H),8.12–8.07(m,1H),7.98(d,J=11.0Hz,1H),7.73(s,1H),7.69–7.63(m,1H),7.60–7.56(m,1H),7.49(d,J=9.0Hz,1H),7.28–7.22(m,1H),3.45–3.38(m,2H),2.15–2.08(m,1H),2.07–1.99(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.59(m,1H),1.58–1.52(m,1H),1.34(d,J=6.0Hz,3H),1.18–1.11(m,1H).
Example 8: compound 37 and compound 38
Compound 37 (trans, racemic) and compound 38 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (40mg) and 6-chloro-2, 3-diaminopyridine.
Compound 37(4.03mg) was obtained as the first eluting isomer in 7% yield as a white solid. MS (ESI) M/z409.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.79(s,1H),8.80(s,1H),8.11–8.04(m,1H),8.02–7.87(m,2H),7.66(t,J=8.0Hz,1H),7.44(s,1H),7.24(d,J=8.0Hz,1H),3.30–3.23(m,1H),2.98–2.89(m,1H),2.00–1.91(m,2H),1.90–1.80(m,2H),1.61–1.47(m,3H),1.45–1.35(m,5H).
Compound 38(7.12mg), the second eluting isomer, was obtained as a white solid in 12% yield. MS (ESI) M/z409.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.81(s,1H),8.87(d,J=4.5Hz,1H),8.10(dd,J=9.5,6.0Hz,1H),8.03–7.90(m,2H),7.67(td,J=9.0,3.0Hz,1H),7.59(d,J=4.5Hz,1H),7.23(d,J=8.5Hz,1H),3.47–3.39(m,2H),2.18–2.12(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.71(m,2H),1.69–1.61(m,1H),1.59–1.53(m,1H),1.35(d,J=7.0Hz,3H),1.17–1.11(m,1H).
Example 9: compound 39 and compound 40
Compound 39 (trans, racemic) and compound 40 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (40mg) and 5-chloro-2, 3-diaminopyridine.
Compound 39(5.08mg) was obtained as the first eluting isomer in 9% yield as a white solid. MS (ESI) M/z409.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.80(s,1H),8.81(s,1H),8.12–8.05(m,1H),8.04–7.88(m,2H),7.65(t,J=8.0Hz,1H),7.43(s,1H),7.26(d,J=8.0Hz,1H),3.31–3.23(m,1H),2.99–2.88(m,1H),2.02–1.90(m,2H),1.93–1.81(m,2H),1.60–1.46(m,3H),1.46–1.34(m,5H).
Compound 40(8.37mg), the second eluting isomer, was obtained as a white solid in 15% yield. MS (ESI) M/z409.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.81(s,1H),8.81(s,1H),8.12–8.04(m,1H),8.03–7.87(m,2H),7.64(t,J=8.0Hz,1H),7.45(s,1H),7.26(d,J=8.0Hz,1H),3.46–3.37(m,2H),2.15–2.07(m,1H),2.05–1.98(m,1H),1.93–1.85(m,2H),1.84–1.68(m,2H),1.67–1.60(m,1H),1.57–1.50(m,1H),1.36(d,J=6.5Hz,3H),1.25–1.14(m,1H).
Example 10: compound 41 and Compound 42
Compound 41 (trans, racemic) and compound 42 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (40mg) and 6-chloro-3, 4-diaminopyridine.
Compound 41(2.98mg) was obtained as the first eluting isomer in 5% yield as a white solid. MS (ESI) M/z409.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.89(s,1H),8.87(s,1H),8.63(s,1H),8.14–8.08(m,1H),7.98(d,J=11.0Hz,1H),7.70–7.55(m,3H),3.48–3.40(m,1H),3.01–2.92(m,1H),2.05–1.94(m,2H),1.96–1.85(m,2H),1.65–1.49(m,3H),1.48–1.38(m,5H).
Compound 42(3.17mg), the second eluting isomer, was obtained as a white solid in 6% yield。MS(ESI):m/z409.4(M+H)+.1H NMR(500MHz,d6-DMSO)δ12.90(s,1H),8.87(s,1H),8.63(s,1H),8.14–8.07(m,1H),7.99(d,J=11.0Hz,1H),7.71–7.56(m,3H),3.49–3.40(m,2H),2.18–2.11(m,1H),2.07–2.01(m,1H),1.93–1.83(m,2H),1.82–1.72(m,2H),1.69–1.61(m,1H),1.60–1.53(m,1H),1.36(d,J=6.0Hz,3H),1.17–1.10(m,1H).
Example 11: compound 29 and compound 30
Compound 29 (trans, racemic) and compound 30 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (40mg) and 4-chloro-5-fluoro-1, 2-phenylenediamine.
Compound 29(3.45mg) was obtained as the first eluting isomer in 5% yield as a white solid. MS (ESI) M/z426.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.49(s,1H),8.79(d,J=4.5Hz,1H),8.10–8.04(m,1H),7.97(d,J=11.0Hz,1H),7.68–7.57(m,2H),7.48(d,J=9.5Hz,1H),7.44-7.41(m,1H),3.29-3.23(m,1H),2.94-2.88(m,1H),1.99-1.90(m,2H),1.88-1.79(m,2H),1.61–1.46(m,3H),1.44-1.34(m,5H).
Compound 30(4.15mg), the second eluting isomer, was obtained as a white solid in 6% yield. MS (ESI) M/z426.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.54(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J=11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J=6.5Hz,3H),1.18–1.11(m,1H).
Example 12: compound 45 and compound 46
Compound 45 (trans, racemic) and compound 46 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (40mg) and 2-amino-4-chlorophenol.
Compound 45(6.36mg) was obtained as the first eluting isomer in 12% yield as a white solid. MS (ESI) M/z409.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ8.87(d,J=4.5Hz,1H),8.11(dd,J=9.0,6.0Hz,1H),8.00(dd,J=11.0,3.0Hz,1H),7.93(d,J=2.0Hz,1H),7.74(d,J=8.5Hz,1H),7.69(td,J=8.5,3.0Hz,1H),7.65(d,J=4.5Hz,1H),7.42(dd,J=8.5,2.0Hz,1H),3.65–3.56(m,1H),3.48–3.44(m,1H),2.17–2.11(m,1H),2.05–1.98(m,1H),1.92–1.71(m,5H),1.67–1.61(m,1H),1.39(d,J=7.0Hz,3H),1.30–1.25(m,1H).
Compound 46(9.27mg), the second eluting isomer, was obtained as a white solid in 17% yield. MS (ESI) M/z409.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ8.86(d,J=4.5Hz,1H),8.10(dd,J=9.0,6.0Hz,1H),8.01(dd,J=11.0,3.0Hz,1H),7.92(d,J=2.0Hz,1H),7.72(d,J=8.5Hz,1H),7.68(td,J=8.5,3.0Hz,1H),7.63(d,J=4.5Hz,1H),7.41(dd,J=8.5,2.0Hz,1H),3.64–3.50(m,2H),2.17–2.11(m,1H),2.05–1.98(m,1H),1.92–1.71(m,5H),1.67–1.61(m,1H),1.39(d,J=7.0Hz,3H),1.30–1.25(m,1H).
Example 13: compound 43 and compound 44
Compound 43 (trans, racemic) and compound 44 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (40mg) and 2-amino-5-chlorophenol.
Compound 43(8.42mg) was obtained as the first eluting isomer in 16% yield as a white solid. MS (ESI) M/z409.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ8.86(d,J=4.5Hz,1H),8.10(dd,J=9.0,6.0Hz,1H),8.01(dd,J=11.0,3.0Hz,1H),7.92(d,J=2.0Hz,1H),7.72(d,J=8.5Hz,1H),7.68(td,J=8.5,3.0Hz,1H),7.63(d,J=4.5Hz,1H),7.41(dd,J=8.5,2.0Hz,1H),3.64–3.56(m,1H),3.48–3.43(m,1H),2.17–2.11(m,1H),2.05–1.98(m,1H),1.92–1.71(m,5H),1.67–1.61(m,1H),1.39(d,J=7.0Hz,3H),1.30–1.25(m,1H).
Compound 44(10.05mg), the second eluting isomer, was obtained as a white solid in 19% yield. MS (ESI) M/z409.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ8.86(d,J=4.5Hz,1H),8.10(dd,J=9.0,6.0Hz,1H),8.01(dd,J=11.0,3.0Hz,1H),7.92(d,J=2.0Hz,1H),7.72(d,J=8.5Hz,1H),7.68(td,J=8.5,3.0Hz,1H),7.63(d,J=4.5Hz,1H),7.41(dd,J=8.5,2.0Hz,1H),3.64–3.50(m,2H),2.17–2.11(m,1H),2.05–1.98(m,1H),1.92–1.71(m,5H),1.67–1.61(m,1H),1.39(d,J=7.0Hz,3H),1.30–1.25(m,1H).
Example 14: compound 48
Compound 48 was prepared via general scheme four starting from intermediate H "(40 mg) and 4-methyl-1, 2-phenylenediamine. Compound 48(28.67mg) was obtained as a white solid in 56% yield. (ESI): M/z386.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.32(s,1H),8.82(s,1H),8.11–8.04(m,1H),8.00(d,J=11.0Hz,1H),7.66(t,J=8.5Hz,1H),7.39(s,1H),7.37–7.29(m,1H),7.29–7.19(m,1H),6.91(d,J=8.0Hz,1H),3.42–3.37(m,1H),2.37(s,3H),2.28–2.20(m,1H),2.08–2.02(m,1H),1.95–1.86(m,3H),1.59–1.46(m,2H),1.46–1.41(m,1H),1.23(d,J=13.5Hz,1H),1.15–1.03(m,2H).
Example 15: compound 49
Compound 49 was prepared via general scheme five starting from intermediate I' "(40 mg) and 4-chloro-1, 2-phenylenediamine. Compound 49(15.23mg) was obtained as a white solid in 28% yield. (ESI): M/z420.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.32(s,1H),8.82(s,1H),8.11–8.04(m,1H),8.00(d,J=11.0Hz,1H),7.66(t,J=8.5Hz,1H),7.39(s,1H),7.37–7.29(m,1H),7.29–7.19(m,1H),6.91(d,J=8.0Hz,1H),2.45(s,3H),3.42–3.37(m,1H),2.28–2.20(m,1H),2.08–2.02(m,1H),1.95–1.86(m,3H),1.59–1.46(m,2H),1.46–1.41(m,1H),1.15–1.03(m,2H).
Example 16: compound 19 and compound 20
Compound 19 and compound 20 were obtained from compound 18 of example 2 by chiral column resolution. Wherein, the compound 19 corresponds to the former in chiral resolution, and the compound 20 corresponds to the latter in chiral resolution.
Compound 19: MS (ESI) M/z392.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.33(s,1H),8.86(s,1H),8.13–8.07(m,1H),7.98(d,J=10.5Hz,1H),7.67(t,J=8.5Hz,1H),7.58(s,1H),7.44–7.39(m,1H),7.24(d,J=8.5Hz,1H),7.01–6.92(m,1H),3.45–3.35(m,2H),2.15–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.53(m,1H),1.33(d,J=6.0Hz,3H),1.21–1.14(m,1H).
Compound 20: MS (ESI) M/z392.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.34(s,1H),8.87(s,1H),8.13–8.07(m,1H),7.98(d,J=10.5Hz,1H),7.67(t,J=8.5Hz,1H),7.58(s,1H),7.44–7.39(m,1H),7.24(d,J=8.5Hz,1H),7.01–6.92(m,1H),3.45–3.35(m,2H),2.15–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.53(m,1H),1.34(d,J=6.5Hz,3H),1.21–1.14(m,1H).
Example 17: compound 23 and compound 24
Compound 23 and compound 24 were obtained from compound 22 in example 3 by chiral column resolution. Wherein, the compound 23 corresponds to the former in chiral resolution, and the compound 24 corresponds to the latter in chiral resolution.
Compound 23: MS (ESI) M/z388.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.03(s,1H),8.86(s,1H),8.13–8.06(m,1H),7.97(d,J=10.5Hz,1H),7.66(t,J=9.0Hz,1H),7.58(s,1H),7.41–7.18(m,2H),6.93(s,1H),3.46–3.34(m,2H),2.38(s,3H),2.16–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.70(m,2H),1.66–1.58(m,1H),1.57–1.50(m,1H),1.33(d,J=6.5Hz,3H),1.21–1.14(m,1H).
Compound 24: MS (ESI) M/z388.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.07(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.97(d,J=10.5Hz,1H),7.66(t,J=9.0Hz,1H),7.58(s,1H),7.41–7.18(m,2H),6.93(s,1H),3.46–3.34(m,2H),2.38(s,3H),2.16–2.09(m,1H),2.06–1.99(m,1H),1.93–1.83(m,2H),1.82–1.70(m,2H),1.66–1.58(m,1H),1.57–1.50(m,1H),1.33(d,J=6.5Hz,3H),1.21–1.14(m,1H).
Example 18: compound 15 and compound 16
Compound 15 and compound 16 were obtained from compound 14 in example 4 by chiral column resolution. Wherein compound 15 corresponds to the former in chiral resolution and compound 16 corresponds to the latter in chiral resolution.
Compound 15: MS (ESI) M/z408.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.41(s,1H),8.87(s,1H),8.12–8.06(m,1H),7.98(d,J=10.5Hz,1H),7.67(t,J=8.5Hz,1H),7.61–7.56(m,2H),7.46(d,J=8.5Hz,1H),7.17–7.11(m,1H),3.45–3.37(m,2H),2.16–2.09(m,1H),2.07–2.00(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.35(d,J=6.5Hz,3H),1.19–1.12(m,1H).
Compound 16: MS (ESI) M/z408.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.46(s,1H),8.87(s,1H),8.12–8.06(m,1H),7.98(d,J=10.5Hz,1H),7.67(t,J=8.5Hz,1H),7.62–7.40(m,3H),7.14(d,J=8.5Hz,1H),3.45–3.37(m,2H),2.16–2.09(m,1H),2.07–2.00(m,1H),1.93–1.83(m,2H),1.82–1.71(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.35(d,J=6.5Hz,3H),1.19–1.12(m,1H).
Example 19: compound 31 and compound 32
Compound 31 and compound 32 were obtained from compound 30 of example 11 by chiral column resolution. Wherein, the compound 31 corresponds to the former in chiral resolution, and the compound 32 corresponds to the latter in chiral resolution.
Compound 31: MS (ESI) M/z426.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.55(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J=11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J=6.5Hz,3H),1.18–1.11(m,1H).
Compound 32: MS (ESI) M/z426.4(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.54(s,1H),8.86(s,1H),8.13–8.06(m,1H),7.98(d,J=11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J=6.5Hz,3H),1.18–1.11(m,1H).
Example 20: compound 51 and Compound 52
Compound 51 (trans, racemic) and compound 52 (cis, racemic) were prepared via general route one and general route three, starting from intermediate F (40mg) and 4, 5-difluoro-1, 2-phenylenediamine.
To give Compound 51(3.45mg), the firstThe isomer eluted, white solid, yield 5%. MS (ESI) M/z410.2(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.49(s,1H),8.79(d,J=4.5Hz,1H),8.10–8.04(m,1H),7.97(d,J=11.0Hz,1H),7.68–7.57(m,2H),7.48(d,J=9.5Hz,1H),7.44-7.41(m,1H),3.29-3.23(m,1H),2.94-2.88(m,1H),1.99-1.90(m,2H),1.88-1.79(m,2H),1.61–1.46(m,3H),1.44-1.34(m,5H).
Compound 52(4.15mg), the second eluting isomer, was obtained as a white solid in 6% yield. MS (ESI) M/z410.2(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.54(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J=11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J=6.5Hz,3H),1.18–1.11(m,1H).
Example 21: compound 53 and compound 54
Compound 53 and compound 54 were obtained by chiral column resolution of compound 52 in example 21. Wherein, the compound 53 corresponds to the former in chiral resolution, and the compound 54 corresponds to the latter in chiral resolution.
Compound 53: MS (ESI) M/z410.2(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.54(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J=11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J=6.5Hz,3H),1.18–1.11(m,1H).
Compound 54: MS (ESI) M/z410.2(M + H)+.1H NMR(500MHz,d6-DMSO)δ12.54(s,1H),8.87(s,1H),8.13–8.06(m,1H),7.98(d,J=11.0Hz,1H),7.78–7.63(s,2H),7.61–7.40(m,2H),3.45–3.39(m,2H),2.16–2.08(m,1H),2.07–2.00(m,1H),1.92–1.83(m,2H),1.82–1.70(m,2H),1.68–1.60(m,1H),1.59–1.52(m,1H),1.34(d,J=6.5Hz,3H),1.18–1.11(m,1H).